Diclofenac Potassium Capsules are indicated for relief of mild to moderate acute pain in adult and pediatric patients 12 years of age and older. (1)

{ "type": "p", "children": [], "text": "\nDiclofenac Potassium Capsules are indicated for relief of mild to moderate acute pain in adult and pediatric patients 12 years of age and older. (1)" }

Carefully consider the potential benefits and risks of Diclofenac Potassium Capsules and other treatment options before deciding to use Diclofenac Potassium Capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

For treatment of mild to moderate acute pain in adult and pediatric patients 12 years of age and older, the dosage is 25 mg four times a day.

Patients with hepatic disease may require reduced doses of Diclofenac Potassium Capsules compared to patients with normal hepatic function [see Clinical Pharmacology (12)]. As with other diclofenac products, start treatment at the lowest dose. If efficacy is not achieved with the lowest dose, discontinue use.

Different dose strengths and formulations of oral diclofenac are not interchangeable. This difference should be taken into consideration when changing strengths or formulations. The only approved dosing regimen for Diclofenac Potassium Capsules are 25 mg four times a day.

Diclofenac Potassium Capsules: 25 mg

{ "type": "p", "children": [], "text": "\nDiclofenac Potassium Capsules: 25 mg" }

Diclofenac Potassium Capsules are contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Diclofenac Potassium Capsules are contraindicated in the following patients:" }

{ "type": "ul", "children": [ "Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]", "History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients[see Warnings and Precautions (5.7, 5.8)]", "In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]", "Diclofenac Potassium Capsules contains gelatin and is contraindicated in patients with known hypersensitivity to bovine protein." ], "text": "" }

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and a l-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of Diclofenac Potassium Capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Diclofenac Potassium Capsule is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In a large open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in a l trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female sex, doses of 150 mg or more, and duration of use for more then 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with Diclofenac Potassium Capsules, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Diclofenac Potassium Capsules should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Diclofenac Potassium Capsules immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver-related event in patients treated with Diclofenac Potassium Capsules, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Diclofenac Potassium Capsules with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

NSAIDs, including Diclofenac Potassium Capsules, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of Diclofenac Potassium Capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Diclofenac Potassium Capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of Diclofenac Potassium Capsules in patients with advanced renal disease. The renal effects of Diclofenac Potassium Capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating Diclofenac Potassium Capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Diclofenac Potassium Capsules [see Drug Interactions (7)]. Avoid the use of Diclofenac Potassium Capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Diclofenac Potassium Capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross- reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Diclofenac Potassium Capsules are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When Diclofenac Potassium Capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur withoutwarning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Diclofenac Potassium Capsules at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac Potassium Capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Diclofenac Potassium Capsules. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue Diclofenac Potassium Capsules and evaluate the patient immediately.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including Diclofenac Potassium Capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs, including Diclofenac Potassium Capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including Diclofenac Potassium Capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Diclofenac Potassium Capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Diclofenac Potassium Capsules treatment extends beyond 48 hours. Discontinue Diclofenac Potassium Capsules if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Diclofenac Potassium Capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including Diclofenac Potassium Capsules, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplateletagents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

The pharmacological activity of Diclofenac Potassium Capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with the rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Diclofenac Potassium Capsules was evaluated in 965 adult subjects. In patients treated with Diclofenac Potassium Capsules 25 mg (N=345) or a higher dose, three or four times a day, for 4 to 5 days, the most common adverse reactions (i.e., reported in ≥ 1% of Diclofenac Potassium Capsules treated patients) were as follows: gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, dizziness, headache, somnolence, pruritus, and increased sweating. (see Table 1).

The safety of Diclofenac Potassium Capsules was evaluated in 125 pediatric patients, 12 years to 17 years of age. Forty-nine (49) patients with mild to moderate acute pain from a surgical procedure or an acute painful condition were treated with Diclofenac Potassium Capsules 25 mg up to four times a day, for 4 days. Seventy-six (76) pediatric patients who underwent insertion of either orthodontic separators or arch wires were treated with a single-dose of either Diclofenac Potassium Capsules 25 mg or Diclofenac Potassium Capsules 50 mg after completion of the procedure. The most common adverse reactions in the multiple-dose studies were nausea (14.3%), headache (10.2%), constipation (8.2%), abdominal pain (4.1%), vomiting (4.1%), dizziness (4.1%), back pain (4.1%), and musculoskeletal pain (4.1%).

<div class="scrollingtable"><table width="100%"> <caption> <span>    Table 1 Incidence of Treatment Emergent Adverse Reactions with Incidence ≥ 1% of Diclofenac Potassium Capsules Treated Patients in Multiple-Dose Studies</span> </caption> <colgroup> <col width="33%"/> <col width="33%"/> <col width="33%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="left" colspan="3"> <p class="First First Footnote">*There was greater use of concomitant opioid rescue medication in placebo treated patients than in Diclofenac Potassium Capsules treated patients</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">  MedDRA System Organ Class and</span> <br/> <span class="Bold">  Preferred Term</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">  Diclofenac Potassium Capsules *</span> <br/> <span class="Bold">  25 mg</span> <br/> <span class="Bold">  n=345</span> <br/> <span class="Bold">  n (%)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">  Placebo*</span> <br/> <span class="Bold">  n=327</span> <br/> <span class="Bold">  n (%)</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Any Adverse Events</td><td align="center" class="Botrule Rrule" valign="top">144 (41.7)</td><td align="center" class="Botrule Rrule" valign="top">181 (55.4)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Nausea</td><td align="center" class="Botrule Rrule" valign="top">57 (16.5)</td><td align="center" class="Botrule Rrule" valign="top">66 (20.2)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Headache</td><td align="center" class="Botrule Rrule" valign="top">43 (12.5)</td><td align="center" class="Botrule Rrule" valign="top">56 (17.1)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Abdominal Pain</td><td align="center" class="Botrule Rrule" valign="top">24 (7.0)</td><td align="center" class="Botrule Rrule" valign="top">11 (3.4)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Vomiting</td><td align="center" class="Botrule Rrule" valign="top">20 (5.8)</td><td align="center" class="Botrule Rrule" valign="top">17 (5.2)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Dizziness</td><td align="center" class="Botrule Rrule" valign="top">12 (3.5)</td><td align="center" class="Botrule Rrule" valign="top">66 (20.2)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Constipation</td><td align="center" class="Botrule Rrule" valign="top">11 (3.2)</td><td align="center" class="Botrule Rrule" valign="top">9 (2.8)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Somnolence</td><td align="center" class="Botrule Rrule" valign="top">9 (2.6)</td><td align="center" class="Botrule Rrule" valign="top">6 (1.8)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Diarrhea</td><td align="center" class="Botrule Rrule" valign="top">8 (2.3)</td><td align="center" class="Botrule Rrule" valign="top">9 (2.8)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Pruritus</td><td align="center" class="Botrule Rrule" valign="top">5 (1.4)</td><td align="center" class="Botrule Rrule" valign="top">6 (1.8)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Dyspepsia</td><td align="center" class="Botrule Rrule" valign="top">4 (1.2)</td><td align="center" class="Botrule Rrule" valign="top">8 (2.4)</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">Sweating Increase</td><td align="center" class="Botrule Rrule" valign="top">4 (1.2)</td><td align="center" class="Botrule Rrule" valign="top">2 (0.6)</td> </tr> </tbody> </table></div>

In patients taking other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are:

Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.

Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus.

Additional adverse experiences reported in patients taking other NSAIDs occasionally include:

Body as a Whole: fever, infection, sepsis

Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope

Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

Respiratory System: asthma, dyspnea

Skin and Appendages: alopecia, photosensitivity, sweating increased

Special Senses: blurred vision

Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure

Other adverse reactions in patients taking other NSAIDs, which occur rarely are:

Body as a Whole: anaphylactic reactions, appetite changes, death

Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis

Digestive System: colitis, eructation, liver failure, pancreatitis

Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia

Metabolic and Nutritional: hyperglycemia

Nervous System: convulsions, coma, hallucinations, meningitis

Respiratory System: respiratory depression, pneumonia

Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome, urticaria

Special Senses: conjunctivitis, hearing impairment

The following adverse reactions have been identified during postapproval use of diclofenac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

See Table 3 for clinically significant drug interactions with diclofenac.

{ "type": "p", "children": [], "text": "\nSee Table 3 for clinically significant drug interactions with diclofenac." }

<div class="scrollingtable"><table width="100%"> <caption> <span>    Table 3:  Clinically Significant Drug Interactions with diclofenac</span> </caption> <colgroup> <col width="50%"/> <col width="50%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Drugs That Interfere with Hemostasis</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top"> <ul class="Disc"> <li>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</li> <li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Monitor patients with concomitant use of Diclofenac Potassium Capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class="Italics">[see Warnings and Precautions (<a href="#ID60">5.12</a></span><span class="Italics">)]</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Aspirin</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class="Italics">[see Warnings and Precautions (</span><span class="Italics"><a href="#ID39">5.2</a>)]</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Concomitant use of Diclofenac Potassium Capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class="Italics">[see Warnings and Precautions </span><span class="Italics">(<a href="#ID60">5.12</a>)]</span> <br/> Diclofenac Potassium Capsules are not a substitute for low dose aspirin for cardiovascular protection</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top"> <ul class="Disc"> <li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"> <ul class="Disc"> <li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top"> <ul class="Disc"> <li>During concomitant use of Diclofenac Potassium Capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</li> <li>During concomitant use of Diclofenac Potassium Capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class="Italics">[see Warnings and </span><span class="Italics">Precautions (<a href="#ID48">5.6</a>)].</span> </li> <li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Diuretics</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top"> During concomitant use of Diclofenac Potassium Capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class="Italics">[see Warnings and </span><span class="Italics">Precautions (<a href="#ID48">5.6</a>)]</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold"> Digoxin</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">During concomitant use of Diclofenac Potassium Capsules and digoxin, monitor serum digoxin levels.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Lithium</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">During concomitant use of Diclofenac Potassium Capsules and lithium, monitor patients for signs of lithium toxicity.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Methotrexate</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">During concomitant use of Diclofenac Potassium Capsules and methotrexate, monitor patients for methotrexate toxicity.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Cyclosporine</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Concomitant use of Diclofenac Potassium Capsules and cyclosporine may increase cyclosporine's nephrotoxicity.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">During concomitant use of Diclofenac Potassium Capsules and cyclosporine, monitor patients for signs of worsening renal function.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">NSAIDs and Salicylates</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class="Italics">[see Warnings and Precautions (<a href="#ID39">5.2</a>)]</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Pemetrexed</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Concomitant use of Diclofenac Potassium Capsules and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">During concomitant use of Diclofenac Potassium Capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.</td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top">NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.<br/>  In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">CYP2C9 Inhibitors or Inducers:</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co- administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers <span class="Italics">[see Clinical Pharmacology (<a href="#ID100">12.3</a>)].</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>    Table 3:  Clinically Significant Drug Interactions with diclofenac</span>\n</caption>\n<colgroup>\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Drugs That Interfere with Hemostasis</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</li>\n<li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Monitor patients with concomitant use of Diclofenac Potassium Capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#ID60\">5.12</a></span><span class=\"Italics\">)]</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Aspirin</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\"><a href=\"#ID39\">5.2</a>)]</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Concomitant use of Diclofenac Potassium Capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class=\"Italics\">[see Warnings and Precautions </span><span class=\"Italics\">(<a href=\"#ID60\">5.12</a>)]</span>\n<br/> Diclofenac Potassium Capsules are not a substitute for low dose aspirin for cardiovascular protection</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>During concomitant use of Diclofenac Potassium Capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</li>\n<li>During concomitant use of Diclofenac Potassium Capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class=\"Italics\">[see Warnings and </span><span class=\"Italics\">Precautions (<a href=\"#ID48\">5.6</a>)].</span>\n</li>\n<li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> During concomitant use of Diclofenac Potassium Capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class=\"Italics\">[see Warnings and </span><span class=\"Italics\">Precautions (<a href=\"#ID48\">5.6</a>)]</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\"> Digoxin</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">During concomitant use of Diclofenac Potassium Capsules and digoxin, monitor serum digoxin levels.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Lithium</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">During concomitant use of Diclofenac Potassium Capsules and lithium, monitor patients for signs of lithium toxicity.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Methotrexate</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">During concomitant use of Diclofenac Potassium Capsules and methotrexate, monitor patients for methotrexate toxicity.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Cyclosporine</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Concomitant use of Diclofenac Potassium Capsules and cyclosporine may increase cyclosporine's nephrotoxicity.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">During concomitant use of Diclofenac Potassium Capsules and cyclosporine, monitor patients for signs of worsening renal function.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">NSAIDs and Salicylates</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#ID39\">5.2</a>)]</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Pemetrexed</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Concomitant use of Diclofenac Potassium Capsules and pemetrexed may increase the risk of pemetrexed associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">During concomitant use of Diclofenac Potassium Capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.<br/>  In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">CYP2C9 Inhibitors or Inducers:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co- administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#ID100\">12.3</a>)].</span></td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of NSAIDs, including Diclofenac Potassium Capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of Diclofenac Potassium Capsules use between about 20 and 30 weeks of gestation, and avoid Diclofenac Potassium Capsules use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including Diclofenac Potassium Capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

In animal reproduction studies, no evidence of malformations was observed in mice, rats, and rabbits given diclofenac during the period of organogenesis at doses up to approximately 1, 1, and 2 times, respectively, the maximum recommended human dose (MRHD) of Diclofenac Potassium Capsules, despite the presence of maternal and fetal toxicity at these doses. In published studies, administration of clinically relevant doses of diclofenac to pregnant rats produced adverse effects on brain, kidney, and testicular development [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including Diclofenac Potassium Capsules, can cause premature closure of the fetal ductus arteriosus (see Data).

Oligohydramnios/Neonatal Renal Impairment:

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest dose and shortest duration possible. If Diclofenac Potassium Capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Diclofenac Potassium Capsules and follow up according to clinical practice (see Data).

Labor or Delivery

There are no studies on the effects of Diclofenac Potassium Capsules during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Diclofenac has been shown to cross the placental barrier in humans.

Animal data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD] of Diclofenac Potassium Capsules, 100 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 1 and 2 times, respectively, the MRHD based on BSA comparison).

In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.2 and 0.4 times the MRHD based on BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats.

In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0.1 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3.6 mg/kg, IP; 0.3 times the MRHD based on BSA comparison), and caused adverse effects on the developing testes (6.1 mg/kg, PO; 0.6 times the MRHD based on BSA comparison).

Risk Summary

Data from published literature reports with oral preparations of diclofenac indicate the presence of diclofenac in small amounts human milk (see Data). There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Diclofenac Potassium Capsules and any potential adverse effects on the breastfed infant from the Diclofenac Potassium Capsules or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Diclofenac Potassium Capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Diclofenac Potassium Capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Males

Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear [See Nonclinical Toxicology (13.1)].

The safety and effectiveness of Diclofenac Potassium Capsules in pediatric patients 12 years to 17 years of age have been established. Use of Diclofenac Potassium Capsules in this age group is based on extrapolation of efficacy from adequate and well-controlled studies in adults and supported by pharmacokinetic and safety data from two open-label studies in 49 patients 12 years to 17 years of age with mild to moderate acute pain and one active-controlled study in 76 pediatric patients 12 years to 16 years of age with orthodontic discomfort. Based on the available data, the plasma diclofenac concentration in adolescent patients was comparable to that observed in healthy adults. The safety profile of Diclofenac Potassium Capsules in adolescent patients was similar to adults.

The safety and effectiveness of Diclofenac Potassium Capsules in patients less than 12 years of age have not been established.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].

Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

{ "type": "p", "children": [], "text": "\nSymptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. " }

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

{ "type": "p", "children": [], "text": "Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. " }

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

{ "type": "p", "children": [], "text": "For additional information about overdosage treatment contact a poison control center (1-800-222-1222). " }

Diclofenac Potassium Capsules is a nonsteroidal anti-inflammatory drug, available as liquid-filled capsules of 25 mg base, equivalent to 28.3 mg potassium salt for oral administration. Diclofenac potassium is a white to slight yellowish crystalline powder. It is sparingly soluble in water at 25°C. The chemical name is benzeneacetic acid, 2-[(2,6dichlorophenyl) amino]-, monopotassium salt. The molecular weight is 334.24. Its molecular formula is C14H10Cl2NKO2, and it has the following chemical structure.

{ "type": "p", "children": [], "text": "Diclofenac Potassium Capsules is a nonsteroidal anti-inflammatory drug, available as liquid-filled capsules of 25 mg base, equivalent to 28.3 mg potassium salt for oral administration. Diclofenac potassium is a white to slight yellowish crystalline powder. It is sparingly soluble in water at 25°C. The chemical name is benzeneacetic acid, 2-[(2,6dichlorophenyl) amino]-, monopotassium salt. The molecular weight is 334.24. Its molecular formula is C14H10Cl2NKO2, and it has the following chemical structure. " }

The inactive ingredients in Diclofenac Potassium Capsules include: polyethylene glycol 400, glycerin, sorbitol, povidone, polysorbate 80, hydrochloric acid, purified water. The capsule shell contains gelatin, glycerin, lecithin, medium chain triglyceride, purified water, sorbitol, and opacode black ink (Shellac*Glaze, Isopropyl Alcohol, Ferrosoferric oxide, n-Butyl Alcohol, Propylene Glycol, Ammonium Hydroxide 28 %).

{ "type": "p", "children": [], "text": "\nThe inactive ingredients in Diclofenac Potassium Capsules include: polyethylene glycol 400, glycerin, sorbitol, povidone, polysorbate 80, hydrochloric acid, purified water. The capsule shell contains gelatin, glycerin, lecithin, medium chain triglyceride, purified water, sorbitol, and opacode black ink (Shellac*Glaze, Isopropyl Alcohol, Ferrosoferric oxide, n-Butyl Alcohol, Propylene Glycol, Ammonium Hydroxide 28 %).\n" }

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of Diclofenac Potassium Capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

The pharmacokinetics of Diclofenac Potassium Capsules was assessed in 24 healthy, normal adult volunteers who received 25 mg Diclofenac Potassium Capsules under fasting conditions. The mean pharmacokinetic parameters for Diclofenac Potassium Capsules are shown in Table 4. The pharmacokinetics of Diclofenac Potassium Capsules was also assessed in pediatric patients 12 to 17 years of age [see Specific Populations: Pediatric] and was found to be similar to adults.

<div class="scrollingtable"><table width="100%"> <caption> <span>    Table 4 Mean Pharmacokinetics of Diclofenac Potassium Capsules in Adults</span> </caption> <colgroup> <col width="33%"/> <col width="33%"/> <col width="33%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Toprule" valign="top"><span class="Bold">  PK Parameter</span></td><td align="center" class="Botrule Toprule" valign="top"><span class="Bold">  Number of Subjects</span></td><td align="center" class="Botrule Toprule" valign="top"><span class="Bold">  Mean</span> ± <span class="Bold"> Standard Deviation</span></td> </tr> <tr> <td align="center" valign="top"> T<span class="Sub">max</span> (hr)</td><td align="center" valign="top">24</td><td align="center" valign="top">0.47 ± 0.17</td> </tr> <tr> <td align="center" valign="top">Terminal Half-life (hr)</td><td align="center" valign="top">24</td><td align="center" valign="top">1.07 ± 0.29</td> </tr> <tr> <td align="center" valign="top"> C<span class="Sub">max</span> (ng/mL)</td><td align="center" valign="top">24</td><td align="center" valign="top">1087 ± 419</td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="bottom">AUC(0-∞) (ng.h/mL)</td><td align="center" class="Botrule" valign="top">24</td><td align="center" class="Botrule" valign="top">597 ± 151</td> </tr> </tbody> </table></div>

Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of diclofenac in plasma occurred.

The extent of diclofenac absorption is not significantly affected when Diclofenac Potassium Capsules is taken with food. However, the rate of absorption is reduced by food, as indicated by a two-fold increase of Tmax and a 47% decrease in Cmax.

Distribution

The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg.

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15 to 105 μg/mL) achieved with recommended doses.

Diclofenac has been shown to cross the placental barrier in humans.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Elimination

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acyl glucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy- diclofenac.

In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy-and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 1 hour.

Specific Populations

Pediatric: The pharmacokinetics of Diclofenac Potassium Capsules was assessed in 24 pediatric patients 12 years to 17 years of age with mild to moderate acute pain who received 25 mg Diclofenac Potassium Capsules every six hours as needed for pain for up to four days. The mean pharmacokinetic parameters of Diclofenac Potassium Capsules on Day 1 in pediatric patients 12 years to 17 years of age are shown in Table 5. Peak plasma levels were noted in one hour, with an elimination half-life of less than 2 hours. The pharmacokinetics of Diclofenac Potassium Capsules in pediatric patients 12 years to 17 years of age was similar to that in adults.

<div class="scrollingtable"><table width="612"> <caption> <span> Table 5 Mean Pharmacokinetics of Diclofenac Potassium Capsules (Day1) in Pediatric Patients 12 Years to 17 Years of Age </span> </caption> <colgroup> <col width="196"/> <col width="170"/> <col width="246"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Toprule"><span class="Bold"> PK Parameter</span></td><td align="center" class="Botrule Toprule"><span class="Bold"> Number of Subjects</span></td><td align="center" class="Botrule Toprule"><span class="Bold"> Mean ± Standard Deviation</span></td> </tr> <tr> <td align="center">Tmax (hr)</td><td align="center">24</td><td align="center">0.94 ± 0.42</td> </tr> <tr> <td align="center">Terminal Half-life (hr)</td><td align="center">24</td><td align="center">1.81 ± 0.92</td> </tr> <tr> <td align="center">Cmax (ng/mL)</td><td align="center">24</td><td align="center">699 ± 464</td> </tr> <tr class="Last"> <td align="center" class="Botrule">AUC(0-0) (ng0h/mL)</td><td align="center" class="Botrule">24</td><td align="center" class="Botrule">659 ± 208</td> </tr> </tbody> </table></div>

Race: Pharmacokinetic differences due to race have not been studied.

Hepatic Impairment: Hepatic metabolism accounts for almost 100% of diclofenac elimination. Therefore, in patients with hepatic impairment, start with the lowest dose and if efficacy is not achieved, consider use of an alternate product [see Warnings and Precautions (5.3)].

Renal Impairment: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. In patients with renal impairment (inulin clearance 60 to 90, 30 to 60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6)].

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

Carcinogenesis

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.2 times the maximum recommended human dose (MRHD) of Diclofenac Potassium Capsules, 100 mg/day, based on body surface area (BSA) comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.014 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.04 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters.

Impairment of Fertility

Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.4 times the MRHD based on BSA comparison) did not affect fertility.

However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (1 times the MRHD based on BSA comparison) for 14 days and at 0.25 mg/kg (0.025 times the MRHD based on BSA comparison) for 30 days produced adverse effects on male reproductive hormones and testes.

The efficacy of Diclofenac Potassium Capsules in adults was demonstrated in two multicenter, randomized, double-blind, placebo-controlled, parallel arm, multiple-dose clinical trials comparing Diclofenac Potassium Capsules 25 mg and placebo in patients with pain following bunionectomy with osteotomy. Once patients met the criteria for randomization (pain intensity ≥4 on a 0 to 10 numerical pain rating scale) they received their initial dose of study medication followed by a remediation dose when requested by the patient, and were then dosed every six hours over four days. Pain intensity was recorded at 3 and 6 hours postdose during the fixed dosing period. In Study 1, mean baseline pain intensity scores were 6.9 in the Diclofenac Potassium Capsules group (range: 4 to 10) and 7.3 in the placebo group (range: 4 to 10). In both studies, patients treated with Diclofenac Potassium Capsules had a lower mean pain intensity score over the 48-hour inpatient period following the first remediation dose (see Figure 1). The median time to onset of pain relief was less than one hour for Diclofenac Potassium Capsules 25 mg across the clinical trials. The results were similar in Study 2.

{ "type": "p", "children": [], "text": "\nThe efficacy of Diclofenac Potassium Capsules in adults was demonstrated in two multicenter, randomized, double-blind, placebo-controlled, parallel arm, multiple-dose clinical trials comparing Diclofenac Potassium Capsules 25 mg and placebo in patients with pain following bunionectomy with osteotomy. Once patients met the criteria for randomization (pain intensity ≥4 on a 0 to 10 numerical pain rating scale) they received their initial dose of study medication followed by a remediation dose when requested by the patient, and were then dosed every six hours over four days. Pain intensity was recorded at 3 and 6 hours postdose during the fixed dosing period. In Study 1, mean baseline pain intensity scores were 6.9 in the Diclofenac Potassium Capsules group (range: 4 to 10) and 7.3 in the placebo group (range: 4 to 10). In both studies, patients treated with Diclofenac Potassium Capsules had a lower mean pain intensity score over the 48-hour inpatient period following the first remediation dose (see Figure 1). The median time to onset of pain relief was less than one hour for Diclofenac Potassium Capsules 25 mg across the clinical trials. The results were similar in Study 2." }

Diclofenac Potassium Capsules 25 mg, are translucent, pale yellow, liquid-filled capsules printed with "25" in black ink supplied as:

{ "type": "p", "children": [], "text": "\nDiclofenac Potassium Capsules 25 mg, are translucent, pale yellow, liquid-filled capsules printed with \"25\" in black ink supplied as:" }

NDC Number 72336-432-12                    Bottles of 120 Capsules

{ "type": "p", "children": [], "text": "NDC Number 72336-432-12                    Bottles of 120 Capsules" }

Storage

{ "type": "p", "children": [], "text": "\nStorage \n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]." }

Protect from moisture and light. Dispense in a tight, light resistant container as defined in USP.

{ "type": "p", "children": [], "text": "Protect from moisture and light. Dispense in a tight, light resistant container as defined in USP." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Diclofenac Potassium Capsules and periodically during the course of ongoing therapy.

{ "type": "p", "children": [], "text": "\nAdvise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Diclofenac Potassium Capsules and periodically during the course of ongoing therapy." }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events \n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]." }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation \n" }

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].\n" }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity \n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop Diclofenac Potassium Capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and \"flu-like\" symptoms). If these occur, instruct patients to stop Diclofenac Potassium Capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)]. \n" }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema \n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. \n" }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions \n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. \n" }

Serious Skin Reactions, including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions, including DRESS \n" }

Advise patients to stop taking Diclofenac Potassium Capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].

{ "type": "p", "children": [], "text": "Advise patients to stop taking Diclofenac Potassium Capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].\n" }

Female Fertility

{ "type": "p", "children": [], "text": "\nFemale Fertility \n" }

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Diclofenac Potassium Capsules, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential who desire pregnancy that NSAIDs, including Diclofenac Potassium Capsules, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].\n" }

Fetal Toxicity

{ "type": "p", "children": [], "text": "\nFetal Toxicity \n" }

Inform pregnant women to avoid use of Diclofenac Potassium Capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Diclofenac Potassium Capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform pregnant women to avoid use of Diclofenac Potassium Capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Diclofenac Potassium Capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].\n" }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs \n" }

Inform patients that the concomitant use of Diclofenac Potassium Capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of Diclofenac Potassium Capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in \"over the counter\" medications for treatment of colds, fever, or insomnia." }

Use of NSAIDs and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDs and Low-Dose Aspirin \n" }

Inform patients not to use low-dose aspirin concomitantly with Diclofenac Potassium Capsules until they talk to their healthcare provider [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with Diclofenac Potassium Capsules until they talk to their healthcare provider [see Drug Interactions (7)].\n" }

US Patents: 6,365,180; 7,662,858; 7,884,095; 7,939,518; 8,110,606; 6,287,594; 8,623,920

{ "type": "p", "children": [], "text": "US Patents: 6,365,180; 7,662,858; 7,884,095; 7,939,518; 8,110,606; 6,287,594; 8,623,920" }

Dispense with Medication Guide available at: www.avetpharma.com/product.

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at: www.avetpharma.com/product." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Strides Pharma Science Limited

{ "type": "p", "children": [], "text": "\nStrides Pharma Science Limited\n" }

Bengaluru – 562106, India

{ "type": "p", "children": [], "text": "Bengaluru – 562106, India" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Lifsa Drugs LLC

{ "type": "p", "children": [], "text": "\nLifsa Drugs LLC\n" }

New Brunswick, NJ 08901

{ "type": "p", "children": [], "text": "New Brunswick, NJ 08901 " }

1.866.378.4799

{ "type": "p", "children": [], "text": "1.866.378.4799" }

Revised: 01/2025

{ "type": "p", "children": [], "text": "\nRevised: 01/2025\n" }

<div class="scrollingtable"><table width="65%"> <colgroup> <col width="30%"/> <col width="69%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold"> What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span> <br/> <span class="Bold">  NSAIDs can cause serious side effects, including: </span> <br/> <ul class="Disc"> <li> <span class="Bold"> Increased risk of a heart attack or stroke that can lead to death</span>. This risk may happen early in treatment and may increase:<ul class="Circle"> <li>with increasing doses of NSAIDs</li> <li>with longer use of NSAIDs</li> </ul> </li> </ul> <span class="Bold">  Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.</span> <br/> <ul class="Disc"> <li> <span class="Bold"> Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: </span> <ul class="Circle"> <li>anytime during use </li> <li>without warning symptoms</li> <li>that may cause death</li> </ul> </li> </ul> <span class="Bold">  The risk of getting an ulcer or bleeding increases with</span> :</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <ul class="Circle"> <li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <ul class="Circle"> <li>taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs"</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>increasing doses of NSAIDs</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>older age</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>longer use of NSAIDS</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>poor health</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>smoking</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>advanced liver disease</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>drinking alcohol</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>bleeding problems</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold"> NSAIDs should only be used</span> : <br/> <ul class="Circle"> <li>exactly as prescribed</li> <li>at the lowest dose possible for your treatment</li> <li>for the shortest time needed</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">  What are NSAIDs? </span> <br/>  NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">  Who should not take NSAIDs? </span> <br/> <span class="Bold">  Do not take NSAIDs: </span> <br/> <ul class="Disc"> <li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.</li> <li>right before or after heart bypass surgery.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">  Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: </span> <br/> <ul class="Disc"> <li>have liver or kidney problems</li> <li>have high blood pressure</li> <li>have asthma</li> <li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class="Bold">  You should not take NSAIDs after about 30 weeks of pregnancy.</span> </li> <li>are breastfeeding or plan to breast feed.</li> </ul> <span class="Bold"> Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements</span> . NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class="Bold">  Do not start taking any new medicine without talking to your healthcare provider first. </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">  What are the possible side effects of NSAIDs? </span> <br/> <span class="Bold">  NSAIDs can cause serious side effects, including: </span> <br/> <span class="Bold">  See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span> <br/> <ul class="Disc"> <li>new or worse high blood pressure</li> <li>heart failure</li> <li>liver problems including liver failure</li> <li>kidney problems including kidney failure</li> <li>low red blood cells (anemia)</li> <li>life-threatening skin reactions</li> <li>life-threatening allergic reactions</li> <li> <span class="Bold"> Other side effects of NSAIDs include: </span>  stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.</li> </ul> <span class="Bold">  Get emergency help right away if you get any of the following symptoms: </span></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>shortness of breath or trouble breathing</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>slurred speech</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>chest pain</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>swelling of the face or throat</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>weakness in one part or side of your body</li> </ul> </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold"> Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: </span></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>nausea</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>vomit blood</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>more tired or weaker than usual</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>there is blood in your bowel movement or it is black and sticky like tar</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>diarrhea</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>unusual weight gain</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>itching</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>skin rash or blisters with fever</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>your skin or eyes look yellow</li> </ul> </td><td class="Botrule Rrule" valign="top"> <ul class="Circle"> <li>swelling of the arms, legs, hands and feet</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>indigestion or stomach pain</li> </ul> </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <ul class="Circle"> <li>flu-like symptoms</li> </ul> </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">  If you take too much of your NSAID, call your healthcare provider or get medical help right away. </span> <br/> These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">  Other information about NSAIDs </span> <br/> <span class="Bold">  • </span>   Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. <br/> <span class="Bold">  •  </span>  Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold"> General information about the safe and effective use of NSAIDs </span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. <br/> If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"65%\">\n<colgroup>\n<col width=\"30%\"/>\n<col width=\"69%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\"> Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\"> What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span>\n<br/>\n<span class=\"Bold\">  NSAIDs can cause serious side effects, including: </span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\"> Increased risk of a heart attack or stroke that can lead to death</span>. This risk may happen early in treatment and may increase:<ul class=\"Circle\">\n<li>with increasing doses of NSAIDs</li>\n<li>with longer use of NSAIDs</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">  Do not take NSAIDs right before or after a heart surgery called a \"coronary artery bypass graft (CABG).\" Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\"> Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: </span>\n<ul class=\"Circle\">\n<li>anytime during use </li>\n<li>without warning symptoms</li>\n<li>that may cause death</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">  The risk of getting an ulcer or bleeding increases with</span> :</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<ul class=\"Circle\">\n<li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<ul class=\"Circle\">\n<li>taking medicines called \"corticosteroids\", \"anticoagulants\", \"SSRIs\", or \"SNRIs\"</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>increasing doses of NSAIDs</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>older age</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>longer use of NSAIDS</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>poor health</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>smoking</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>advanced liver disease</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>drinking alcohol</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>bleeding problems</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\"> NSAIDs should only be used</span> : <br/>\n<ul class=\"Circle\">\n<li>exactly as prescribed</li>\n<li>at the lowest dose possible for your treatment</li>\n<li>for the shortest time needed</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">  What are NSAIDs? </span>\n<br/>  NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">  Who should not take NSAIDs? </span>\n<br/>\n<span class=\"Bold\">  Do not take NSAIDs: </span>\n<br/>\n<ul class=\"Disc\">\n<li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.</li>\n<li>right before or after heart bypass surgery.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">  Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: </span>\n<br/>\n<ul class=\"Disc\">\n<li>have liver or kidney problems</li>\n<li>have high blood pressure</li>\n<li>have asthma</li>\n<li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class=\"Bold\">  You should not take NSAIDs after about 30 weeks of pregnancy.</span>\n</li>\n<li>are breastfeeding or plan to breast feed.</li>\n</ul>\n<span class=\"Bold\"> Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements</span> . NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class=\"Bold\">  Do not start taking any new medicine without talking to your healthcare provider first. </span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">  What are the possible side effects of NSAIDs? </span>\n<br/>\n<span class=\"Bold\">  NSAIDs can cause serious side effects, including: </span>\n<br/>\n<span class=\"Bold\">  See \"What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span>\n<br/>\n<ul class=\"Disc\">\n<li>new or worse high blood pressure</li>\n<li>heart failure</li>\n<li>liver problems including liver failure</li>\n<li>kidney problems including kidney failure</li>\n<li>low red blood cells (anemia)</li>\n<li>life-threatening skin reactions</li>\n<li>life-threatening allergic reactions</li>\n<li>\n<span class=\"Bold\"> Other side effects of NSAIDs include: </span>  stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.</li>\n</ul>\n<span class=\"Bold\">  Get emergency help right away if you get any of the following symptoms: </span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>shortness of breath or trouble breathing</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>slurred speech</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>chest pain</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>swelling of the face or throat</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>weakness in one part or side of your body</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\"> Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: </span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>nausea</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>vomit blood</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>more tired or weaker than usual</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>there is blood in your bowel movement or it is black and sticky like tar</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>diarrhea</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>unusual weight gain</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>itching</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>skin rash or blisters with fever</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>your skin or eyes look yellow</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>swelling of the arms, legs, hands and feet</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>indigestion or stomach pain</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<ul class=\"Circle\">\n<li>flu-like symptoms</li>\n</ul>\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">  If you take too much of your NSAID, call your healthcare provider or get medical help right away. </span>\n<br/> These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">  Other information about NSAIDs </span>\n<br/>\n<span class=\"Bold\">  • </span>   Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. <br/>\n<span class=\"Bold\">  •  </span>  Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\"> General information about the safe and effective use of NSAIDs </span>\n<br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. <br/> If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.</td>\n</tr>\n</tbody>\n</table></div>" }

Manufactured by: Strides Pharma Science Limited Bengaluru – 562106, India

{ "type": "p", "children": [], "text": "Manufactured by:\nStrides Pharma Science Limited\nBengaluru – 562106, India" }

Manufactured for: Lifsa Drugs LLC. New Brunswick, NJ 089011.866.378.4799

{ "type": "p", "children": [], "text": "Manufactured for:\nLifsa Drugs LLC.\nNew Brunswick, NJ 089011.866.378.4799" }

Revised: 01/2025

{ "type": "p", "children": [], "text": "\nRevised: 01/2025\n" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Pharmacist: Dispense the Medication Guide to each Patient

{ "type": "p", "children": [], "text": "\nPharmacist: Dispense the Medication Guide to each Patient\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Usual adult dosage: 1 capsule four times daily or as instructed by physician.

{ "type": "p", "children": [], "text": "\nUsual adult dosage:\n1 capsule four times daily or as instructed by physician." }

Dispense with Medication Guide available at:www.lifsapharma.com

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at:www.lifsapharma.com" }

Diclofenac sodium and misoprostol delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in adult patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions ( 5.3)] .

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in adult patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions ( 5.3)] . " }

The recommended dosage for the treatment of osteoarthritis for maximal GI mucosal protection is diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg three times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg two times a day can be used, but these dosages are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 150 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows:

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="43%"/> <col width="20%"/> <col width="20%"/> <col width="17%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">  <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Osteoarthritis</span> <br/> <span class="Bold">Regimen</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Diclofenac Sodium</span> <br/> <span class="Bold">(mg/day)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Misoprostol</span> <br/> <span class="Bold">(mcg/day)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">three times a day <br/> two times a day* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">150 <br/> 100 <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">600 <br/> 400 <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">two times a day* <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">150 <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">400 <br/> </p> </td> </tr> </tbody> </table></div>

*For patients who experience intolerance; these dosages are less effective in preventing ulcers

The recommended dosage for the treatment of rheumatoid arthritis is diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg three or four times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg two times a day can be used, but are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 200 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows:

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="47%"/> <col width="18%"/> <col width="20%"/> <col width="15%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">  <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Rheumatoid</span> <br/> <span class="Bold">Arthritis</span> <br/> <span class="Bold">Regimen</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Diclofenac Sodium</span> <br/> <span class="Bold">(mg/day)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Misoprostol</span> <br/> <span class="Bold">(mcg/day)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">four times a day <br/> three times a day <br/> two times a day* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">200 <br/> 150 <br/> 100 <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">800 <br/> 600 <br/> 400 <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">two times a day* <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">150 <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">400 <br/> </p> </td> </tr> </tbody> </table></div>

* For patients who experience intolerance; these dosages are less effective in preventing ulcers

Diclofenac sodium and misoprostol delayed-release tablets contains misoprostol, which provides protection against gastric and duodenal ulcers [see Clinical Studies ( 14)] . For gastric ulcer prevention, the 200 mcg four and three times a day regimens are therapeutically equivalent, but more protective than the two times a day regimen. For duodenal ulcer prevention, the four times a day regimen is more protective than the three or two times a day regimens. However, the four times a day regimen is less well tolerated than the three times a day regimen because of usually self-limited diarrhea related to the misoprostol dose [see Adverse Reactions ( 6.1)] , and the two times a day regimen may be better tolerated than three times a day in some patients.

Dosages may be individualized using the separate products (misoprostol and diclofenac sodium), after which the patient may be switched to the appropriate diclofenac sodium and misoprostol delayed-release tablets dosage. If clinically indicated, misoprostol co-therapy with diclofenac sodium and misoprostol delayed-release tablets to optimize the misoprostol dose and/or frequency of administration, may be appropriate. Do not exceed a total misoprostol dose of 800 mcg/day and do not administer more than 200 mcg of misoprostol at any one time.

When concomitant use of CYP2C9 inhibitors is necessary, the maximum total daily dose of diclofenac is 100 mg per day. Do not exceed a dosage of diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg twice daily [see Drug Interactions ( 7)] .

For additional information, refer to the Prescribing Information for the individual products of diclofenac sodium and misoprostol.

Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as a uncoated tablets in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol.

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as a uncoated tablets in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol." }

{ "type": "", "children": [], "text": "" }

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients:" }

{ "type": "", "children": [], "text": "" }

Misoprostol

Administration of misoprostol, a component of diclofenac sodium and misoprostol delayed-release tablets, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered to pregnant women to induce labor or an abortion. Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women. Diclofenac sodium and misoprostol delayed-release tablets are not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others [see Use in Specific Populations ( 8.1)] .

If diclofenac sodium and misoprostol delayed-release tablets are prescribed, verify the pregnancy status of females of reproductive potential prior to initiation of treatment and advise the use effective contraception during treatment with diclofenac sodium and misoprostol delayed-release tablets   [see Use in Specific Populations ( 8.3)] .

Diclofenac

Premature Closure of Fetal Ductus Arteriosus

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at about 30 weeks of gestation and later.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required [see Use in Specific Populations ( 8.1)] .

Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions ( 5.3)] .

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications ( 4)] .

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium and misoprostol delayed-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

In clinical trials with diclofenac sodium and misoprostol delayed-release tablets, meaningful elevation of alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT], more than 3 times the upper limit of the normal range [ULN]) occurred in 1.6% of 2,184 patients treated with  diclofenac sodium and misoprostol delayed-release tablets and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with diclofenac sodium and misoprostol delayed-release tablets. The misoprostol component of diclofenac sodium and misoprostol delayed-release tablets does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component.

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium and misoprostol delayed-release tablets should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium and misoprostol delayed-release tablets immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium and misoprostol delayed-release tablets, the lowest effective dose should be used for the shortest duration possible. Exercise caution when prescribing diclofenac sodium and misoprostol delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions ( 7)] .

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions ( 7)] .

Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium and misoprostol delayed-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of diclofenac sodium and misoprostol delayed-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium and misoprostol delayed-release tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium and misoprostol delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium and misoprostol delayed-release tablets [see Drug Interactions ( 7)]. Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium and misoprostol delayed-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Diclofenac sodium and misoprostol delayed-release tablets has been associated with anaphylactic reactions in patients with and without known hypersensitivity to the individual components of diclofenac sodium and misoprostol and in patients with aspirin-sensitive asthma [see Contraindications ( 4) and Warnings and Precautions ( 5.9)] .

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity [see Contraindications ( 4)] . When diclofenac sodium and misoprostol delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium and misoprostol delayed-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications ( 4)] .

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium and misoprostol delayed-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium and misoprostol delayed-release tablets and evaluate the patient immediately.

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium and misoprostol delayed-release tablets has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac a component diclofenac sodium and misoprostol delayed-release tablets, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet drugs (e.g., aspirin), and SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions ( 7)] .

The pharmacological activity of diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions ( 5.3, 5.7)] .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reaction information for diclofenac sodium and misoprostol delayed-release tablets is derived from multinational controlled clinical trials in over 2,000 patients receiving diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg or diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg, as well as from blinded, controlled trials of diclofenac sodium delayed-release tablets and misoprostol tablets.

Gastrointestinal

GI disorders had the highest reported incidence of adverse reactions for patients receiving diclofenac sodium and misoprostol delayed-release tablets. These events were generally minor, but led to discontinuation of therapy in 9% of patients on diclofenac sodium and misoprostol delayed-release tablets and 5% of patients on diclofenac sodium. For GI ulcer rates, [see Clinical Studies ( 14)].

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="28%"/> <col width="39%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">GI disorder</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Diclofenac Sodium and Misoprostol Delayed-Release Tablets</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Diclofenac Sodium</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">21% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">15% <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">19% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">11% <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspepsia <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">14% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">11% <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">11% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">6% <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Flatulence <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">9% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">4% <br/> </p> </td> </tr> </tbody> </table></div>

Diclofenac sodium and misoprostol delayed-release tablets can cause more abdominal pain, diarrhea, and other GI symptoms than diclofenac alone.

Diarrhea and abdominal pain developed early in the course of therapy, and were usually self-limited (resolved after 2 to 7 days). Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if diclofenac sodium and misoprostol delayed-release tablets are prescribed. The incidence of diarrhea can be minimized by administering diclofenac sodium and misoprostol delayed-release tablets with food and by avoiding co-administration with magnesium-containing antacids.

Gynecological

Gynecological disorders previously reported with misoprostol use have also been reported for women receiving diclofenac sodium and misoprostol delayed-release tablets (see below). Postmenopausal vaginal bleeding may be related to administration of diclofenac sodium and misoprostol delayed-release tablets. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology [see Boxed Warnings, Contraindications ( 4) and Warnings and Precautions ( 5)] .

Other adverse experiences reported occasionally with diclofenac sodium and misoprostol delayed-release tablets, diclofenac or other NSAIDs, or misoprostol are:

Body as a whole:asthenia, fatigue, malaise.

Central and peripheral nervous system:dizziness, drowsiness, headache, insomnia, paresthesia, vertigo.

Digestive:anorexia, appetite changes, constipation, dry mouth, dysphagia, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI neoplasm benign, peptic ulcer, tenesmus, vomiting.

Female reproductive disorders:breast pain, dysmenorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.

Hemic and lymphatic system:epistaxis, leukopenia, melena, purpura, decreased hematocrit.

Metabolic and nutritional: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, dehydration, hyponatremia.

Musculoskeletal system:arthralgia, myalgia.

Psychiatric:anxiety, concentration impaired, depression, irritability.

Respiratory system: asthma, coughing, hyperventilation.

Skin and appendages: alopecia, eczema, pemphigoid reaction, photosensitivity, sweating increased, pruritus.

Special senses:taste perversion, tinnitus.

Renal and urinary disorders: dysuria, nocturia, polyuria, proteinuria, urinary tract infection.

Vision: diplopia.

The following adverse reactions have been identified during post approval of diclofenac sodium and misoprostol delayed-release tablets, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole:death, fever, infection, sepsis, chills, edema.

Cardiovascular system:arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased creatine phosphokinase (CPK), increased lactate dehydrogenase (LDH), myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis.

Central and peripheral nervous system:coma, convulsions, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor.

Congenital, familial and genetic disorders:birth defects.

Digestive:enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis.

Female reproductive disorders:intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage.

Hemic and lymphatic system:agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia.

Hypersensitivity:angioedema, laryngeal/pharyngeal edema, urticaria.

Liver and biliary system:abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice.

Male reproductive disorders:impotence, perineal pain.

Metabolic and nutritional:blood urea nitrogen (BUN) increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention.

Pregnancy, puerperium and perinatal conditions:abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death.

Psychiatric:confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction.

Reproductive system and breast disorders:female fertility decreased.

Respiratory system:dyspnea, pneumonia, respiratory depression.

Skin and appendages:acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE), cutaneous reactions (bullous eruption).

Special senses:hearing impairment, taste loss.

Renal and urinary disorders:cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulonephritis.

Vision:amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.

See Table 1 for clinically significant drug interactions with diclofenac and misoprostol.

{ "type": "p", "children": [], "text": "See Table 1 for clinically significant drug interactions with diclofenac and misoprostol." }

Table 1: Clinically Significant Drug Interactions with Diclofenac and Misoprostol

{ "type": "p", "children": [], "text": "\nTable 1: Clinically Significant Drug Interactions with Diclofenac and Misoprostol\n" }

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="24%"/> <col width="76%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Drugs That Interfere with Hemostasis</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.   <br/> </dd> <dt>•</dt> <dd>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients with concomitant use of diclofenac sodium and misoprostol delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.26">5.12</a>)] </span>. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Aspirin</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.17">5.3</a>)] </span>. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of diclofenac sodium and misoprostol delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.26">5.12</a>)] </span>. <br/>   <br/> Diclofenac sodium and misoprostol delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol).   <br/> </dd> <dt>•</dt> <dd>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.   <br/> </dd> <dt>•</dt> <dd>During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.   <br/> </dd> <dt>•</dt> <dd>During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.21">5.7</a>)] </span>. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Diuretics </span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.21">5.7</a>)] </span>. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Digoxin</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and digoxin, monitor serum digoxin levels. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Lithium</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and lithium, monitor patients for signs of lithium toxicity. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Methotrexate</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cyclosporine</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of diclofenac and cyclosporine may increase cyclosporine’s nephrotoxicity. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">NSAIDs and Salicylates</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.17">5.3</a>)] </span>. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of diclofenac sodium and misoprostol delayed-release tablets with other NSAIDs or salicylates is not recommended. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Pemetrexed</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. <br/>   <br/> Avoid diclofenac sodium and misoprostol delayed-release tablets for a period of two days before, the day of, and two days following administration of pemetrexed. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Antacids</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of diclofenac sodium and misoprostol delayed-release tablets and magnesium-containing antacids is not recommended. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Corticosteroids</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients with concomitant use of diclofenac sodium and misoprostol delayed-release tablets with corticosteroids for signs of bleeding <span class="Italics">[see Warnings and Precautions ( <a href="#Section_5.17">5.3</a>)] </span>. <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">CYP2C9 Inhibitors or Inducers</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Clinical Impact:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g., voriconzaole) may enhance the exposure and toxicity of diclofenac <span class="Italics">[see Clinical Pharmacology ( <a href="#Section_12.3">12.3</a>)] </span>whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac. <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Italics">Intervention:</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">CYP2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of diclofenac sodium and misoprostol delayed-release tablets 50 mg/ 200 mcg twice daily <span class="Italics">[</span>see <span class="Italics">Dosage and Administration ( <a href="#Section_2.4">2.4</a>)] </span>. <br/>   <br/> CYP2C9 inducers: A dosage adjustment may be warranted when diclofenac sodium and misoprostol delayed-release tablets are administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary. <br/> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" cellspacing=\"0pt\" width=\"100%\">\n<col width=\"24%\"/>\n<col width=\"76%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs That Interfere with Hemostasis</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.   <br/>\n</dd>\n<dt>•</dt>\n<dd>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients with concomitant use of diclofenac sodium and misoprostol delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.26\">5.12</a>)] </span>. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Aspirin</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.17\">5.3</a>)] </span>. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of diclofenac sodium and misoprostol delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.26\">5.12</a>)] </span>. <br/>   <br/> Diclofenac sodium and misoprostol delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol).   <br/>\n</dd>\n<dt>•</dt>\n<dd>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.   <br/>\n</dd>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.   <br/>\n</dd>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.21\">5.7</a>)] </span>. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics </span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.21\">5.7</a>)] </span>. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Digoxin</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and digoxin, monitor serum digoxin levels. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Lithium</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and lithium, monitor patients for signs of lithium toxicity. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Methotrexate</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Cyclosporine</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of diclofenac and cyclosporine may increase cyclosporine’s nephrotoxicity. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NSAIDs and Salicylates</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.17\">5.3</a>)] </span>. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of diclofenac sodium and misoprostol delayed-release tablets with other NSAIDs or salicylates is not recommended. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Pemetrexed</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">During concomitant use of diclofenac sodium and misoprostol delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. <br/>   <br/> Avoid diclofenac sodium and misoprostol delayed-release tablets for a period of two days before, the day of, and two days following administration of pemetrexed. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antacids</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of diclofenac sodium and misoprostol delayed-release tablets and magnesium-containing antacids is not recommended. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Corticosteroids</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients with concomitant use of diclofenac sodium and misoprostol delayed-release tablets with corticosteroids for signs of bleeding <span class=\"Italics\">[see Warnings and Precautions ( <a href=\"#Section_5.17\">5.3</a>)] </span>. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">CYP2C9 Inhibitors or Inducers</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g., voriconzaole) may enhance the exposure and toxicity of diclofenac <span class=\"Italics\">[see Clinical Pharmacology ( <a href=\"#Section_12.3\">12.3</a>)] </span>whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac. <br/>\n</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">CYP2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of diclofenac sodium and misoprostol delayed-release tablets 50 mg/ 200 mcg twice daily <span class=\"Italics\">[</span>see <span class=\"Italics\">Dosage and Administration ( <a href=\"#Section_2.4\">2.4</a>)] </span>. <br/>   <br/> CYP2C9 inducers: A dosage adjustment may be warranted when diclofenac sodium and misoprostol delayed-release tablets are administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary. <br/>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications ( 4)]. If a woman becomes pregnant while taking diclofenac sodium and misoprostol delayed-release tablets, discontinue the drug and advise the woman of the potential risks to her and to a fetus.

There are no adequate and well-controlled studies of diclofenac sodium and misoprostol delayed-release tablets in pregnant women; however, there is information available about the active drug components of diclofenac sodium and misoprostol delayed-release tablets, diclofenac sodium and misoprostol. Administration of misoprostol to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions ( 5.1)] . Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac a component of diclofenac sodium and misoprostol delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment ( see Data). There are clinical considerations when misoprostol and diclofenac are used in pregnant women (see Clinical Considerations). In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eighth week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. Diclofenac sodium and misoprostol delayed-release tablets, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete.

Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses.

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications ( 4)]. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

Fetal/Neonatal Adverse Reactions

Misoprostol

Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death (misoprostol is not approved for this use). Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications ( 4)].

Diclofenac

Premature Closure of Fetal Ductus Arteriosus:

NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later in pregnancy (see Data).

Oligohydramnios/Neonatal Renal Impairment:

Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment (see Data).

Labor or Delivery

There are no studies on the effects of diclofenac sodium and misoprostol delayed-release tablets or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death. The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational age and with prior uterine surgery, including cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

Data

Human Data

Misoprostol

Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

Diclofenac

Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive.

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

The reproductive and developmental effects of both the combination of diclofenac sodium and misoprostol and each component of diclofenac sodium and misoprostol delayed-release tablets alone have been studied in animals. In all studies there was no evidence of teratogenicity. In an oral teratology study in pregnant rabbits, diclofenac sodium and misoprostol delayed-release tablets was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m 2/day, 0.8 times the MRHD based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m 2/day, 0.8 times the MRHD based on body surface area) and there was no evidence of teratogenicity. At the high dose, there was evidence of embryotoxicity (resorption and decreased fetal body weight) and maternal toxicity (decreased food intake and weight gain).

In oral teratology studies with misoprostol in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m 2/day, 16 times the MRHD based on body surface area) and pregnant rabbits at doses up to 1 mg/kg/day (12 mg/m 2/day, 20 times the MRHD based on body surface area), there was no evidence of teratogenicity.

In oral teratology studies with diclofenac sodium in pregnant mice at doses up to 20 mg/kg/day (60 mg/m 2/day, 0.4 times the MRHD based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m 2/day, 0.4 times the MRHD based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m 2/day, 0.8 times the MRHD based on body surface area), there was no evidence of teratogenicity.

Risk Summary

No lactation studies have been conducted with diclofenac sodium and misoprostol delayed-release tablets; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk [see Clinical Pharmacology ( 12.3)] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium and misoprostol delayed-release tablets and any potential adverse effects on the breastfed infant from the diclofenac sodium and misoprostol delayed-release tablets or from the underlying maternal condition.

Diclofenac sodium and misoprostol delayed-release tablets are not recommended in women of childbearing potential [see Warnings and Precautions ( 5.1)] . If diclofenac sodium and misoprostol delayed-release tablets are prescribed, patients must be advised of the abortifacient property and warned not to give the drug to others.

Pregnancy Testing

Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating  diclofenac sodium and misoprostol delayed-release tablets.

Contraception

Females

Diclofenac sodium and misoprostol delayed-release tablets can cause fetal harm when administered to a pregnant woman [see Contraindications ( 4) and Use in Specific Populations ( 8.1)]. Advise females of reproductive potential to use effective contraception during treatment with diclofenac sodium and misoprostol delayed-release tablets.

Diclofenac sodium and misoprostol delayed-release tablets may be prescribed if the patient:

Safety and effectiveness of diclofenac sodium and misoprostol delayed-release tablets in pediatric patients have not been established.

Geriatric patients (those 65 years of age and older), compared to younger adult patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions [see Warnings and Precautions ( 5.2, 5.3, 5.7)] . In addition, the risk of diclofenac-associated adverse reactions may be greater in geriatric patients with renal impairment or those taking concomitant ACE inhibitors or ARBs [see Drug Interactions ( 7) and Use in Specific Populations ( 8.6)] .

Avoid use of diclofenac sodium and misoprostol delayed-release tablets in geriatric patients with cardiovascular and/or renal risk factors. If use cannot be avoided, use the lowest recommended dosage for the shortest duration and monitor for cardiac and renal adverse reactions [see Dosage and Administration ( 2.1)] . Monitor renal function in geriatric patients during treatment with diclofenac sodium and misoprostol delayed-release tablets, especially in patients with concomitant use of ACE inhibitors or ARBs .

Of the 2,184 patients in clinical studies with diclofenac sodium and misoprostol delayed-release tablets, 557 (25.5%) were 65 years of age and over. No overall differences in effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in effectiveness between geriatric patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

No clinically meaningful differences in the pharmacokinetics of diclofenac and misoprostol were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology ( 12.3)].

Diclofenac and misoprostol are primarily excreted by the kidney. Long-term administration of NSAIDs has resulted in renal toxicity. Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium and misoprostol delayed-release tablets. Monitor renal function, especially during concomitant use of ACE inhibitors or ARBs. Also, monitor renal function in patients with hepatic impairment. Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with advanced renal disease. If use cannot be avoided in patients with advanced renal disease, use the lowest dosage for the shortest duration, monitor the patient’s renal function and monitor for clinical signs of worsening renal function [see Warnings and Precautions ( 5.7), Drug Interactions ( 7) and Clinical Pharmacology ( 12.3)] .

Manage patients with symptomatic and supportive care following an acute NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving.

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The toxic dose of diclofenac sodium and misoprostol delayed-release tablets has not been determined. However, signs of overdosage from the components of the product have been described.

{ "type": "p", "children": [], "text": "The toxic dose of diclofenac sodium and misoprostol delayed-release tablets has not been determined. However, signs of overdosage from the components of the product have been described." }

Diclofenac

{ "type": "p", "children": [], "text": "\nDiclofenac\n" }

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions ( 5.2, 5.3, 5.5, 5.7)] .

{ "type": "p", "children": [], "text": "Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions ( 5.2, 5.3, 5.5, 5.7)] . " }

Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia.

{ "type": "p", "children": [], "text": "Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia." }

If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

{ "type": "p", "children": [], "text": "If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding." }

Misoprostol

{ "type": "p", "children": [], "text": "\nMisoprostol\n" }

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.

{ "type": "p", "children": [], "text": "The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia." }

Diclofenac Sodium and Misoprostol Delayed-Release Tablets 

{ "type": "p", "children": [], "text": "\nDiclofenac Sodium and Misoprostol Delayed-Release Tablets \n" }

Symptoms of acute overdosage with diclofenac sodium and misoprostol delayed-release tablets should be treated with supportive and symptomatic therapy. There are no specific antidotes. In case of acute overdosage, emesisis and/or gastric lavage may be considered dependent upon amount ingested and time since ingestion. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven.

{ "type": "p", "children": [], "text": "Symptoms of acute overdosage with diclofenac sodium and misoprostol delayed-release tablets should be treated with supportive and symptomatic therapy. There are no specific antidotes. In case of acute overdosage, emesisis and/or gastric lavage may be considered dependent upon amount ingested and time since ingestion. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven." }

Diclofenac sodium and misoprostol delayed-release tablets, USP is a combination product containing diclofenac sodium, an NSAID with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release  tablets are white to off-white, round, biconvex, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg) or 75 mg (diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg) of diclofenac sodium (equivalent to 46.39 mg or 69.58 mg of diclofenac, respectively) surrounded by an outer mantle containing 200 mcg misoprostol.

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets, USP is a combination product containing diclofenac sodium, an NSAID with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release  tablets are white to off-white, round, biconvex, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg) or 75 mg (diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg) of diclofenac sodium (equivalent to 46.39 mg or 69.58 mg of diclofenac, respectively) surrounded by an outer mantle containing 200 mcg misoprostol." }

Diclofenac sodium, USP is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium, USP is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium, USP is sparingly soluble in water. Its chemical formula and name are:

{ "type": "p", "children": [], "text": "Diclofenac sodium, USP is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium, USP is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium, USP is sparingly soluble in water. Its chemical formula and name are:" }

C 14H 10Cl 2NO 2Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt.

{ "type": "p", "children": [], "text": "C 14H 10Cl 2NO 2Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. " }

Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:

{ "type": "p", "children": [], "text": "Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:" }

C 22H 38O 5[M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.

{ "type": "p", "children": [], "text": "C 22H 38O 5[M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate. " }

Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide; corn starch; crospovidone; hydrogenated castor oil; hypromellose; lactose monohydrate; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone; sodium hydroxide;  talc; triethyl citrate.

{ "type": "p", "children": [], "text": "Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide; corn starch; crospovidone; hydrogenated castor oil; hypromellose; lactose monohydrate; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone; sodium hydroxide;  talc; triethyl citrate. \n" }

Diclofenac sodium and misoprostol delayed-release tablets are a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog.

Diclofenac

The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivoeffects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Misoprostol

Misoprostol is a synthetic PGE1 analog with gastric antisecretory and mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by NSAIDs.

Misoprostol can increase bicarbonate and mucus production, but it has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to differentiate whether the ability of misoprostol to reduce the risk of gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both.

In vitrostudies on canine parietal cells using titrated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereo-specific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained.

Misoprostol, over the range of 50 mcg to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter-lived, and only the 200 mcg dose had substantial effects on nocturnal secretion or on histamine- and meal-stimulated secretion.

Misoprostol also produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor intrinsic factor output.

General Pharmacokinetic Characteristics

The pharmacokinetic profiles of diclofenac and misoprostol administered as the fixed combination (diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg or 75 mg/200 mcg) are similar to the profiles when the two drugs are administered as separate tablets (see Table 2). No pharmacokinetic interaction between the two drugs has been observed following multiple dosing. The diclofenac total exposure [area under the curve (AUC)] is dose-proportional within the range of 25 mg to 150 mg. Approximately dose-proportional increase in misoprostol exposure was also observed within the range of 200 mcg to 400 mcg. Neither diclofenac nor misoprostol accumulated in plasma following repeated doses of diclofenac sodium and misoprostol delayed-release tablets given every 12 hours under fasted conditions.

Table 2: Pharmacokinetic Parameters of Diclofenac and Misoprostol Acid Following Single Oral Doses ofDiclofenac Sodium and Misoprostol Delayed-Release Tabletsor Separate Products in Healthy Subjects

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">MISOPROSTOL ACID Mean (SD)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Treatment (n=36)</span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">C <span class="Sub">max</span>(pg/mL) </span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">T <span class="Sub">max</span>(hr) </span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">AUC <span class="Sub">(0 to 4h)</span></span> <br/> <span class="Bold">(pg <span class="Sup">●</span>hr/mL) </span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg <br/>   <br/> Misoprostol <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">441 (137) <br/>   <br/>   <br/>   <br/>   <br/> 478 (201) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">0.30 (0.13) <br/>   <br/>   <br/>   <br/>   <br/> 0.30 (0.10) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">266 (95) <br/>   <br/>   <br/>   <br/>   <br/> 295 (143) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg <br/>   <br/> Misoprostol <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">304 (110) <br/>   <br/>   <br/>   <br/>   <br/> 290 (130) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">0.26 (0.09) <br/>   <br/>   <br/>   <br/>   <br/> 0.35 (0.12) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">117 (49) <br/>   <br/>   <br/>   <br/>   <br/> 176 (58) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">DICLOFENAC Mean (SD)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Treatment (n=36)</span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">C <span class="Sub">max</span>(ng/mL) </span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">T <span class="Sub">max</span>(hr) </span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">AUC <span class="Sub">(0 to 12h)</span></span> <br/> <span class="Bold">(ng●hr/mL)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg <br/>   <br/> Diclofenac Sodium <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1207 (364) <br/>   <br/>   <br/>   <br/>   <br/> 1298 (441) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2.4 (1.0) <br/>   <br/>   <br/>   <br/>   <br/> 2.4 (1.0) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1380 (272) <br/>   <br/>   <br/>   <br/>   <br/> 1357 (290) <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg <br/>   <br/> Diclofenac Sodium <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2025 (2005) <br/>   <br/>   <br/>   <br/>   <br/> 2367 (1318) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2.0 (1.4) <br/>   <br/>   <br/>   <br/>   <br/> 1.9 (0.7) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2773 (1347) <br/>   <br/>   <br/>   <br/>   <br/> 2609 (1185) <br/> </p> </td> </tr> </tbody> </table></div>

SD: Standard deviation of the mean; AUC: Area under the curve; C max: Peak concentration; T max: Time to peak concentration

Absorption

Diclofenac: Diclofenac is completely absorbed from the GI tract after oral administration under fasted condition, and peak plasma levels are achieved in 2 hours (range 1 to 4 hours), and the area under the plasma concentration curve (AUC) is dose-proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.5 and 2 mcg/mL for 50 mg and 75 mg doses, respectively. The diclofenac in diclofenac sodium and misoprostol delayed-release tablets is in a pharmaceutical formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH environment of the duodenum. Only 50% of the absorbed dose is systemically available due to first pass metabolism (i.e., oral bioavailability is 50%).

Misoprostol: Misoprostol is rapidly absorbed following oral administration of diclofenac sodium and misoprostol delayed-release tablets, and misoprostol acid (active metabolite) reaches a maximum plasma concentration in approximately 20 minutes. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food, and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid; this effect does not appear to be clinically important.

Food decreases the multiple-dose bioavailability profile of diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg and diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg.

Distribution

Diclofenac: The volume of distribution of diclofenac is approximately 0.55 L/kg. More than 99% of diclofenac is bound to plasma albumin.

Misoprostol: The plasma protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.

After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/mL (CV 77%) after single 200 mcg and 600 mcg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to <1 pg/mL at 5 hours post-dose. These data may not reflect drug level in mature milk and in a daily dosing regimen for osteoarthritis or rheumatoid arthritis.

Elimination

Metabolism

Diclofenac: Metabolism is predominantly mediated via CYP2C9 in the liver. Five metabolites (4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac) have been identified. The major metabolite (4'-hydroxy-diclofenac) has very weak pharmacologic activity.

Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac.

Misoprostol: Undergoes rapid and extensive metabolism to its biologically active metabolite, misoprostol acid.

Excretion

Diclofenac: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine and 35% in the bile. The elimination half-life of diclofenac is approximately 2 hours. The clearance of diclofenac is approximately 350 mL/min (equivalent to 21 L/h).

Conjugates of unchanged diclofenac account for 5% to 10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20% to 30% of the dose excreted in the urine and for 10% to 20% of the dose excreted in the bile.

Conjugates of three other metabolites together account for 10% to 20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life = 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity.

Misoprostol: After oral administration of radio-labeled misoprostol, approximately 70% of detected radioactivity appears in the urine. The elimination half-life is approximately 30 minutes.

Specific Populations

Geriatric Patients

No differences in the pharmacokinetics of diclofenac were observed in geriatric subjects (66 to 81 years; N=10) compared to younger adult subjects (26 to 46 years; N=10) following administration of diclofenac 50 mg twice daily for 4 weeks.

Though the mean AUC value of misoprostol acid for elderly subjects was 41% higher in geriatric healthy subjects (mean age, 69.5±4.6 years, N=24) compared to younger adult healthy subjects (mean age, 25.4±4.2 years, N=24) following single dose of misoprostol 400 μg, the increase in exposure is not clinically meaningful.

In a multiple-dose crossover study of diclofenac sodium and misoprostol delayed-release tablets administered twice daily to 24 subjects aged 65 years of age and older, misoprostol did not affect the pharmacokinetics of diclofenac [see Use in Specific Populations ( 8.5)] .

Racial or Ethnic Groups

Pharmacokinetic differences due to race have not been identified.

Patients with Renal Impairment

In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min) following intravenous administration of 50 mg diclofenac, AUC values and elimination rates were comparable to those in healthy subjects.

Pharmacokinetic studies with misoprostol in patients with severe renal impairment requiring hemodialysis (n=8, mean creatinine clearance 6.2±3.3 mL/min/1.73m 2) who received a single dose of 400 mcg misoprostol during a interdialytic period showed an approximate doubling of elimination half-life, C max, and AUC of misoprostol acid compared to healthy subjects [see Use in Specific Populations ( 8.6)] .

Patients with Hepatic Impairment

In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubin, N=10), diclofenac concentrations and urinary elimination values following administration of 100 mg oral solution were comparable to those in healthy subjects.

In a study of subjects with mild to moderate hepatic impairment, mean misoprostol acid AUC and C maxshowed approximately twice high as the mean values obtained in healthy subjects. Three subjects who had the lowest antipyrine and lowest indocyanine green clearance values had the highest misoprostol acid AUC and C maxvalues.

Drug Interaction Studies

Diclofenac

Aspirin:When diclofenac sodium and misoprostol delayed-release tablets was administered with aspirin, the protein binding of diclofenac was reduced, although the clearance of the free diclofenac was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions ( 7)] .

Voriconazole: When a single dose diclofenac (50 mg) was co-administered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2), the mean C maxand AUC of diclofenac were increased by 114% and 78%, respectively, when compared to diclofenac alone [see Drug Interactions ( 7)] .

In vitro, diclofenac interferes minimally with the protein binding of prednisolone (10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence, in vitro, on the protein binding of diclofenac in human serum.

Other drugs: In small groups of patients (7 to 10 patients/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline or digitoxin did not significantly affect C maxand AUC of diclofenac.

Misoprostol

Diazepam: Misoprostol given for 1 week had no effect on the steady-state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart.

Other drugs: Pharmacokinetic studies also showed a lack of drug interaction with antipyrine or propranolol given with misoprostol.

Carcinogenesis

Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of diclofenac sodium and misoprostol delayed-release tablets given alone.

In a 24 month rat carcinogenicity study, misoprostol administered orally at doses up to 2.4 mg/kg/day (14.4 mg/m 2/day, 24 times the MRHD of 0.6 mg/m 2/day) was not tumorigenic. In a 21-month mouse carcinogenicity study, misoprostol administered orally at doses up to 16 mg/kg/day (48 mg/m 2/day), 80 times the MRHD based on body surface area, was not tumorigenic.

In a 24-month rat carcinogenicity study, diclofenac sodium administered orally at up to 2 mg/kg/day (12 mg/m 2/day) was not tumorigenic. In a 24-month mouse carcinogenicity study, oral diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m 2/day, 0.006 times the MRHD based on body surface area) in males and 1 mg/kg/day (3 mg/m 2/day, 0.02 times the MRHD based on body surface area) in females was not tumorigenic.

Mutagenesis

Diclofenac sodium and misoprostol combination in 250:1 ratio was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test, or the mouse bone marrow micronucleus test.

Impairment of Fertility

The effects of diclofenac sodium and misoprostol on male or female fertility have not been studied in animals; however, there are data with diclofenac sodium and misoprostol given alone. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m 2/day, 1 to 100 times the MRHD based on body surface area) produced dose-related pre-and post-implantation losses and a significant decrease in the number of live pups born at the highest dose (60 mg/m 2/day, 100 times the MRHD based on body surface area). Diclofenac sodium at oral doses up to 4 mg/kg/day (24 mg/m 2/day, 0.16 times the MRHD based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.

Osteoarthritis

{ "type": "p", "children": [], "text": "\nOsteoarthritis\n" }

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis.

{ "type": "p", "children": [], "text": "Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis." }

Rheumatoid Arthritis

{ "type": "p", "children": [], "text": "\nRheumatoid Arthritis\n" }

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis.

{ "type": "p", "children": [], "text": "Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis." }

Upper Gastrointestinal Safety

{ "type": "p", "children": [], "text": "\nUpper Gastrointestinal Safety\n" }

Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in osteoarthritis and rheumatoid arthritis patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 3).

{ "type": "p", "children": [], "text": "Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in osteoarthritis and rheumatoid arthritis patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 3)." }

Table 3

{ "type": "p", "children": [], "text": "\nTable 3\n" }

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Misoprostol 200 mcg Dosage Regimen</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">two times a</span> <br/> <span class="Bold">day</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">three times a</span> <br/> <span class="Bold">day</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">four times a</span> <br/> <span class="Bold">day</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gastric ulcer <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">11% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">6%* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">3%* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">3%* <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Duodenal ulcer <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">6% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2%* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">3%* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1%* <br/> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" cellspacing=\"0pt\" width=\"100%\">\n<col width=\"20%\"/>\n<col width=\"20%\"/>\n<col width=\"20%\"/>\n<col width=\"20%\"/>\n<col width=\"20%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Misoprostol 200 mcg Dosage Regimen</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">  <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Placebo</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">two times a</span>\n<br/>\n<span class=\"Bold\">day</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">three times a</span>\n<br/>\n<span class=\"Bold\">day</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">four times a</span>\n<br/>\n<span class=\"Bold\">day</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Gastric ulcer <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">11% <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">6%* <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">3%* <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">3%* <br/>\n</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Duodenal ulcer <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">6% <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">2%* <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">3%* <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">1%* <br/>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

N=1623; 12 weeks

{ "type": "p", "children": [], "text": "N=1623; 12 weeks" }

*Misoprostol significantly different from placebo (p<0.05)

{ "type": "p", "children": [], "text": "*Misoprostol significantly different from placebo (p<0.05)" }

Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving  diclofenac sodium and misoprostol delayed-release tablets have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 4).

{ "type": "p", "children": [], "text": "Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving  diclofenac sodium and misoprostol delayed-release tablets have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 4)." }

Table 4

{ "type": "p", "children": [], "text": "\nTable 4\n" }

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="43%"/> <col width="42%"/> <col width="15%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Osteoarthritis patients with history of</span> <br/> <span class="Bold">ulcer or erosive disease (N=572), 6 weeks</span> <br/> </p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Incidence of ulcers</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastric</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Duodenal</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg three times a day <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">3%* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">6% <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg two times a day <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">4%* <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">3% <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diclofenac sodium 75 mg two times a day <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">11% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">7% <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Placebo <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">3% <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1% <br/> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" cellspacing=\"0pt\" width=\"100%\">\n<col width=\"43%\"/>\n<col width=\"42%\"/>\n<col width=\"15%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Osteoarthritis patients with history of</span>\n<br/>\n<span class=\"Bold\">ulcer or erosive disease (N=572), 6 weeks</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Incidence of ulcers</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Gastric</span>\n<br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Duodenal</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg three times a day <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">3%* <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">6% <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg two times a day <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">4%* <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">3% <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Diclofenac sodium 75 mg two times a day <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">11% <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">7% <br/>\n</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Placebo <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">3% <br/>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">1% <br/>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

*Statistically significantly different from diclofenac (p<0.05)

{ "type": "p", "children": [], "text": "*Statistically significantly different from diclofenac (p<0.05) \n" }

Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as a uncoated tablets in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol.

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as a uncoated tablets in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol." }

75 mg/200 mcg dosage strength is a white to off-white, round, biconvex uncoated tablet, debossed  with “D 75 M” on one side and plain on other side. 

{ "type": "p", "children": [], "text": "75 mg/200 mcg dosage strength is a white to off-white, round, biconvex uncoated tablet, debossed  with “D 75 M” on one side and plain on other side. \n" }

The dosage strengths are supplied in:

{ "type": "p", "children": [], "text": "The dosage strengths are supplied in:" }

{ "type": "", "children": [], "text": "" }

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. \n" }

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium and misoprostol delayed-release tablets and periodically during the course of ongoing therapy.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium and misoprostol delayed-release tablets and periodically during the course of ongoing therapy." }

Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs

{ "type": "p", "children": [], "text": "\nUterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs\n" }

{ "type": "", "children": [], "text": "" }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Advise females of reproductive potential that diclofenac sodium and misoprostol delayed-release tablets may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations ( 8.3)] .

{ "type": "p", "children": [], "text": "Advise females of reproductive potential that diclofenac sodium and misoprostol delayed-release tablets may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations ( 8.3)] . " }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events\n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions ( 5.2)] .

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions ( 5.2)] . " }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation\n" }

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ( 5.3)] .

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ( 5.3)] . " }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium and misoprostol delayed-release tablets and seek immediate medical therapy [see Warnings and Precautions ( 5.4)] .

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium and misoprostol delayed-release tablets and seek immediate medical therapy [see Warnings and Precautions ( 5.4)] . " }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema\n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions ( 5.6)] .

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions ( 5.6)] . " }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions\n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications ( 4) and Warnings and Precautions ( 5.8)] .  

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications ( 4) and Warnings and Precautions ( 5.8)] .   " }

Serious Skin Reactions, including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions, including DRESS\n" }

Advise patients to stop taking diclofenac sodium and misoprostol delayed-release tablets immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible [see Warnings and Precautions ( 5.10, 5.11)] .

{ "type": "p", "children": [], "text": "Advise patients to stop taking diclofenac sodium and misoprostol delayed-release tablets immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible [see Warnings and Precautions ( 5.10, 5.11)] . " }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs\n" }

Inform patients that the concomitant use of diclofenac sodium and misoprostol delayed-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions ( 5.3) and Drug Interactions ( 7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of diclofenac sodium and misoprostol delayed-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions ( 5.3) and Drug Interactions ( 7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. " }

Use of NSAIDS and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDS and Low-Dose Aspirin\n" }

Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium and misoprostol delayed-release tablets until they talk to their healthcare provider [see Drug Interactions ( 7)] .

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium and misoprostol delayed-release tablets until they talk to their healthcare provider [see Drug Interactions ( 7)] . " }

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.microlabsusa.com.

{ "type": "p", "children": [], "text": "This product’s labeling may have been updated. For the most recent prescribing information, please visit www.microlabsusa.com." }

Manufactured by: Micro Labs Limited INDIA.

{ "type": "p", "children": [], "text": "Manufactured by: \nMicro Labs Limited\n INDIA. " }

Manufactured for: Micro Labs USA, Inc. Somerset, NJ 08873

{ "type": "p", "children": [], "text": "Manufactured for: \nMicro Labs USA, Inc.\n Somerset, NJ 08873 " }

Rev. 12/2024

{ "type": "p", "children": [], "text": "\nRev. 12/2024 \n\n" }

Medication Guide for Diclofenac Sodium (dye-KLOE-fen-ak SOE-dee-um) and Misoprostol (MYE-soe-PROST-ol) Delayed-Release Tablets for oral use

{ "type": "p", "children": [], "text": "\nMedication Guide for \n\n Diclofenac Sodium (dye-KLOE-fen-ak SOE-dee-um) and Misoprostol (MYE-soe-PROST-ol) Delayed-Release Tablets \n\n for oral use \n" }

What is the most important information I should know about diclofenac sodium and misoprostol delayed-release tablets?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about diclofenac sodium and misoprostol delayed-release tablets?\n" }

Diclofenac sodium and misoprostol delayed-release tablets contains diclofenac (a nonsteroidal anti-inflammatory drug (NSAID)) and misoprostol, and can cause uterus to tear (uterine rupture), abortion, premature birth, or birth defects. The risk of uterine rupture increases as your pregnancy advances, if you have given birth to 5 or more children, and if you have had surgery on the uterus, such as a cesarean delivery.

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets contains diclofenac (a nonsteroidal anti-inflammatory drug (NSAID)) and misoprostol, and can cause uterus to tear (uterine rupture), abortion, premature birth, or birth defects. The risk of uterine rupture increases as your pregnancy advances, if you have given birth to 5 or more children, and if you have had surgery on the uterus, such as a cesarean delivery." }

Do not take diclofenac sodium and misoprostol delayed-release tablets if you are pregnant.

{ "type": "p", "children": [], "text": "\nDo not take diclofenac sodium and misoprostol delayed-release tablets if you are pregnant.\n" }

{ "type": "", "children": [], "text": "" }

What is the most important information I should know about medicines containing Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\n\n What is the most important information I should know about medicines containing Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? \n\nNSAIDs can cause serious side effects, including:\n" }

{ "type": "", "children": [], "text": "" }

Do not take NSAID containing medicines right before or after a heart surgery called a “coronary artery bypass graft (CABG)."

{ "type": "p", "children": [], "text": "\nDo not take NSAID containing medicines right before or after a heart surgery called a “coronary artery bypass graft (CABG).\"\n" }

Avoid taking NSAID containing medicines after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

{ "type": "p", "children": [], "text": "\nAvoid taking NSAID containing medicines after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.\n" }

{ "type": "", "children": [], "text": "" }

The risk of getting an ulcer or bleeding increases with:

{ "type": "p", "children": [], "text": "\nThe risk of getting an ulcer or bleeding increases with:\n" }

{ "type": "", "children": [], "text": "" }

NSAID containing medicines should only be used:

{ "type": "p", "children": [], "text": "\nNSAID containing medicines should only be used:\n" }

{ "type": "", "children": [], "text": "" }

What are diclofenac sodium and misoprostol delayed-release tablets?

{ "type": "p", "children": [], "text": "\nWhat are diclofenac sodium and misoprostol delayed-release tablets?\n" }

Diclofenac sodium and misoprostol delayed-release tablets contains 2 medicines:

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets contains 2 medicines: \n" }

1. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID). See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? 2. Misoprostol is a medicine used to protect the lining of the esophagus, stomach and intestines while taking diclofenac.

{ "type": "p", "children": [], "text": "1. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID). See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?\n 2. Misoprostol is a medicine used to protect the lining of the esophagus, stomach and intestines while taking diclofenac. " }

Diclofenac sodium and misoprostol delayed-release tablets are a prescription medicine used to treat:

{ "type": "p", "children": [], "text": "Diclofenac sodium and misoprostol delayed-release tablets are a prescription medicine used to treat:" }

{ "type": "", "children": [], "text": "" }

It is not known if diclofenac sodium and misoprostol delayed-release tablets are safe and effective for use in children.

{ "type": "p", "children": [], "text": "It is not known if diclofenac sodium and misoprostol delayed-release tablets are safe and effective for use in children." }

What are NSAIDs?

{ "type": "p", "children": [], "text": "\nWhat are NSAIDs?\n" }

NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis.

{ "type": "p", "children": [], "text": "NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis." }

Who should not take diclofenac sodium and misoprostol delayed-release tablets?

{ "type": "p", "children": [], "text": "\nWho should not take diclofenac sodium and misoprostol delayed-release tablets?\n" }

Do not take diclofenac sodium and misoprostol delayed-release tablets:

{ "type": "p", "children": [], "text": "\nDo not take diclofenac sodium and misoprostol delayed-release tablets:\n" }

{ "type": "", "children": [], "text": "" }

Before taking diclofenac sodium and misoprostol delayed-release tablets, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore taking diclofenac sodium and misoprostol delayed-release tablets, tell your healthcare provider about all of your medical conditions, including if you:\n" }

{ "type": "", "children": [], "text": "" }

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.NSAIDs and some other medicines can interact with each other and cause serious side effects . Do not start taking any new medicine without talking to your healthcare provider first.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.NSAIDs and some other medicines can interact with each other and cause serious side effects . Do not start taking any new medicine without talking to your healthcare provider first.\n" }

What are the possible side effects of NSAIDs?

{ "type": "p", "children": [], "text": "\n\n What are the possible side effects of NSAIDs? \n" }

NSAIDs can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nNSAIDs can cause serious side effects, including:\n" }

See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

{ "type": "p", "children": [], "text": "\nSee “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?\n" }

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Get emergency help right away if you get any of the following symptoms:

{ "type": "p", "children": [], "text": "\nGet emergency help right away if you get any of the following symptoms:\n" }

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>shortness of breath or trouble breathing</dd> </dl> </td><td class="Botrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>slurred speech</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>chest pain</dd> </dl> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>swelling of the face or throat</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>weakness in one part or side of your body</dd> </dl> </td><td class="Botrule Rrule" valign="top"> <p class="First">  <br/> </p> </td> </tr> </tbody> </table></div>

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Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

{ "type": "p", "children": [], "text": "\nStop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:\n" }

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>nausea</dd> </dl> </td><td class="Botrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>vomit blood</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>more tired or weaker than usual</dd> </dl> </td><td class="Botrule Rrule" rowspan="2" valign="top"> <dl> <dt>•</dt> <dd>there is blood in your bowel movement or it is black and sticky like tar</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>diarrhea</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>itching</dd> </dl> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>unusual weight gain</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>your skin or eyes look yellow</dd> </dl> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>skin rash or blister with fever</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>indigestion or stomach pain</dd> </dl> </td><td class="Botrule Rrule" rowspan="2" valign="top"> <dl> <dt>•</dt> <dd>swelling of the arms, legs, hands and feet</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>flu-like symptoms</dd> </dl> </td> </tr> </tbody> </table></div>

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If you take too much of your NSAID, call your healthcare provider or get medical help right away.

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These are not all the possible side effects of NSAIDs. For more information, ask your healthcare  provider or pharmacist about NSAIDs.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of NSAIDs. For more information, ask your healthcare  provider or pharmacist about NSAIDs." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Other information about NSAIDs

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General information about the safe and effective use of NSAIDs

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of NSAIDs\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them." }

If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

{ "type": "p", "children": [], "text": "If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals." }

Active ingredients:diclofenac sodium, misoprostol.

{ "type": "p", "children": [], "text": "\nActive ingredients:diclofenac sodium, misoprostol. " }

Inactive ingredients:colloidal silicon dioxide, corn starch, crospovidone, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone, sodium hydroxide, talc, triethyl citrate.

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This product’s labeling may have been updated. For the most recent prescribing information, please visit www.microlabsusa.com.

{ "type": "p", "children": [], "text": "This product’s labeling may have been updated. For the most recent prescribing information, please visit www.microlabsusa.com." }

For more information, go to www.microlabsusa.com or call 1-855-839-8195.

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This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Manufactured by: Micro Labs Limited INDIA. Manufactured for: Micro Labs USA, Inc. Somerset, NJ 08873 Rev. 12/2024

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Repackaged By: Preferred Pharmaceuticals Inc.

{ "type": "p", "children": [], "text": "\nRepackaged By: Preferred Pharmaceuticals Inc.\n" }

NDC 68788-8214

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  Rx Only Diclofenac Sodium and Misoprostol Delayed- Release Tablets, USP 75 mg/ 200 mcg Pharmacist: Dispense the enclosed Medication Guide to each patient. MICRO LABS LIMITED

{ "type": "p", "children": [], "text": "  Rx Only Diclofenac Sodium and Misoprostol Delayed- Release Tablets, USP 75 mg/ 200 mcg Pharmacist: Dispense the enclosed Medication Guide to each patient. \n MICRO LABS LIMITED " }

Repackaged By: Preferred Pharmaceuticals Inc.

{ "type": "p", "children": [], "text": "\n\nRepackaged By: Preferred Pharmaceuticals Inc.\n" }

Diclofenac sodium gel is indicated for the topical treatment of actinic keratoses (AK).

{ "type": "p", "children": [], "text": "Diclofenac sodium gel is indicated for the topical treatment of actinic keratoses (AK)." }

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

{ "type": "p", "children": [], "text": "Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]." }

Apply diclofenac sodium gel gently to lesion areas twice daily. to adequately cover each lesion. Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. Avoid contact of diclofenac sodium gel with eyes and mucous membranes.

{ "type": "p", "children": [], "text": "Apply diclofenac sodium gel gently to lesion areas twice daily. to adequately cover each lesion. Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. Avoid contact of diclofenac sodium gel with eyes and mucous membranes." }

Topical gel, 3%. Each gram of Diclofenac Sodium Topical Gel contains 30 mg of diclofenac sodium, USP in a clear, transparent, colorless to slightly yellow gel base. Diclofenac Sodium Gel, 3% is supplied in 100 g tubes.

{ "type": "p", "children": [], "text": "Topical gel, 3%. Each gram of Diclofenac Sodium Topical Gel contains 30 mg of diclofenac sodium, USP in a clear, transparent, colorless to slightly yellow gel base. Diclofenac Sodium Gel, 3% is supplied in 100 g tubes." }

Diclofenac sodium gel is contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Diclofenac sodium gel is contraindicated in the following patients:" }

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Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications () and Warnings and Precautions (5.2)].

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium gel is contraindicated in patients with this form of aspirin sensitivity. When diclofenac sodium gel is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium gel at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium gel is contraindicated in patients with previous serious skin reactions to NSAIDs. Do not apply diclofenac sodium gel to open skin wounds, infections, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug [see Contraindications ()].

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first-year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of diclofenac sodium gel in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium gel is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including diclofenac, cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-Treated Patients:

In clinical trials with diclofenac sodium gel, 2 to 3% of subjects had elevations of liver function tests (LFTs) [see Clinical Trials Experience (6.1)]. To minimize the potential risk for an adverse liver-related event in patients treated with diclofenac sodium gel, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium gel with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium gel should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium gel immediately, and perform a clinical evaluation of the patient.

NSAIDs, including diclofenac sodium gel, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)].

Avoid the use of diclofenac sodium gel in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium gel is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical trials regarding the use of diclofenac sodium gel in patients with advanced renal disease. The renal effects of diclofenac sodium gel may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium gel. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium gel [see Drug Interactions (7)].Avoid the use of diclofenac sodium gel in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium gel is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium gel. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium gel and evaluate the patient immediately.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including diclofenac sodium gel, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium gel, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If, after careful consideration of alternative treatment options for actinic keratoses, NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium gel use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac treatment extends beyond 48 hours. Discontinue diclofenac sodium gel if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium gel has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac sodium gel, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

The pharmacological activity of diclofenac sodium gel in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (,5.6, 5.9)].

Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using diclofenac sodium gel. If patients need to be outdoors while using diclofenac sodium gel, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Advise patients to discontinue treatment with diclofenac sodium gel at the first evidence of sunburn.

Avoid contact of diclofenac sodium gel with eyes and mucosa. Advise patients that if contact in the eye, or mucosal membranes occurs, immediately wash out the eye or mucosal membranes with water or saline and consult a physician if irritation persists for more than an hour.

Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use diclofenac sodium gel in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Of the 423 subjects evaluable for safety in adequate and well-controlled trials, 211 were treated with diclofenac sodium gel drug product and 212 were treated with a vehicle gel. Eighty-seven percent (87%) of the diclofenac sodium gel-treated subjects (183 subjects) and 84% of the vehicle-treated subjects (178 subjects) experienced one or more adverse events (AEs) during the trials. The majority of these reactions were mild to moderate in severity and resolved upon discontinuation of therapy.

Of the 211 subjects treated with diclofenac sodium gel, 172 (82%) experienced AEs involving skin and the application site compared to 160 (75%) vehicle-treated subjects. Application site reactions (ASRs) were the most frequent AEs in both diclofenac sodium gel-and vehicle-treated groups. Of note, four reactions, contact dermatitis, rash, dry skin and exfoliation(scaling) were significantly more prevalent in the diclofenac sodium gel group than in the vehicle-treated subjects.

Eighteen percent of diclofenac sodium gel-treated subjects and 4% of vehicle-treated subjects discontinued from the clinical trials due to adverse events (whether considered related to treatment or not). These discontinuations were mainly due to skin irritation or related cutaneous adverse reactions.

Table 1 below presents the AEs reported at an incidence of >1% for subjects treated with either diclofenac sodium gel or vehicle (60- and 90-day treatment groups) during the phase 3 trials.

Table 1. Adverse Events Reported (>1% in Any Treatment Group) During Diclofenac Sodium Gel Phase 3 Clinical Trials Incidences for 60-Day and 90-Day Treatments

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="37%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="17%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">60-day Treatment</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">90-day Treatment</span></th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" valign="top"></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Diclofenac Sodium Gel (%) </span> <br/> </th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gel Vehicle (%) </span> <br/> </th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Diclofenac Sodium Gel (%) </span> <br/> </th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gel Vehicle (%)</span> <br/> </th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top"></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">N=48</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">N=49</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">N=114</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">N=114</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">BODY AS A WHOLE</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">21</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">20</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">20</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">18</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Abdominal Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Accidental Injury</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Allergic Reaction</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Asthenia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Back Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Chest Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Chills</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Flu Syndrome</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Headache</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Infection</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Neck Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">CARDIOVASCULAR SYSTEM</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">4</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">3</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">1</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypertension</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Migraine</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Phlebitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">DIGESTIVE SYSTEM</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">4</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">6</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">8</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Constipation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diarrhea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dyspepsia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">METABOLIC AND NUTRITIONAL DISORDERS</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">8</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">7</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Creatine Phosphokinase Increased</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Creatinine Increased</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Edema</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypercholesteremia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hyperglycemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>SGOT Increased</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>SGPT Increased</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">MUSCULOSKELETAL SYSTEM</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">4</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">3</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">4</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Arthralgia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Arthrosis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Myalgia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">NERVOUS SYSTEM</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">5</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Anxiety</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dizziness</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypokinesia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">RESPIRATORY SYSTEM</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">8</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">8</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">7</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">6</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Asthma</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dyspnea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pharyngitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pneumonia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Rhinitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Sinusitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">SKIN AND APPENDAGES</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">75</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">86</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">86</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">71</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Acne</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Application Site Reaction</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">75</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">71</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">84</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">70</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Acne</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Alopecia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Contact Dermatitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">33</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dry Skin</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Edema</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Exfoliation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hyperesthesia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Paresthesia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Photosensitivity Reaction</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pruritus</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">31</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">59</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">52</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">45</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Rash</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">35</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">46</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vesiculobullous Rash</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Contact Dermatitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dry Skin</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Herpes Simplex</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Maculopapular Rash</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pruritus</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Rash</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Skin Carcinoma</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Skin Nodule</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Skin Ulcer</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">SPECIAL SENSES</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">4</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Conjunctivitis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Eye Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">UROGENITAL SYSTEM</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">4</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">5</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hematuria</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">OTHER</span> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">0</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">3</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Procedure</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> </tbody> </table></div>

Skin and Appendages Adverse Events Reported for Diclofenac Sodium Gel at Less Than 1% Incidence in the Phase 3 Studies: skin hypertrophy, paresthesia, seborrhea, urticaria, application site reactions (skin carcinoma, hypertonia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation).

Adverse Reactions Reported for Oral Diclofenac Dosage Form (not topical diclofenac sodium gel): *Incidence Greater than 1% marked with asterisk.

Body as a Whole: abdominal pain or cramps*, headache*, fluid retention*, abdominal distention*, malaise, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions, chest pain.

Cardiovascular: hypertension, congestive heart failure, palpitations, flushing, tachycardia, premature ventricular contractions, myocardial infarction, hypotension.

Digestive: diarrhea*, indigestion*, nausea*, constipation*, flatulence*, liver test abnormalities*, PUB*, i.e., peptic ulcer, with or without bleeding and/or perforation, or bleeding without ulcer, vomiting, jaundice, melena, esophageal lesions, aphthous stomatitis, dry mouth and mucous membranes, bloody diarrhea, hepatitis, hepatic necrosis, cirrhosis, hepatorenal syndrome, appetite change, pancreatitis with or without concomitant hepatitis, colitis, intestinal perforation.

Hemic and Lymphatic: hemoglobin decrease, leukopenia, thrombocytopenia, eosinophilia, hemolytic anemia, aplastic anemia, agranulocytosis, purpura, allergic purpura, bruising.

Metabolic and Nutritional Disorders: azotemia, hypoglycemia, weight loss.

Nervous System: dizziness*, insomnia, drowsiness, depression, diplopia, anxiety, irritability, aseptic meningitis, convulsions, paresthesia, memory disturbance, nightmares, tremor, tic, abnormal coordination, disorientation, psychotic reaction.

Respiratory: epistaxis, asthma, laryngeal edema, dyspnea, hyperventilation, edema of pharynx.

Skin and Appendages: rash*, pruritus*, alopecia, urticaria, eczema, dermatitis, bullous eruption, erythema multiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis.

Special Senses: tinnitus*, blurred vision, taste disorder, reversible and irreversible hearing loss, scotoma, vitreous floaters, night blindness, amblyopia.

Urogenital: nephrotic syndrome, proteinuria, oliguria, interstitial nephritis, papillary necrosis, acute renal failure, urinary frequency, nocturia, hematuria, impotence, vaginal bleeding.

The following adverse reactions have been identified during post-approval use of diclofenac sodium gel and other topical diclofenac products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions from diclofenac sodium gel: burning sensation, hypersensitivity.

Adverse reactions from other topical diclofenac products: hypoesthesia, gait disturbance, musculoskeletal stiffness.

Skin and Appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

See Table 2 for clinically significant drug interactions with diclofenac.

{ "type": "p", "children": [], "text": "See Table 2 for clinically significant drug interactions with diclofenac." }

Table 2: Clinically Significant Drug Interactions with Diclofenac

{ "type": "p", "children": [], "text": "\nTable 2: Clinically Significant Drug Interactions with Diclofenac\n" }

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="19%"/> <col width="81%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Drugs That Interfere with Hemostasis</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</dd> <dt>•</dt> <dd>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Monitor patients with concomitant use of diclofenac sodium gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class="Italics">[see Warnings and Precautions (</span><span class="Italics">)]</span>.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Aspirin</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class="Italics">[see Warnings and Precautions (</span><span class="Italics">)]</span>.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Concomitant use of diclofenac sodium gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class="Italics">[see Warnings and Precautions (<a href="#ID_c4efb948-81dc-4033-8f95-e778f824b3ca">5.12</a>)]</span>. Diclofenac sodium gel is not a substitute for low dose aspirin for cardiovascular protection.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</dd> <dt>•</dt> <dd>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</dd> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class="Italics">[see Warnings and Precautions (<a href="#ID_d4596a18-840f-44c8-a3ff-161f95300d04">5.9</a>)]</span>.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class="Italics">[see Warnings and Precautions (<a href="#ID_d4596a18-840f-44c8-a3ff-161f95300d04">5.9</a>)]</span>.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Digoxin</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and digoxin, monitor serum digoxin levels.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Lithium</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and lithium, monitor patients for signs of lithium toxicity.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Methotrexate</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and methotrexate, monitor patients for methotrexate toxicity.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cyclosporine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Concomitant use of diclofenac sodium gel and cyclosporine may increase cyclosporine’s nephrotoxicity.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and cyclosporine, monitor patients for signs of worsening renal function.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">NSAIDs and Salicylates</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Concomitant use of diclofenac sodium gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity <span class="Italics">[see Warnings and Precautions (</span><span class="Italics">)]</span>.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>The concomitant use of diclofenac sodium gel with other NSAIDs or salicylates is not recommended.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Pemetrexed</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Concomitant use of diclofenac sodium gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>During concomitant use of diclofenac sodium gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"19%\"/>\n<col width=\"81%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs That Interfere with Hemostasis</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</dd>\n<dt>•</dt>\n<dd>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Monitor patients with concomitant use of diclofenac sodium gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\">)]</span>.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Aspirin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\">)]</span>.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Concomitant use of diclofenac sodium gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#ID_c4efb948-81dc-4033-8f95-e778f824b3ca\">5.12</a>)]</span>. Diclofenac sodium gel is not a substitute for low dose aspirin for cardiovascular protection.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</dd>\n<dt>•</dt>\n<dd>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</dd>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#ID_d4596a18-840f-44c8-a3ff-161f95300d04\">5.9</a>)]</span>.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#ID_d4596a18-840f-44c8-a3ff-161f95300d04\">5.9</a>)]</span>.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Digoxin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and digoxin, monitor serum digoxin levels.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Lithium</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and lithium, monitor patients for signs of lithium toxicity.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Methotrexate</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and methotrexate, monitor patients for methotrexate toxicity.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Cyclosporine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Concomitant use of diclofenac sodium gel and cyclosporine may increase cyclosporine’s nephrotoxicity.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and cyclosporine, monitor patients for signs of worsening renal function.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NSAIDs and Salicylates</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Concomitant use of diclofenac sodium gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\">)]</span>.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>The concomitant use of diclofenac sodium gel with other NSAIDs or salicylates is not recommended.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Pemetrexed</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Concomitant use of diclofenac sodium gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).</dd>\n</dl>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>During concomitant use of diclofenac sodium gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of NSAIDs, including diclofenac sodium gel, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium gel use between about 20 and 30 weeks of gestation and avoid diclofenac sodium gel use at about 30 weeks of gestation and later in pregnancy.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including diclofenac sodium gel, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

In animal reproduction studies, no evidence of malformations was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses at least 15 times, the maximum recommended human dose (MRHD) of diclofenac sodium gel (see Data). Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization, and administration of prostaglandin synthesis inhibitors such as diclofenac sodium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium gel, can cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

If after careful consideration of alternative treatment options for actinic keratoses, an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium gel treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium gel and follow up according to clinical practice.

Labor or Delivery

There are no studies on the effects of diclofenac sodium gel during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use.

Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

The multiples provided in this labeling are based on an MRHD that assumes 10% bioavailability following topical application of 2 g diclofenac sodium gel per day (1 mg/kg diclofenac sodium).

Reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the MRHD based on body surface area (BSA) comparisons) in mice, 10 mg/kg/day (15 times the MRHD based on BSA comparisons) in rats, and 10 mg/kg/day (30 times the MRHD based on BSA comparisons) in rabbits have revealed no evidence of malformations despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats.

Risk Summary

Data from published literature cases with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium gel and any potential adverse effects on the breastfed infant from the diclofenac sodium gel or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). The systemic bioavailability after topical application of diclofenac sodium gel is lower than after oral dosing [see Clinical Pharmacology (12.3)].

Female Infertility

Based on the mechanism of action, the use of prostaglandin mediated NSAIDs, including diclofenac sodium gel, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)].

Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium gel, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Actinic keratoses is not a condition seen within the pediatric population. diclofenac sodium gel should not be used by children.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.4, 5.5, 5.6, 5.9, 5.14)].

Of the 211 subjects treated with diclofenac sodium gel in controlled clinical trials, 143 subjects were 65 years of age and over. Of those 143 subjects, 55 subjects were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, and coma have been reported. [see Warnings and Precautions (5.4, 5.5, 5.7, 5.9)].

{ "type": "p", "children": [], "text": "Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, and coma have been reported. [see Warnings and Precautions (5.4, 5.5, 5.7, 5.9)]." }

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

{ "type": "p", "children": [], "text": "Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding." }

In the event of oral ingestion, resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac.

{ "type": "p", "children": [], "text": "In the event of oral ingestion, resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac." }

For additional information about overdosage treatment, call a poison control center (1-800-222-1222).

{ "type": "p", "children": [], "text": "For additional information about overdosage treatment, call a poison control center (1-800-222-1222)." }

Diclofenac Sodium Topical Gel, 3%, intended for dermatologic use, contains the active ingredient, diclofenac sodium, USP in a clear, transparent, colorless to slightly yellow gel base. Diclofenac sodium, USP is a white to slightly yellowish, hygroscopic crystalline powder, and melts at about 284°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insoluble in chloroform and ether. The chemical name for diclofenac sodium is:

{ "type": "p", "children": [], "text": "Diclofenac Sodium Topical Gel, 3%, intended for dermatologic use, contains the active ingredient, diclofenac sodium, USP in a clear, transparent, colorless to slightly yellow gel base. Diclofenac sodium, USP is a white to slightly yellowish, hygroscopic crystalline powder, and melts at about 284°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insoluble in chloroform and ether. The chemical name for diclofenac sodium is:" }

Sodium [o-(2,6-dichloranilino) phenyl] acetate

{ "type": "p", "children": [], "text": "Sodium [o-(2,6-dichloranilino) phenyl] acetate " }

Diclofenac sodium has a molecular weight of 318.13.

{ "type": "p", "children": [], "text": "Diclofenac sodium has a molecular weight of 318.13." }

The CAS number is CAS-15307-79-6. The structural formula is represented below:

{ "type": "p", "children": [], "text": "The CAS number is CAS-15307-79-6. The structural formula is represented below:" }

Diclofenac Sodium Gel, 3% also contains benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water.

{ "type": "p", "children": [], "text": "Diclofenac Sodium Gel, 3% also contains benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water. " }

1 g of Diclofenac Sodium Topical Gel, 3% contains 30 mg of the active substance, diclofenac sodium, USP.

{ "type": "p", "children": [], "text": "1 g of Diclofenac Sodium Topical Gel, 3% contains 30 mg of the active substance, diclofenac sodium, USP." }

The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown.

The pharmacodynamics of diclofenac sodium gel in the treatment of actinic keratosis has not been assessed.

Absorption

Diclofenac levels were measured at the end of treatment from 60 patients with AK lesions treated with diclofenac sodium gel in three adequate and well-controlled clinical trials. Each patient was administered 0.5 g of diclofenac sodium gel twice a day for up to 105 days. There were up to three 5 cm x 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. Serum concentrations of diclofenac were, on average, at or below 20 ng/mL.

Distribution

Diclofenac binds tightly to serum albumin.

Metabolism

Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise.

Elimination

Diclofenac and its metabolites are excreted mainly in the urine after oral dosing.

There did not appear to be any increase in drug-related neoplasms following daily topical applications of diclofenac sodium gel for 2 years at concentrations up to 0.035% diclofenac sodium and 2.5% hyaluronate sodium in albino mice.

When administered orally for 2 years, diclofenac showed no evidence of carcinogenic potential in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the MRHD based on BSA comparison), or in mice given diclofenac sodium at up to 0.3 mg/kg/day in males and 1 mg/kg/day in females (25% and 83%, respectively, of the MRHD based on BSA comparison).

Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also negative in the transformation assay utilizing BALB/3T3 mouse embryo cells.

Fertility studies have not been conducted with diclofenac sodium gel. Diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the MRHD based on BSA comparison) in male or female rats.

Clinical trials were conducted involving a total of 427 patients (213 treated with diclofenac sodium gel and 214 with a gel vehicle). Each patient had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any patient. All patients were 18 years of age or older (male and female) with no clinically significant medical problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel, 50% glycolic acid peel) and hyaluronan-containing cosmetics. Patients were excluded from participation for reasons of known or suspected hypersensitivity to any diclofenac sodium gel ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Patients were instructed to apply a small amount of diclofenac sodium gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the primary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence.

{ "type": "p", "children": [], "text": "Clinical trials were conducted involving a total of 427 patients (213 treated with diclofenac sodium gel and 214 with a gel vehicle). Each patient had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any patient. All patients were 18 years of age or older (male and female) with no clinically significant medical problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel, 50% glycolic acid peel) and hyaluronan-containing cosmetics. Patients were excluded from participation for reasons of known or suspected hypersensitivity to any diclofenac sodium gel ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Patients were instructed to apply a small amount of diclofenac sodium gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the primary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence." }

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="27%"/> <col width="22%"/> <col width="26%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (all locations)</span> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">Diclofenac Sodium Gel</span> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">Vehicle</span> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">p-value</span> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Study 1 90 days treatment</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>27/58 (47%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>11/59 (19%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>&lt;0.001</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Study 2 90 days treatment</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>18/53 (34%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>10/55 (18%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.061</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Study 3 60 days treatment</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15/48 (31%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5/49 (10%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.021</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>30 days treatment</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>7/49 (14%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/49 (4%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.221</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"27%\"/>\n<col width=\"22%\"/>\n<col width=\"26%\"/>\n<col width=\"25%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (all locations)</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Diclofenac Sodium Gel</span>\n</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Vehicle</span>\n</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">p-value</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Study 1 90 days treatment</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>27/58 (47%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>11/59 (19%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>&lt;0.001</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Study 2 90 days treatment</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>18/53 (34%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>10/55 (18%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.061</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Study 3 60 days treatment</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>15/48 (31%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>5/49 (10%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.021</dd>\n</dl>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>30 days treatment</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>7/49 (14%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/49 (4%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.221</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="27%"/> <col width="14%"/> <col width="15%"/> <col width="14%"/> <col width="16%"/> <col width="15%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" colspan="6" valign="top"><span class="Bold">Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (by location)</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top"></th><th align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Scalp</span></th><th align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Forehead</span></th><th align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Face</span></th><th align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Arm/Forearm</span></th><th align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Back of Hand</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Study 1</p> <p>90 days </p> <p>treatment</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diclofenac Sodium Gel</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1/4 (25%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>17/30 (57%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>9/17 (53%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>4/12 (33%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6/16 (38%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vehicle</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>3/9 (33%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>8/24 (33%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5/17 (29%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>4/12 (33%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/14 (0)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.7646</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0908</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.1682</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.000</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0650</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 2</p> <p>90 days </p> <p>treatment</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diclofenac Sodium Gel </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/6 (33%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>9/19 (47%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>4/5 (80%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5/8 (63%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1/17 (6%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vehicle </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/4 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6/22 (27%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/8 (25%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/5 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>3/16 (19%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.4235</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.1870</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0727</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0888</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.2818</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 3</p> <p>60 days </p> <p>treatment</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diclofenac Sodium Gel </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>3/7 (43%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>13/31 (42%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">10/19 (53%)</p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/1 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/8 (25%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vehicle </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/6 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5/36 (14%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/13 (15%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/2 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1/9 (11%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.2271</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0153</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0433</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>-</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.4637</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 3</p> <p>30 days </p> <p>treatment</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diclofenac Sodium Gel </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/5 (40%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>4/29 (14%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>3/14 (21%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/0 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/9 (0)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vehicle </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/5 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/29 (7%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2/18 (11%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0/1 (0)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1/9 (11%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.2299</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.3748</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.4322</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>-</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.6521</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">All data </p> <p>combined</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diclofenac Sodium Gel </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>8/22 (36%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>43/109 (39%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">26/55 (47%)</p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>9/21 (43%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>9/50 (18%)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vehicle </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>3/24 (13%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>21/111 (19%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">11/56 (20%)</p> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>4/20 (20%)</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5/48 (10%)</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0903</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0013</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.0016</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.2043</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.3662</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"27%\"/>\n<col width=\"14%\"/>\n<col width=\"15%\"/>\n<col width=\"14%\"/>\n<col width=\"16%\"/>\n<col width=\"15%\"/>\n<thead>\n<tr class=\"First\">\n<th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"6\" valign=\"top\"><span class=\"Bold\">Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (by location)</span></th>\n</tr>\n<tr class=\"Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"></th><th align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Bold\">Scalp</span></th><th align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Bold\">Forehead</span></th><th align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Bold\">Face</span></th><th align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Bold\">Arm/Forearm</span></th><th align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Bold\">Back of Hand</span></th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Study 1</p>\n<p>90 days </p>\n<p>treatment</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Diclofenac Sodium Gel</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>1/4 (25%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>17/30 (57%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>9/17 (53%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>4/12 (33%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>6/16 (38%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Vehicle</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>3/9 (33%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>8/24 (33%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>5/17 (29%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>4/12 (33%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/14 (0)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>p-value</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.7646</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0908</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.1682</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>1.000</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0650</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Study 2</p>\n<p>90 days </p>\n<p>treatment</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Diclofenac Sodium Gel </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/6 (33%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>9/19 (47%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>4/5 (80%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>5/8 (63%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>1/17 (6%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Vehicle </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/4 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>6/22 (27%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/8 (25%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/5 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>3/16 (19%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>p-value</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.4235</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.1870</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0727</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0888</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.2818</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Study 3</p>\n<p>60 days </p>\n<p>treatment</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Diclofenac Sodium Gel </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>3/7 (43%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>13/31 (42%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">10/19 (53%)</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/1 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/8 (25%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Vehicle </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/6 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>5/36 (14%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/13 (15%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/2 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>1/9 (11%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>p-value</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.2271</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0153</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0433</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>-</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.4637</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Study 3</p>\n<p>30 days </p>\n<p>treatment</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Diclofenac Sodium Gel </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/5 (40%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>4/29 (14%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>3/14 (21%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/0 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/9 (0)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Vehicle </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/5 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/29 (7%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2/18 (11%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0/1 (0)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>1/9 (11%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>p-value</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.2299</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.3748</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.4322</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>-</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.6521</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">All data </p>\n<p>combined</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Diclofenac Sodium Gel </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>8/22 (36%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>43/109 (39%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">26/55 (47%)</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>9/21 (43%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>9/50 (18%)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>Vehicle </dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>3/24 (13%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>21/111 (19%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">11/56 (20%)</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>4/20 (20%)</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>5/48 (10%)</dd>\n</dl>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>p-value</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0903</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0013</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.0016</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.2043</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0.3662</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Each gram of Diclofenac Sodium Topical Gel, 3% contains 30 mg of diclofenac sodium, USP. Diclofenac Sodium Gel, 3% is available as follows:

{ "type": "p", "children": [], "text": "Each gram of Diclofenac Sodium Topical Gel, 3% contains 30 mg of diclofenac sodium, USP. Diclofenac Sodium Gel, 3% is available as follows:" }

{ "type": "", "children": [], "text": "" }

Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from heat. Avoid freezing.

{ "type": "p", "children": [], "text": "\nStorage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from heat. Avoid freezing." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium gel and periodically during the course of ongoing therapy.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium gel and periodically during the course of ongoing therapy." }

Special Application Instructions

{ "type": "p", "children": [], "text": "\nSpecial Application Instructions\n" }

{ "type": "", "children": [], "text": "" }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions\n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications () and Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications () and Warnings and Precautions (5.1)]." }

Exacerbation of Asthma Related to Aspirin Sensitivity

{ "type": "p", "children": [], "text": "\nExacerbation of Asthma Related to Aspirin Sensitivity\n" }

Inform patients with aspirin sensitive asthma not to use diclofenac sodium gel. Advise patients with preexisting asthma to report any changes in the signs and symptoms of asthma to their healthcare provider [see Contraindications () and Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients with aspirin sensitive asthma not to use diclofenac sodium gel. Advise patients with preexisting asthma to report any changes in the signs and symptoms of asthma to their healthcare provider [see Contraindications () and Warnings and Precautions (5.2)]." }

Serious Skin Reactions including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions including DRESS\n" }

Advise patients to stop using diclofenac sodium gel immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.3, 5.10)].

{ "type": "p", "children": [], "text": "Advise patients to stop using diclofenac sodium gel immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.3, 5.10)]." }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events\n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.4)]." }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation\n" }

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ()].

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ()]." }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). Inform the patient that diclofenac sodium gel may increase the risk of elevated liver enzymes. Advise the patient that laboratory evaluation is needed prior to and periodically during treatment. Advise the patient that if signs or symptoms of liver injury occur, discontinue diclofenac sodium gel and seek medical advice promptly [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). Inform the patient that diclofenac sodium gel may increase the risk of elevated liver enzymes. Advise the patient that laboratory evaluation is needed prior to and periodically during treatment. Advise the patient that if signs or symptoms of liver injury occur, discontinue diclofenac sodium gel and seek medical advice promptly [see Warnings and Precautions (5.6)]." }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema\n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.8)]." }

Female Fertility

{ "type": "p", "children": [], "text": "\nFemale Fertility\n" }

Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium gel, may be associated with reversible delay in ovulation [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium gel, may be associated with reversible delay in ovulation [see Use in Specific Populations (8.3)]." }

Fetal Toxicity

{ "type": "p", "children": [], "text": "\nFetal Toxicity\n" }

Inform pregnant women to avoid use of diclofenac sodium gel and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with diclofenac sodium gel is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform pregnant women to avoid use of diclofenac sodium gel and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with diclofenac sodium gel is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]." }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs\n" }

Inform patients that the concomitant use of diclofenac sodium gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity [see Warnings and Precautions ()and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of diclofenac sodium gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity [see Warnings and Precautions ()and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia." }

Use of NSAIDS and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDS and Low-Dose Aspirin\n" }

Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium gel until they talk to their healthcare provider [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium gel until they talk to their healthcare provider [see Drug Interactions (7)]." }

Exposure to Eyes and Mucosal Membranes

{ "type": "p", "children": [], "text": "\nExposure to Eyes and Mucosal Membranes\n" }

Instruct patients to avoid contact of diclofenac sodium gel with the eyes and mucosal membranes. Advise patients that if eye or mucosal membrane contact occurs, immediately wash out with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions (5.16)].

{ "type": "p", "children": [], "text": "Instruct patients to avoid contact of diclofenac sodium gel with the eyes and mucosal membranes. Advise patients that if eye or mucosal membrane contact occurs, immediately wash out with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions (5.16)]." }

Trademarks are the property of their respective owners.

{ "type": "p", "children": [], "text": "Trademarks are the property of their respective owners." }

Medication Guide available at

{ "type": "p", "children": [], "text": "\nMedication Guide available at\n" }

www.glenmarkpharma-us.com/medguides

{ "type": "p", "children": [], "text": "\nwww.glenmarkpharma-us.com/medguides\n" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Glenmark Pharmaceuticals Limited

{ "type": "p", "children": [], "text": "\nGlenmark Pharmaceuticals Limited\n" }

Colvale-Bardez, Goa 403513, India

{ "type": "p", "children": [], "text": "Colvale-Bardez, Goa 403513, India" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Glenmark Pharmaceuticals Inc., USA

{ "type": "p", "children": [], "text": "\nGlenmark Pharmaceuticals Inc., USA\n" }

Mahwah, NJ 07430

{ "type": "p", "children": [], "text": "Mahwah, NJ 07430" }

Questions? 1 (888) 721-7115

{ "type": "p", "children": [], "text": "Questions? 1 (888) 721-7115" }

www.glenmarkpharma-us.com

{ "type": "p", "children": [], "text": "www.glenmarkpharma-us.com" }

January 2025

{ "type": "p", "children": [], "text": "January 2025" }

Relabeled By: Preferred Pharmaceuticals Inc.

{ "type": "p", "children": [], "text": "\nRelabeled By: Preferred Pharmaceuticals Inc.\n" }

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dispense with Medication Guide available at:</span> </p> <p> <span class="Bold"><a href="http://www.glenmarkpharma-us.com/medguides">www.glenmarkpharma-us.com/medguides</a></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">Diclofenac Sodium (dye-KLOE-fen-ak SOE-dee-um)</span> <br/> <span class="Bold">Gel</span> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about diclofenac sodium gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</span> </p> <p> <span class="Bold">NSAIDs can cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Increased risk of a heart attack or stroke that can lead to death</span>. This risk may happen early in treatment and may increase:<dl> <dt>o</dt> <dd>with increasing doses of NSAIDs</dd> <dt>o</dt> <dd>with longer use of NSAIDs</dd> </dl> </dd> </dl> <p> <span class="Bold">Do not take or use NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)”. Avoid taking NSAIDs after a recent heart attack unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take or use NSAIDs after a recent heart attack.</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:</span> <dl> <dt>o</dt> <dd>anytime during use</dd> <dt>o</dt> <dd>without warning symptoms</dd> <dt>o</dt> <dd>that may cause death</dd> </dl> </dd> </dl> <p> <span class="Bold">The risk of getting an ulcer or bleeding increases with:</span> </p> <dl> <dt>•</dt> <dd>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</dd> <dt>•</dt> <dd>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”</dd> <dt>•</dt> <dd>increasing doses of NSAIDs</dd> <dt>•</dt> <dd>longer use of NSAIDs</dd> <dt>•</dt> <dd>smoking</dd> <dt>•</dt> <dd>drinking alcohol</dd> <dt>•</dt> <dd>older age</dd> <dt>•</dt> <dd>poor health</dd> <dt>•</dt> <dd>advanced liver disease</dd> <dt>•</dt> <dd>bleeding problems</dd> </dl> <p> <span class="Bold">NSAIDs should only be used:</span> </p> <dl> <dt>•</dt> <dd>exactly as prescribed</dd> <dt>•</dt> <dd>at the lowest dose possible for your treatment</dd> <dt>•</dt> <dd>for the shortest time needed</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is diclofenac sodium gel?</span> </p> <p>Diclofenac sodium gel is an NSAID that is used on the skin (topical) to treat a skin condition called actinic keratosis. Diclofenac sodium gel is not for use in children.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> <span class="Bold">Do not use diclofenac sodium gel:</span> </dd> </dl> <dl> <dt>•</dt> <dd>if you have had an allergic reaction to any of the ingredients in diclofenac sodium gel. See the end of this Medication Guide for a complete list of ingredients in diclofenac sodium gel.</dd> <dt>•</dt> <dd>if you have a history of asthma, hives, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe allergic reactions that can sometimes lead to death, have happened in people with a history of these types of allergic reactions to NSAIDs.</dd> <dt>•</dt> <dd>on skin that is inflamed, or has eczema, infected sores (lesions), burns or wounds</dd> <dt>•</dt> <dd>right before or after heart bypass surgery.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Before using diclofenac sodium gel, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have liver or kidney problems</dd> <dt>•</dt> <dd>have high blood pressure</dd> <dt>•</dt> <dd>have asthma</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class="Bold">You should not take NSAIDs after about 30 weeks of pregnancy.</span> </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will use diclofenac sodium gel or breastfeed.</dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. </span>NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class="Bold">Do not start taking any new medicine without talking to your healthcare provider first.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I use diclofenac sodium gel?</span> </p> <dl> <dt>•</dt> <dd>Use diclofenac sodium gel exactly as your healthcare provider tells you to use it.</dd> <dt>•</dt> <dd>Apply diclofenac sodium gel 2 times a day.</dd> <dt>•</dt> <dd>Apply enough diclofenac sodium gel to cover each skin lesion (usually a pea-sized amount) and gently rub in.</dd> <dt>•</dt> <dd>Diclofenac sodium gel may be used for 60 to 90 days. You may not see improvement of skin lesions for up to 30 days after stopping treatment. See your healthcare provider if lesions do not respond to treatment.</dd> <dt>•</dt> <dd>Avoid getting diclofenac sodium gel in your eyes, nose and mouth. If diclofenac sodium gel gets into your eyes, nose or mouth wash out your eyes, nose or mouth with water or saline right away. Call your healthcare provider if irritation continues for more than 1 hour.</dd> <dt>•</dt> <dd>Wash your hands well after applying diclofenac sodium gel.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What should I avoid while using diclofenac sodium gel?</span> </p> <dl> <dt>•</dt> <dd>Avoid spending time in sunlight or artificial light, such as tanning beds or sunlamps. Diclofenac sodium gel can make your skin sensitive to sunlight and the light from tanning beds and sunlamps. Talk to your healthcare provider about sun protection measures and wear loose-fitting clothes that cover your skin while out in sunlight. Stop using diclofenac sodium gel if you notice that you are beginning to get sunburn.</dd> <dt>•</dt> <dd>Do not apply diclofenac sodium gel to open skin wounds, skin infections, or peeling skin.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of diclofenac sodium gel?</span> </p> <p> <span class="Bold">Diclofenac sodium gel and other NSAIDs can cause serious side effects, including:</span> </p> <p> <span class="Bold">See “What is the most important information I should know about diclofenac sodium gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</span> </p> <dl> <dt>•</dt> <dd>life threatening allergic reactions</dd> <dt>•</dt> <dd>worsening of asthma in people who are aspirin-sensitive</dd> <dt>•</dt> <dd>life-threatening skin reactions</dd> <dt>•</dt> <dd>liver problems including liver failure</dd> <dt>•</dt> <dd>new or worse high blood pressure</dd> <dt>•</dt> <dd>heart failure</dd> <dt>•</dt> <dd>kidney problems including kidney failure</dd> <dt>•</dt> <dd>low red blood cells (anemia)</dd> </dl> <p> <span class="Bold">Other side effects of NSAIDs include: </span>stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.</p> <p> <span class="Bold">Get emergency help right away if you get any of the following symptoms:</span> </p> <dl> <dt>•</dt> <dd>shortness of breath or trouble breathing</dd> <dt>•</dt> <dd>chest pain</dd> <dt>•</dt> <dd>weakness in one part or side of your body</dd> <dt>•</dt> <dd>slurred speech</dd> <dt>•</dt> <dd>swelling of the face or throat</dd> </dl> <p> <span class="Bold">Stop using diclofenac sodium gel and call your healthcare provider right away if you get any of the following symptoms:</span> </p> <p>• nausea</p> <p>• more tired or weaker than usual</p> <p>• diarrhea</p> <p>• itching</p> <p>• your skin or eyes look yellow</p> <p>• indigestion or stomach pain</p> <p>• flu-like symptoms</p> <p>• vomit blood</p> <p>• there is blood in your bowel movement or it is black and sticky like tar</p> <p>• unusual weight gain</p> <p>• skin rash or blisters with fever</p> <p>• swelling of the arms, legs, hands and feet</p> <p> <span class="Bold">Application site skin reactions are common with diclofenac sodium gel including: </span>skin redness, itching, rash, dry skin, scaling, and peeling.</p> <p> <span class="Bold">If you take too much NSAID, call your healthcare provider or get medical help right away.</span> </p> <dl> <dt> </dt> <dd>Diclofenac sodium gel may cause fertility problems in females, which may affect your ability to have a child. Talk to your healthcare provider if this a concern for you.</dd> <dt> </dt> <dd>These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.</dd> </dl> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Other information about NSAIDs</span> </p> <dl> <dt>•</dt> <dd>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.</dd> <dt>•</dt> <dd>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I store diclofenac sodium gel?</span> </p> <dl> <dt>•</dt> <dd>Store diclofenac sodium gel at room temperature 68°F to 77°F (20°C to 25°C).</dd> <dt>•</dt> <dd>Keep diclofenac sodium gel away from heat. Avoid freezing diclofenac sodium gel.</dd> </dl> <p> <span class="Bold">Keep diclofenac sodium gel and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of diclofenac sodium gel.</span> </p> <dl> <dt> </dt> <dd>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use diclofenac sodium gel for a condition for which it was not prescribed. Do not give diclofenac sodium gel to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about diclofenac sodium gel, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about diclofenac sodium gel that is written for health professionals.</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in diclofenac sodium gel? </span> </p> <p> <span class="Bold">Active ingredient: </span>diclofenac sodium</p> <p> <span class="Bold">Inactive ingredients: </span>benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water.</p> <p>Trademarks are the property of their respective owners.</p> <p> <span class="Bold">Medication Guide available at </span> </p> <p> <a href="http://www.glenmarkpharma-us.com/medguides">www.glenmarkpharma-us.com/medguides</a> </p> <p>Manufactured by:</p> <p> <span class="Bold">Glenmark Pharmaceuticals Limited</span> </p> <p>Colvale-Bardez, Goa 403513, India </p> <p>Manufactured for:</p> <a name="id583333693"></a><img alt="logo2" src="/dailymed/image.cfm?name=logo2.jpg&amp;setid=5d0a4b41-afbf-45e7-bb1c-587d72314ee0"/><p> <span class="Bold">Glenmark Pharmaceuticals Inc., USA</span> </p> <p>Mahwah, NJ 07430</p> <p>Questions? 1 (888) 721-7115</p> <p> <a href="http://www.glenmarkpharma-us.com">www.glenmarkpharma-us.com</a> </p> <dl> <dt> </dt> <dd>This Medication Guide has been approved by the U.S. Food and Drug Administration</dd> <dt> </dt> <dd> Revised: 01/2025</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Dispense with Medication Guide available at:</span>\n</p>\n<p>\n<span class=\"Bold\"><a href=\"http://www.glenmarkpharma-us.com/medguides\">www.glenmarkpharma-us.com/medguides</a></span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Diclofenac Sodium (dye-KLOE-fen-ak SOE-dee-um)</span>\n<br/>\n<span class=\"Bold\">Gel</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about diclofenac sodium gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</span>\n</p>\n<p>\n<span class=\"Bold\">NSAIDs can cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk of a heart attack or stroke that can lead to death</span>. This risk may happen early in treatment and may increase:<dl>\n<dt>o</dt>\n<dd>with increasing doses of NSAIDs</dd>\n<dt>o</dt>\n<dd>with longer use of NSAIDs</dd>\n</dl>\n</dd>\n</dl>\n<p>\n<span class=\"Bold\">Do not take or use NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)”. Avoid taking NSAIDs after a recent heart attack unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take or use NSAIDs after a recent heart attack.</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:</span>\n<dl>\n<dt>o</dt>\n<dd>anytime during use</dd>\n<dt>o</dt>\n<dd>without warning symptoms</dd>\n<dt>o</dt>\n<dd>that may cause death</dd>\n</dl>\n</dd>\n</dl>\n<p>\n<span class=\"Bold\">The risk of getting an ulcer or bleeding increases with:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</dd>\n<dt>•</dt>\n<dd>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”</dd>\n<dt>•</dt>\n<dd>increasing doses of NSAIDs</dd>\n<dt>•</dt>\n<dd>longer use of NSAIDs</dd>\n<dt>•</dt>\n<dd>smoking</dd>\n<dt>•</dt>\n<dd>drinking alcohol</dd>\n<dt>•</dt>\n<dd>older age</dd>\n<dt>•</dt>\n<dd>poor health</dd>\n<dt>•</dt>\n<dd>advanced liver disease</dd>\n<dt>•</dt>\n<dd>bleeding problems</dd>\n</dl>\n<p>\n<span class=\"Bold\">NSAIDs should only be used:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>exactly as prescribed</dd>\n<dt>•</dt>\n<dd>at the lowest dose possible for your treatment</dd>\n<dt>•</dt>\n<dd>for the shortest time needed</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is diclofenac sodium gel?</span>\n</p>\n<p>Diclofenac sodium gel is an NSAID that is used on the skin (topical) to treat a skin condition called actinic keratosis. Diclofenac sodium gel is not for use in children.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Do not use diclofenac sodium gel:</span>\n</dd>\n</dl>\n<dl>\n<dt>•</dt>\n<dd>if you have had an allergic reaction to any of the ingredients in diclofenac sodium gel. See the end of this Medication Guide for a complete list of ingredients in diclofenac sodium gel.</dd>\n<dt>•</dt>\n<dd>if you have a history of asthma, hives, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe allergic reactions that can sometimes lead to death, have happened in people with a history of these types of allergic reactions to NSAIDs.</dd>\n<dt>•</dt>\n<dd>on skin that is inflamed, or has eczema, infected sores (lesions), burns or wounds</dd>\n<dt>•</dt>\n<dd>right before or after heart bypass surgery.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before using diclofenac sodium gel, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver or kidney problems</dd>\n<dt>•</dt>\n<dd>have high blood pressure</dd>\n<dt>•</dt>\n<dd>have asthma</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class=\"Bold\">You should not take NSAIDs after about 30 weeks of pregnancy.</span>\n</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will use diclofenac sodium gel or breastfeed.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. </span>NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class=\"Bold\">Do not start taking any new medicine without talking to your healthcare provider first.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use diclofenac sodium gel?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Use diclofenac sodium gel exactly as your healthcare provider tells you to use it.</dd>\n<dt>•</dt>\n<dd>Apply diclofenac sodium gel 2 times a day.</dd>\n<dt>•</dt>\n<dd>Apply enough diclofenac sodium gel to cover each skin lesion (usually a pea-sized amount) and gently rub in.</dd>\n<dt>•</dt>\n<dd>Diclofenac sodium gel may be used for 60 to 90 days. You may not see improvement of skin lesions for up to 30 days after stopping treatment. See your healthcare provider if lesions do not respond to treatment.</dd>\n<dt>•</dt>\n<dd>Avoid getting diclofenac sodium gel in your eyes, nose and mouth. If diclofenac sodium gel gets into your eyes, nose or mouth wash out your eyes, nose or mouth with water or saline right away. Call your healthcare provider if irritation continues for more than 1 hour.</dd>\n<dt>•</dt>\n<dd>Wash your hands well after applying diclofenac sodium gel.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while using diclofenac sodium gel?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Avoid spending time in sunlight or artificial light, such as tanning beds or sunlamps. Diclofenac sodium gel can make your skin sensitive to sunlight and the light from tanning beds and sunlamps. Talk to your healthcare provider about sun protection measures and wear loose-fitting clothes that cover your skin while out in sunlight. Stop using diclofenac sodium gel if you notice that you are beginning to get sunburn.</dd>\n<dt>•</dt>\n<dd>Do not apply diclofenac sodium gel to open skin wounds, skin infections, or peeling skin.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of diclofenac sodium gel?</span>\n</p>\n<p>\n<span class=\"Bold\">Diclofenac sodium gel and other NSAIDs can cause serious side effects, including:</span>\n</p>\n<p>\n<span class=\"Bold\">See “What is the most important information I should know about diclofenac sodium gel and medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>life threatening allergic reactions</dd>\n<dt>•</dt>\n<dd>worsening of asthma in people who are aspirin-sensitive</dd>\n<dt>•</dt>\n<dd>life-threatening skin reactions</dd>\n<dt>•</dt>\n<dd>liver problems including liver failure</dd>\n<dt>•</dt>\n<dd>new or worse high blood pressure</dd>\n<dt>•</dt>\n<dd>heart failure</dd>\n<dt>•</dt>\n<dd>kidney problems including kidney failure</dd>\n<dt>•</dt>\n<dd>low red blood cells (anemia)</dd>\n</dl>\n<p>\n<span class=\"Bold\">Other side effects of NSAIDs include: </span>stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.</p>\n<p>\n<span class=\"Bold\">Get emergency help right away if you get any of the following symptoms:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>shortness of breath or trouble breathing</dd>\n<dt>•</dt>\n<dd>chest pain</dd>\n<dt>•</dt>\n<dd>weakness in one part or side of your body</dd>\n<dt>•</dt>\n<dd>slurred speech</dd>\n<dt>•</dt>\n<dd>swelling of the face or throat</dd>\n</dl>\n<p>\n<span class=\"Bold\">Stop using diclofenac sodium gel and call your healthcare provider right away if you get any of the following symptoms:</span>\n</p>\n<p>• nausea</p>\n<p>• more tired or weaker than usual</p>\n<p>• diarrhea</p>\n<p>• itching</p>\n<p>• your skin or eyes look yellow</p>\n<p>• indigestion or stomach pain</p>\n<p>• flu-like symptoms</p>\n<p>• vomit blood</p>\n<p>• there is blood in your bowel movement or it is black and sticky like tar</p>\n<p>• unusual weight gain</p>\n<p>• skin rash or blisters with fever</p>\n<p>• swelling of the arms, legs, hands and feet</p>\n<p>\n<span class=\"Bold\">Application site skin reactions are common with diclofenac sodium gel including: </span>skin redness, itching, rash, dry skin, scaling, and peeling.</p>\n<p>\n<span class=\"Bold\">If you take too much NSAID, call your healthcare provider or get medical help right away.</span>\n</p>\n<dl>\n<dt> </dt>\n<dd>Diclofenac sodium gel may cause fertility problems in females, which may affect your ability to have a child. Talk to your healthcare provider if this a concern for you.</dd>\n<dt> </dt>\n<dd>These are not all of the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.</dd>\n</dl>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Other information about NSAIDs</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.</dd>\n<dt>•</dt>\n<dd>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store diclofenac sodium gel?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store diclofenac sodium gel at room temperature 68°F to 77°F (20°C to 25°C).</dd>\n<dt>•</dt>\n<dd>Keep diclofenac sodium gel away from heat. Avoid freezing diclofenac sodium gel.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Keep diclofenac sodium gel and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of diclofenac sodium gel.</span>\n</p>\n<dl>\n<dt> </dt>\n<dd>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use diclofenac sodium gel for a condition for which it was not prescribed. Do not give diclofenac sodium gel to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about diclofenac sodium gel, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about diclofenac sodium gel that is written for health professionals.</dd>\n</dl>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in diclofenac sodium gel? </span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient: </span>diclofenac sodium</p>\n<p>\n<span class=\"Bold\">Inactive ingredients: </span>benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water.</p>\n<p>Trademarks are the property of their respective owners.</p>\n<p>\n<span class=\"Bold\">Medication Guide available at </span>\n</p>\n<p>\n<a href=\"http://www.glenmarkpharma-us.com/medguides\">www.glenmarkpharma-us.com/medguides</a>\n</p>\n<p>Manufactured by:</p>\n<p>\n<span class=\"Bold\">Glenmark Pharmaceuticals Limited</span>\n</p>\n<p>Colvale-Bardez, Goa 403513, India </p>\n<p>Manufactured for:</p>\n<a name=\"id583333693\"></a><img alt=\"logo2\" src=\"/dailymed/image.cfm?name=logo2.jpg&amp;setid=5d0a4b41-afbf-45e7-bb1c-587d72314ee0\"/><p>\n<span class=\"Bold\">Glenmark Pharmaceuticals Inc., USA</span>\n</p>\n<p>Mahwah, NJ 07430</p>\n<p>Questions? 1 (888) 721-7115</p>\n<p>\n<a href=\"http://www.glenmarkpharma-us.com\">www.glenmarkpharma-us.com</a>\n</p>\n<dl>\n<dt> </dt>\n<dd>This Medication Guide has been approved by the U.S. Food and Drug Administration</dd>\n<dt> </dt>\n<dd> Revised: 01/2025</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Relabeled By: Preferred Pharmaceuticals Inc.

{ "type": "p", "children": [], "text": "\nRelabeled By: Preferred Pharmaceuticals Inc.\n" }

Diclofenac Sodium Gel, 3%

{ "type": "p", "children": [], "text": "\nDiclofenac Sodium Gel, 3%\n" }

NDC:68788-9435-1

{ "type": "p", "children": [], "text": "\nNDC:68788-9435-1\n" }

Diclofenac sodium topical solution is indicated for the treatment of the pain of osteoarthritis of the knee(s).

{ "type": "p", "children": [], "text": "Diclofenac sodium topical solution is indicated for the treatment of the pain of osteoarthritis of the knee(s). " }

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.2)].

For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day.

Apply diclofenac sodium topical solution to clean, dry skin.

The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required.

After the priming procedure, diclofenac sodium topical solution is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee.

Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.

Diclofenac sodium topical solution, USP 2% w/w

{ "type": "p", "children": [], "text": "Diclofenac sodium topical solution, USP 2% w/w " }

Diclofenac sodium topical solution is contraindicated in the following patients:

{ "type": "p", "children": [], "text": "Diclofenac sodium topical solution is contraindicated in the following patients: " }

{ "type": "ul", "children": [ "Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]\n", "History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]\n", "In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]\n" ], "text": "" }

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of diclofenac sodium topical solution in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium topical solution is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most post-marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with oral diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In post-marketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac.

Post-marketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of oral diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and post-marketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium topical solution should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium topical solution immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver-related event in patients treated with diclofenac sodium topical solution, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium topical solution with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

NSAIDs, including diclofenac sodium topical solution, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of diclofenac sodium topical solution in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium topical solution is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of diclofenac sodium topical solution in patients with advanced renal disease. The renal effects of diclofenac sodium topical solution may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium topical solution. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium topical solution [see Drug Interactions (7)]. Avoid the use of diclofenac sodium topical solution in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium topical solution is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium topical solution is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When diclofenac sodium topical solution is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium topical solution at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium topical solution is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. Do not apply diclofenac sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium topical solution. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium topical solution and evaluate the patient immediately.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including diclofenac sodium topical solution, in pregnant women at about 30 weeks gestation  and later. NSAIDs, including diclofenac sodium topical solution, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including diclofenac sodium topical solution, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 and 30 weeks gestation, limit diclofenac sodium topical solution use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium topical solution treatment extends beyond 48 hours. Discontinue diclofenac sodium topical solution if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium topical solution has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac sodium topical solution, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

The pharmacological activity of diclofenac sodium topical solution in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

Instruct patients to avoid exposure to natural or artificial sunlight on treated knee(s) because studies in animals indicated topical diclofenac treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. The potential effects of diclofenac sodium topical solution on skin response to ultraviolet damage in humans are not known.

Avoid contact of diclofenac sodium topical solution with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

Concomitant use of oral NSAIDs with diclofenac sodium topical solution 1.5% resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Therefore, do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Diclofenac Sodium Topical Solution, 2%

The data described below reflect exposure to diclofenac sodium topical solution of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population’s mean age was approximately 60 years, 85% of patients were Caucasian, 65% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution were application site skin reactions. These events were the most common reason for withdrawing from the study.

Application Site Reactions:

In this controlled trial, application site reactions were characterized by one or more of the following: dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing (<1%).

Other Common Adverse Reactions:

Table 1 lists all adverse reactions occurring in >1% of patients receiving diclofenac sodium topical solution, where the rate in the diclofenac sodium topical solution group exceeded vehicle, from a controlled study conducted in patients with osteoarthritis.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="7.65in"/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Table 1: Incidence of Adverse Reactions Occurring in &gt;1% of Subjects with Osteoarthritis Using </span><span class="Bold">Diclofenac Sodium Topical Solution and More Often than in Subjects with OA Using Vehicle Control (Pooled)</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Lrule Toprule"> <p class="First"> <span class="Bold">Diclofenac Sodium Topical Solution<br/> N=130 <br/> n (%)</span> </p> </td><td class="Lrule Toprule"> <p class="First"> <span class="Bold">Vehicle Control <br/> N=129 n <br/> (%)</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Urinary tract infection </p> </td><td class="Lrule Toprule"> <p class="First">4 (3%)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1%)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Application site induration </p> </td><td class="Lrule Toprule"> <p class="First">2 (2%)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1%)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Contusion </p> </td><td class="Lrule Toprule"> <p class="First">2 (2%)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1%)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Sinus congestion </p> </td><td class="Lrule Toprule"> <p class="First">2 (2%)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1%)</p> </td> </tr> <tr class="Last"> <td class="Toprule"> <p class="First">Nausea </p> </td><td class="Lrule Toprule"> <p class="First">2 (2%)</p> </td><td class="Lrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

Diclofenac sodium topical solution 1.5%

The safety of diclofenac sodium topical solution 2% is based in part, on prior experience with diclofenac sodium topical solution 1.5%. The data described below reflect exposure to diclofenac sodium topical solution 1.5% of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies.

Application Site Reactions:

In controlled trials, application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of diclofenac sodium topical solution 1.5% and oral diclofenac. In the open-label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%.

Other Common Adverse Reactions:

In controlled trials, subjects treated with diclofenac sodium topical solution 1.5% experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 2). The combination of diclofenac sodium topical solution 1.5% and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases.

Table 2 lists all adverse reactions occurring in ≥1% of patients receiving diclofenac sodium topical solution 1.5%, where the rate in the diclofenac sodium topical solution 1.5% group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="7.65in"/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Table 2: Adverse Reactions Occurring in ≥1% of Patients Treated with </span><span class="Bold">Diclofenac Sodium Topical Solution 1.5% in Placebo and Oral Diclofenac-Controlled Trials</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Treatment Group:</span> </p> </td><td class="Lrule Toprule"> <p class="First"> <span class="Bold">Diclofenac Sodium Topical Solution </span><span class="Bold">1.5% <br/> N=911</span> </p> </td><td class="Lrule Toprule"> <p class="First"> <span class="Bold">Topical Placebo <br/> N=332</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Lrule Toprule"> <p class="First"> <span class="Bold">N (%)</span> </p> </td><td class="Lrule Toprule"> <p class="First"> <span class="Bold">N (%)</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Dry Skin (Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">292 (32)</p> </td><td class="Lrule Toprule"> <p class="First">17 (5)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Contact Dermatitis (Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">83 (9)</p> </td><td class="Lrule Toprule"> <p class="First">6 (2)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Dyspepsia </p> </td><td class="Lrule Toprule"> <p class="First">72 (8)</p> </td><td class="Lrule Toprule"> <p class="First">13 (4)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Abdominal Pain </p> </td><td class="Lrule Toprule"> <p class="First">54 (6)</p> </td><td class="Lrule Toprule"> <p class="First">10 (3)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Flatulence </p> </td><td class="Lrule Toprule"> <p class="First">35 (4)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Pruritus (Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">34 (4)</p> </td><td class="Lrule Toprule"> <p class="First">7 (2)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Diarrhea </p> </td><td class="Lrule Toprule"> <p class="First">33 (4)</p> </td><td class="Lrule Toprule"> <p class="First">7 (2)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Nausea </p> </td><td class="Lrule Toprule"> <p class="First">33 (4)</p> </td><td class="Lrule Toprule"> <p class="First">3 (1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Pharyngitis </p> </td><td class="Lrule Toprule"> <p class="First">40 (4)</p> </td><td class="Lrule Toprule"> <p class="First">13 (4)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Constipation </p> </td><td class="Lrule Toprule"> <p class="First">29 (3)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Edema </p> </td><td class="Lrule Toprule"> <p class="First">26 (3)</p> </td><td class="Lrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Rash (Non-Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">25 (3)</p> </td><td class="Lrule Toprule"> <p class="First">5 (2)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Infection </p> </td><td class="Lrule Toprule"> <p class="First">25 (3)</p> </td><td class="Lrule Toprule"> <p class="First">8 (2)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Ecchymosis </p> </td><td class="Lrule Toprule"> <p class="First">19 (2)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Dry Skin (Non-Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">19 (2)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Contact Dermatitis, vesicles (Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">18 (2)</p> </td><td class="Lrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Paresthesia (Non-Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">14 (2)</p> </td><td class="Lrule Toprule"> <p class="First">3 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Accidental Injury </p> </td><td class="Lrule Toprule"> <p class="First">22 (2)</p> </td><td class="Lrule Toprule"> <p class="First">7 (2)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Pruritus (Non-Application Site) </p> </td><td class="Lrule Toprule"> <p class="First">15 (2)</p> </td><td class="Lrule Toprule"> <p class="First">2 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Sinusitis </p> </td><td class="Lrule Toprule"> <p class="First">10 (1)</p> </td><td class="Lrule Toprule"> <p class="First">2 (&lt;1)</p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Halitosis </p> </td><td class="Lrule Toprule"> <p class="First">11 (1)</p> </td><td class="Lrule Toprule"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr class="Last"> <td class="Toprule"> <p class="First">Application Site Reaction (not otherwise specified) </p> </td><td class="Lrule Toprule"> <p class="First">11 (1)</p> </td><td class="Lrule Toprule"> <p class="First">3 (&lt;1)</p> </td> </tr> </tbody> </table></div>

In post-marketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution 1.5%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: abdominal pain, accidental injury, allergic reactions, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, neck rigidity, pain

Cardiovascular: palpitation, cardiovascular disorder

Gastrointestinal: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, lip swelling, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis, swollen tongue

Metabolic and Nutritional: creatinine increased

Musculoskeletal: leg cramps, myalgia

Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site

Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis, throat swelling

Skin and Appendages: At the Application Site: rash, skin burning sensation;

Other Skin and Appendages Adverse Reactions: eczema, skin discoloration, urticaria, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE)

Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion

Vascular: blood pressure increased, hypertension

See Table 3 for clinically significant drug interactions with diclofenac.

{ "type": "p", "children": [], "text": "See Table 3 for clinically significant drug interactions with diclofenac. " }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="7.65in"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Table 3: Clinically Significant Drug Interactions with Diclofenac</span> </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Drugs That Interfere with Hemostasis</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <ul class="Disc"> <li>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone. </li> <li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class="Italics">[see <a href="#www.splportal.comLINK_4d25731f-c5f7-4ca7-8735-2cda9c18292e">Warnings and Precautions (5.12)</a>]</span> </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Aspirin</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class="Italics">[see <a href="#www.splportal.comLINK_fbf3173d-3696-4128-b8c4-96b2284c5fdd">Warnings and Precautions (5.2)</a>]</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class="Italics">[see <a href="#www.splportal.comLINK_4d25731f-c5f7-4ca7-8735-2cda9c18292e">Warnings and Precautions (5.12)</a>]</span>. Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection. </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <ul class="Disc"> <li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). </li> <li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. </li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <ul class="Disc"> <li>During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. </li> <li>During concomitant use of diclofenac sodium topical solution and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class="Italics">[see <a href="#www.splportal.comLINK_5129aec0-3003-4b5a-9d39-f6ffb990f7a1">Warnings and Precautions (5.6)</a>]</span>. </li> <li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. </li> </ul> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class="Italics">[see <a href="#www.splportal.comLINK_5129aec0-3003-4b5a-9d39-f6ffb990f7a1">Warnings and Precautions (5.6)</a>]</span>. </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Digoxin</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels. </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Lithium</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity. </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Methotrexate</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity. </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Cyclosporine</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity. </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs of worsening renal function. </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">NSAIDs and Salicylates</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class="Italics">[see <a href="#www.splportal.comLINK_fbf3173d-3696-4128-b8c4-96b2284c5fdd">Warnings and Precautions (5.2)</a>]</span> </p> <p>Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%). </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. </p> <p>Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Pemetrexed</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). </p> </td> </tr> <tr class="Last"> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. </p> <p>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. </p> <p>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"7.65in\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Table 3: Clinically Significant Drug Interactions with Diclofenac</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs That Interfere with Hemostasis</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<ul class=\"Disc\">\n<li>Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone. </li>\n<li>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_4d25731f-c5f7-4ca7-8735-2cda9c18292e\">Warnings and Precautions (5.12)</a>]</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Aspirin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_fbf3173d-3696-4128-b8c4-96b2284c5fdd\">Warnings and Precautions (5.2)</a>]</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_4d25731f-c5f7-4ca7-8735-2cda9c18292e\">Warnings and Precautions (5.12)</a>]</span>. Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<ul class=\"Disc\">\n<li>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). </li>\n<li>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<ul class=\"Disc\">\n<li>During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. </li>\n<li>During concomitant use of diclofenac sodium topical solution and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_5129aec0-3003-4b5a-9d39-f6ffb990f7a1\">Warnings and Precautions (5.6)</a>]</span>. </li>\n<li>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_5129aec0-3003-4b5a-9d39-f6ffb990f7a1\">Warnings and Precautions (5.6)</a>]</span>. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Digoxin</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Lithium</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Methotrexate</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Cyclosporine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs of worsening renal function. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">NSAIDs and Salicylates</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <span class=\"Italics\">[see <a href=\"#www.splportal.comLINK_fbf3173d-3696-4128-b8c4-96b2284c5fdd\">Warnings and Precautions (5.2)</a>]</span>\n</p>\n<p>Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%). </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. </p>\n<p>Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Pemetrexed</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. </p>\n<p>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. </p>\n<p>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. </p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of NSAIDs, including diclofenac sodium topical solution, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium topical solution use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium topical solution use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including diclofenac sodium topical solution, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations were observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.6, 0.6, and 1.3 times, respectively, the maximum recommended human dose (MRHD) of 162 mg diclofenac sodium via diclofenac sodium topical solution, despite the presence of maternal and fetal toxicity at these doses (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions

Premature Closure of the Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium topical solution, can cause premature closure of the fetal ductus arteriosus (see Data).

Oligohydramnios/Neonatal Renal Impairment:

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium topical solution treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium topical solution and follow up according to clinical practice (see Data).

Labor or Delivery

There are no studies on the effects of diclofenac sodium topical solution during labor or delivery. In animal studies, NSAIDs, including diclofenac inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these post-marketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.6 times the maximum recommended human dose [MRHD] of diclofenac sodium topical solution, 162 mg diclofenac sodium/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.6 and 1.3-times, respectively, the MRHD based on BSA comparison). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in diclofenac sodium topical solution) are equivocal as to potential teratogenicity.

In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.12 and 0.24 times the MRHD, respectively, based on BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats.

In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0.06 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3.6 mg/kg, IP; 0.2 times the MRHD based on BSA comparison), and caused adverse effects on the developing testes (6.1 mg/kg, oral; 0.4 times the MRHD based on BSA comparison).

Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium topical solution and any potential adverse effects on the breastfed infant from the diclofenac sodium topical solution or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium topical solution, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium topical solution, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Males

Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear [see Nonclinical Toxicology (13.1)].

Safety and effectiveness in pediatric patients have not been established.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Of the 911 patients treated with diclofenac sodium topical solution 1.5% in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with diclofenac sodium topical solution 1.5% in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to diclofenac sodium topical solution 1.5% for this elderly population.

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

{ "type": "p", "children": [], "text": "Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. " }

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in diclofenac sodium topical solution. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

{ "type": "p", "children": [], "text": "Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in diclofenac sodium topical solution. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. " }

For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).

{ "type": "p", "children": [], "text": "For additional information about overdosage treatment, contact a poison control center (1-800-222-1222). " }

Diclofenac sodium topical solution, USP contains 2% diclofenac sodium USP, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug, and is available as a clear, colorless to faintly pink or orange solution for topical application. The chemical name is 2[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following chemical structure.

{ "type": "p", "children": [], "text": "Diclofenac sodium topical solution, USP contains 2% diclofenac sodium USP, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug, and is available as a clear, colorless to faintly pink or orange solution for topical application. The chemical name is 2[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following chemical structure." }

Each 1 gram of solution contains 20 mg of diclofenac sodium, USP. The inactive ingredients: alcohol (30.74% v/v), dimethyl sulfoxide USP (DMSO, 45.5% w/w), hydroxypropyl cellulose, propylene glycol, and purified water.

{ "type": "p", "children": [], "text": "Each 1 gram of solution contains 20 mg of diclofenac sodium, USP. The inactive ingredients: alcohol (30.74% v/v), dimethyl sulfoxide USP (DMSO, 45.5% w/w), hydroxypropyl cellulose, propylene glycol, and purified water. " }

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of diclofenac sodium topical solution, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Absorption:

After administration of diclofenac sodium topical solution (40 mg/knee every 12 h; total daily diclofenac exposure: 80 mg/knee) for 7.5 days, the mean (SD) AUC0-12 and mean (SD) Cmax were 77.27 (49.89) ng•h/mL and 12.16 (7.66) ng/mL, respectively, on Day 1; and 204.58 (111.02) ng•h/mL and 25.24 (12.95) ng/mL, respectively, at steady-state on Day 8. After administration of diclofenac sodium topical solution 1.5% (19.3 mg/knee every 6 h; total daily diclofenac exposure 77.2 mg/knee), the mean (SD) AUC0-12 and mean (SD) Cmax were 27.46 (23.97) ng•h/mL and 2.30 (2.02) ng/mL, respectively, on Day 1; and 141.49 (92.47) ng•h/mL and 17.04 (11.28) ng/mL, respectively, at steady-state on Day 8.

The pharmacokinetics and effect of diclofenac sodium topical solution were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of diclofenac sodium topical solution under these conditions is not recommended.

Distribution:

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Elimination

Metabolism:

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac.

Excretion:

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.

Little or no free unchanged diclofenac is excreted in the urine.

Specific Populations:

Pediatric: The pharmacokinetics of diclofenac sodium topical solution has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been studied.

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

Carcinogenesis

Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day approximately 0.85 and 1.7 times, respectively, the maximum recommended human topical dose of diclofenac sodium topical solution (based on apparent bioavailability and body surface area comparison).

In a dermal carcinogenicity study conducted in albino mice, daily topical applications of diclofenac sodium for two years at concentrations up to 0.035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) did not increase neoplasm incidence.

In a photococarcinogenicity study conducted in hairless mice, topical application of diclofenac sodium at doses up to 0.035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) resulted in an earlier median time of onset of tumors.

Mutagenesis

Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal aberration assay of bone marrow cells.

Impairment of Fertility

Fertility studies have not been conducted with diclofenac sodium topical solution. Diclofenac sodium administered to male and female rats at doses up to 4 mg/kg/day (approximately 3.4 times the MRHD of diclofenac sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies conducted in rats found no effect of dermally applied DMSO on fertility, reproductive performance, or offspring performance.

However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (0.6 times the MRHD) for 14 days and at 0.25 mg/kg (0.01 times the MRHD) for 30 days produced adverse effects on male reproductive hormones and testes.

Ocular Effects

No adverse effects were observed using indirect ophthalmoscopy after multiple-daily dermal application to rats for 26 weeks and minipigs for 52 weeks of DMSO at twice the concentration found in diclofenac sodium topical solution. Published studies of dermal or oral administration of DMSO to rabbits, dogs and pigs described refractive changes of lens curvature and cortical fibers indicative of myopic changes and/or incidences of lens opacity or discoloration when evaluated using slit-lamp biomicroscopy examination, although no ocular abnormalities were observed in rhesus monkeys during daily oral or dermal treatment with DMSO for 9 to 18 months.

Diclofenac Sodium Topical Solution

The use of diclofenac sodium topical solution for the treatment of pain of osteoarthritis of the knee was evaluated in a single double-blind controlled trial conducted in the US, involving patients treated with diclofenac sodium topical solution at a dose of 2 pumps twice a day for 4 weeks. Diclofenac sodium topical solution was compared to topical vehicle, applied directly to the study knee. In this trial, patients treated with diclofenac sodium topical solution experienced a greater reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale compared to patients treated with vehicle. Numerical results of the WOMAC pain subscale are summarized in Table 4.

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" colspan="3"><span class="Bold">Table 4: Change in Treatment Outcomes after 4 Weeks of Treatment with  Diclofenac Sodium Topical Solution</span> </td> </tr> <tr> <td> <span class="Bold">Efficacy Variable </span></td><td align="center" colspan="2"> <span class="Bold">Treatment</span></td> </tr> <tr> <td align="center"> </td><td align="center"> <span class="Bold">Diclofenac Sodium Topical Solution</span> <br/> <span class="Bold"> N=130</span></td><td align="center"> <span class="Bold">Vehicle Control <br/> N=129</span></td> </tr> <tr> <td> WOMAC Pain Subscale*</td><td align="center"> </td><td align="center"> </td> </tr> <tr> <td>Baseline </td><td align="center"> 12.4</td><td align="center">12.6</td> </tr> <tr> <td>Mean Change from Baseline </td><td align="center">-4.5 </td><td align="center"> -3.6</td> </tr> <tr class="Last"> <td colspan="3">* WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale.  </td> </tr> </tbody> </table></div>

Diclofenac sodium topical solution, USP is supplied as a clear, colorless to faintly pink or orange solution containing 20 mg of diclofenac sodium, USP per gram of solution, in a white polypropylene-dose pump bottle with a clear cap. Each pump actuation delivers 20 mg of diclofenac sodium, USP in 1 gram of solution. It is available as follows:

{ "type": "p", "children": [], "text": "Diclofenac sodium topical solution, USP is supplied as a clear, colorless to faintly pink or orange solution containing 20 mg of diclofenac sodium, USP per gram of solution, in a white polypropylene-dose pump bottle with a clear cap. Each pump actuation delivers 20 mg of diclofenac sodium, USP in 1 gram of solution. It is available as follows:" }

112 g Bottle     NDC 65162-683-12

{ "type": "p", "children": [], "text": "112 g Bottle     NDC 65162-683-12 " }

Storage

{ "type": "p", "children": [], "text": "\nStorage \n" }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. " }

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium topical solution and periodically during the course of ongoing therapy.

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium topical solution and periodically during the course of ongoing therapy. " }

Cardiovascular Thrombotic Events

{ "type": "p", "children": [], "text": "\nCardiovascular Thrombotic Events \n" }

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. " }

Gastrointestinal Bleeding, Ulceration, and Perforation

{ "type": "p", "children": [], "text": "\nGastrointestinal Bleeding, Ulceration, and Perforation \n" }

Advise patients to report symptoms of ulceration and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients to report symptoms of ulceration and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. " }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity \n" }

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium topical solution and seek immediate medical therapy [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium topical solution and seek immediate medical therapy [see Warnings and Precautions (5.3)]. " }

Heart Failure and Edema

{ "type": "p", "children": [], "text": "\nHeart Failure and Edema\n" }

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. " }

Anaphylactic Reactions

{ "type": "p", "children": [], "text": "\nAnaphylactic Reactions \n" }

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. " }

Serious Skin Reactions, including DRESS

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions, including DRESS\n" }

Advise patients to stop using diclofenac sodium topical solution immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].

{ "type": "p", "children": [], "text": "Advise patients to stop using diclofenac sodium topical solution immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. " }

Female Fertility

{ "type": "p", "children": [], "text": "\nFemale Fertility \n" }

Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium topical solution, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium topical solution, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. " }

Fetal Toxicity

{ "type": "p", "children": [], "text": "\nFetal Toxicity \n" }

Inform pregnant women to avoid use of diclofenac sodium topical solution and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.11)]. If treatment with diclofenac sodium topical solution is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform pregnant women to avoid use of diclofenac sodium topical solution and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.11)]. If treatment with diclofenac sodium topical solution is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)]. " }

Avoid Concomitant Use of NSAIDs

{ "type": "p", "children": [], "text": "\nAvoid Concomitant Use of NSAIDs \n" }

Inform patients that the concomitant use of diclofenac sodium topical solution with other NSAIDs or salicylates (e.g.,diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

{ "type": "p", "children": [], "text": "Inform patients that the concomitant use of diclofenac sodium topical solution with other NSAIDs or salicylates (e.g.,diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. " }

Use of NSAIDs and Low-Dose Aspirin

{ "type": "p", "children": [], "text": "\nUse of NSAIDs and Low-Dose Aspirin \n" }

Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium topical solution until they talk to their healthcare provider [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium topical solution until they talk to their healthcare provider [see Drug Interactions (7)]. " }

Eye Exposure

{ "type": "p", "children": [], "text": "\nEye Exposure \n" }

Instruct patients to avoid contact of diclofenac sodium topical solution with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

{ "type": "p", "children": [], "text": "Instruct patients to avoid contact of diclofenac sodium topical solution with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. " }

Prevention of Secondary Exposure

{ "type": "p", "children": [], "text": "\nPrevention of Secondary Exposure \n" }

Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which diclofenac sodium topical solution was applied until the knee(s) is completely dry.

{ "type": "p", "children": [], "text": "Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which diclofenac sodium topical solution was applied until the knee(s) is completely dry. " }

Special Application Instructions

{ "type": "p", "children": [], "text": "\nSpecial Application Instructions \n" }

Instruct patients not to apply diclofenac sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and reduce tolerability of the drug.

{ "type": "p", "children": [], "text": "Instruct patients not to apply diclofenac sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and reduce tolerability of the drug. " }

Instruct patients to wait until the area treated with diclofenac sodium topical solution is completely dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication.

{ "type": "p", "children": [], "text": "Instruct patients to wait until the area treated with diclofenac sodium topical solution is completely dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication. " }

Instruct patients to minimize or avoid exposure of treated knee(s) to natural or artificial sunlight.

{ "type": "p", "children": [], "text": "Instruct patients to minimize or avoid exposure of treated knee(s) to natural or artificial sunlight. " }

Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807

{ "type": "p", "children": [], "text": "Distributed by: \nAmneal Pharmaceuticals LLC\nBridgewater, NJ 08807" }

Rev. 05-2025-03

{ "type": "p", "children": [], "text": "Rev. 05-2025-03" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="7.65in"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule"> <p class="First"> <span class="Bold">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span> </p> <p> <span class="Bold">NSAIDs can cause serious side effects, including: </span> </p> <ul class="Disc"> <li> <span class="Bold">Increased risk of a heart attack or stroke that can lead to death.</span> This risk may happen early in treatment and may increase: </li> </ul> <ul class="Circle"> <li>with increasing doses of NSAIDs  </li> <li>with longer use of NSAIDs </li> </ul> <p> <span class="Bold">Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” </span> </p> <p> <span class="Bold">Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. </span> </p> <ul class="Disk"> <li> <span class="Bold">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: </span> </li> </ul> <ul class="Circle"> <li>anytime during use </li> <li>without warning symptoms </li> <li>that may cause death </li> </ul> <p> <span class="Bold">The risk of getting an ulcer or bleeding increases with: </span> </p> <ul class="Circle"> <li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs </li> <li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” </li> <li>increasing doses of NSAIDs </li> <li>longer use of NSAIDs </li> <li>smoking </li> <li>drinking alcohol </li> <li>older age </li> <li>poor health </li> <li>advanced liver disease </li> <li>bleeding problems </li> </ul> <p> <span class="Bold">NSAIDs should only be used: </span> </p> <ul class="Circle"> <li>exactly as prescribed </li> <li>at the lowest dose possible for your treatment </li> <li>for the shortest time needed </li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">What are NSAIDs? <br/> </span>NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Who should not take NSAIDs? <br/> Do not take NSAIDS: </span> </p> <ul class="Disc"> <li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. </li> <li>right before or after heart bypass surgery. </li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Before taking NSAIDs, tell your health care provider about all of your medical conditions, including if you: </span> </p> <ul class="Disc"> <li>have liver or kidney problems </li> <li>have high blood pressure </li> <li>have asthma </li> <li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class="Bold">You should not take NSAIDs after about 30 weeks of pregnancy.</span> </li> <li>are breastfeeding or plan to breast feed. </li> </ul> <p> <span class="Bold">Tell your health care provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements.</span> NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class="Bold">Do not start taking new medicine without talking to your health care provider first.</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">What are the possible side effects of NSAIDs? <br/> NSAIDs can cause serious side effects, including: <br/> See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” </span> </p> <ul class="Disc"> <li>new or worse high blood pressure </li> <li>heart failure </li> <li>liver problems including liver failure </li> <li>kidney problems including kidney failure </li> <li>low red blood cells (anemia) </li> <li>life-threatening skin reactions </li> <li>life-threatening allergic reactions </li> <li> <span class="Bold">Other side effects of NSAIDs include:</span> stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting and dizziness. </li> </ul> <p> <span class="Bold">Get emergency help right away if you get any of the following symptoms: </span> </p> <ul class="Disc"> <li>shortness of breath or trouble breathing </li> <li>chest pain </li> <li>weakness in one part or side of your body </li> <li>slurred speech </li> <li>swelling of the face or throat </li> </ul> <p> <span class="Bold">Stop taking your NSAID and call your health care provider right away if you get any of the following symptoms: </span> </p> <ul class="Disc"> <li>nausea </li> <li>more tired or weaker than usual </li> <li>diarrhea </li> <li>itching </li> <li>your skin or eyes look yellow </li> <li>indigestion or stomach pain </li> <li>flu-like symptoms </li> <li>vomit blood </li> <li>there is blood in your bowel movement or it is black and sticky like tar </li> <li>unusual weight gain </li> <li>skin rash or blisters with fever </li> <li>swelling of the arms, legs, hands, and feet </li> </ul> <p> <span class="Bold">If you take too much of your NSAID, call your health care provider or get medical help right away. <br/> </span>These are not all the possible side effects of NSAIDs. For more information, ask your health care provider or pharmacist about NSAIDs. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Other information about NSAIDs </span> </p> <ul class="Disc"> <li>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. </li> <li>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your health care provider before using over-the-counter NSAIDs for more than 10 days. </li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">General information about the safe and effective use of NSAIDs <br/> </span>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. <br/> If you would like more information about NSAIDs, talk with your health care provider. You can ask your pharmacist or health care provider for information about NSAIDs that is written for health professionals. </p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Distributed by: <br/> <span class="Bold">Amneal Pharmaceuticals LLC<br/> </span>Bridgewater, NJ 08807<br/> For more information, go to www.amneal.com or call 1-877-835-5472. </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">This Medication Guide has been approved by the U.S. Food and Drug Administration.                      Revised: 08-2022-01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"7.65in\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? </span>\n</p>\n<p>\n<span class=\"Bold\">NSAIDs can cause serious side effects, including: </span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of a heart attack or stroke that can lead to death.</span> This risk may happen early in treatment and may increase: </li>\n</ul>\n<ul class=\"Circle\">\n<li>with increasing doses of NSAIDs  </li>\n<li>with longer use of NSAIDs </li>\n</ul>\n<p>\n<span class=\"Bold\">Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).” </span>\n</p>\n<p>\n<span class=\"Bold\">Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. </span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: </span>\n</li>\n</ul>\n<ul class=\"Circle\">\n<li>anytime during use </li>\n<li>without warning symptoms </li>\n<li>that may cause death </li>\n</ul>\n<p>\n<span class=\"Bold\">The risk of getting an ulcer or bleeding increases with: </span>\n</p>\n<ul class=\"Circle\">\n<li>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs </li>\n<li>taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” </li>\n<li>increasing doses of NSAIDs </li>\n<li>longer use of NSAIDs </li>\n<li>smoking </li>\n<li>drinking alcohol </li>\n<li>older age </li>\n<li>poor health </li>\n<li>advanced liver disease </li>\n<li>bleeding problems </li>\n</ul>\n<p>\n<span class=\"Bold\">NSAIDs should only be used: </span>\n</p>\n<ul class=\"Circle\">\n<li>exactly as prescribed </li>\n<li>at the lowest dose possible for your treatment </li>\n<li>for the shortest time needed </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What are NSAIDs? <br/>\n</span>NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take NSAIDs? <br/>\n Do not take NSAIDS: </span>\n</p>\n<ul class=\"Disc\">\n<li>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. </li>\n<li>right before or after heart bypass surgery. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking NSAIDs, tell your health care provider about all of your medical conditions, including if you: </span>\n</p>\n<ul class=\"Disc\">\n<li>have liver or kidney problems </li>\n<li>have high blood pressure </li>\n<li>have asthma </li>\n<li>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. <span class=\"Bold\">You should not take NSAIDs after about 30 weeks of pregnancy.</span>\n</li>\n<li>are breastfeeding or plan to breast feed. </li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your health care provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements.</span> NSAIDs and some other medicines can interact with each other and cause serious side effects. <span class=\"Bold\">Do not start taking new medicine without talking to your health care provider first.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of NSAIDs? <br/>\n NSAIDs can cause serious side effects, including: <br/>\n See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?” </span>\n</p>\n<ul class=\"Disc\">\n<li>new or worse high blood pressure </li>\n<li>heart failure </li>\n<li>liver problems including liver failure </li>\n<li>kidney problems including kidney failure </li>\n<li>low red blood cells (anemia) </li>\n<li>life-threatening skin reactions </li>\n<li>life-threatening allergic reactions </li>\n<li>\n<span class=\"Bold\">Other side effects of NSAIDs include:</span> stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting and dizziness. </li>\n</ul>\n<p>\n<span class=\"Bold\">Get emergency help right away if you get any of the following symptoms: </span>\n</p>\n<ul class=\"Disc\">\n<li>shortness of breath or trouble breathing </li>\n<li>chest pain </li>\n<li>weakness in one part or side of your body </li>\n<li>slurred speech </li>\n<li>swelling of the face or throat </li>\n</ul>\n<p>\n<span class=\"Bold\">Stop taking your NSAID and call your health care provider right away if you get any of the following symptoms: </span>\n</p>\n<ul class=\"Disc\">\n<li>nausea </li>\n<li>more tired or weaker than usual </li>\n<li>diarrhea </li>\n<li>itching </li>\n<li>your skin or eyes look yellow </li>\n<li>indigestion or stomach pain </li>\n<li>flu-like symptoms </li>\n<li>vomit blood </li>\n<li>there is blood in your bowel movement or it is black and sticky like tar </li>\n<li>unusual weight gain </li>\n<li>skin rash or blisters with fever </li>\n<li>swelling of the arms, legs, hands, and feet </li>\n</ul>\n<p>\n<span class=\"Bold\">If you take too much of your NSAID, call your health care provider or get medical help right away. <br/>\n</span>These are not all the possible side effects of NSAIDs. For more information, ask your health care provider or pharmacist about NSAIDs. <br/>\n Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Other information about NSAIDs </span>\n</p>\n<ul class=\"Disc\">\n<li>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. </li>\n<li>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your health care provider before using over-the-counter NSAIDs for more than 10 days. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of NSAIDs <br/>\n</span>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. <br/>\n If you would like more information about NSAIDs, talk with your health care provider. You can ask your pharmacist or health care provider for information about NSAIDs that is written for health professionals. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">Distributed by: <br/>\n<span class=\"Bold\">Amneal Pharmaceuticals LLC<br/>\n</span>Bridgewater, NJ 08807<br/>\n For more information, go to www.amneal.com or call 1-877-835-5472. </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">This Medication Guide has been approved by the U.S. Food and Drug Administration.                      Revised: 08-2022-01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Diclofenac (dye kloe’ fen ak) Sodium Topical Solution, USP 2% w/w

{ "type": "p", "children": [], "text": "\nDiclofenac (dye kloe’ fen ak) Sodium Topical Solution, USP 2% w/w\n" }

Read the Medication Guide that comes with diclofenac sodium first. Be sure that you read, understand and follow these Instructions for Use before you use diclofenac sodium for the first time.

{ "type": "p", "children": [], "text": "Read the Medication Guide that comes with diclofenac sodium first. Be sure that you read, understand and follow these Instructions for Use before you use diclofenac sodium for the first time." }

Important: For use on the skin only (topical). Do not get diclofenac sodium in your eyes, nose or mouth.

{ "type": "p", "children": [], "text": "\nImportant: For use on the skin only (topical). Do not get diclofenac sodium in your eyes, nose or mouth.\n" }

Before you use diclofenac sodium:

{ "type": "p", "children": [], "text": "\nBefore you use diclofenac sodium: \n" }

{ "type": "ul", "children": [ "Apply diclofenac sodium exactly as your healthcare provider tells you. Talk with your healthcare provider or pharmacist if you are not sure. ", "Only use diclofenac sodium to treat pain from osteoarthritis in your knee or knees. ", "Apply diclofenac sodium on clean, dry skin that does not have any cuts, infections or rashes. ", "Use diclofenac sodium two times a day on your knee or knees as prescribed. ", "If you get diclofenac sodium in your eyes, rinse your eyes right away with water or saline. Call your healthcare provider if your eyes are irritated for more than one hour." ], "text": "" }

Diclofenac sodium comes in a pump bottle.

{ "type": "p", "children": [], "text": "\nDiclofenac sodium comes in a pump bottle. \n" }

If you are using a diclofenac sodium pump bottle follow the steps below:

{ "type": "p", "children": [], "text": "\nIf you are using a diclofenac sodium pump bottle follow the steps below: \n" }

Before you use diclofenac sodium pump bottle for the first time, you will need to prime the pump. To prime the pump, remove the cap (See Figure A) and fully press the top of the pump all the way down 4 times while holding the bottle in an upright position (See Figure B). Dispense this portion of the medicine into a tissue or paper towel and throw it away in a trash can. The pump is now ready to use. You should not need to prime the pump again.

{ "type": "p", "children": [], "text": "\nBefore you use diclofenac sodium pump bottle for the first time, you will need to prime the pump. To prime the pump, remove the cap (See Figure A) and fully press the top of the pump all the way down 4 times while holding the bottle in an upright position (See Figure B). Dispense this portion of the medicine into a tissue or paper towel and throw it away in a trash can. The pump is now ready to use. You should not need to prime the pump again." }

Figure A.

{ "type": "p", "children": [], "text": "\n\nFigure A.\n" }

Figure B.

{ "type": "p", "children": [], "text": "\nFigure B.\n" }

Steps for using diclofenac sodium pump bottle:

{ "type": "p", "children": [], "text": "\nSteps for using diclofenac sodium pump bottle: \n" }

Step 1:       Wash your hands with soap and water before applying diclofenac sodium.

{ "type": "p", "children": [], "text": "Step 1:       Wash your hands with soap and water before applying diclofenac sodium. " }

Step 2:       Remove the bottle cap and press the pump head down firmly and fully to dispense diclofenac sodium into the palm of your hand. Release the pump head and then press the pump head down firmly and fully a second time. When you use your diclofenac sodium pump bottle, you can hold the bottle at an angle. Put 2 pumps of diclofenac sodium on your hand (See Figure C).

{ "type": "p", "children": [], "text": "Step 2:       Remove the bottle cap and press the pump head down firmly and fully to dispense diclofenac sodium into the palm of your hand. Release the pump head and then press the pump head down firmly and fully a second time. When you use your diclofenac sodium pump bottle, you can hold the bottle at an angle. Put 2 pumps of diclofenac sodium on your hand (See Figure C)." }

Figure C.

{ "type": "p", "children": [], "text": "\nFigure C. \n" }

Step 3:       Apply diclofenac sodium evenly around the front, back, and sides of your knee. Diclofenac sodium should be applied without massaging the knee (See Figures D and E).

{ "type": "p", "children": [], "text": "Step 3:       Apply diclofenac sodium evenly around the front, back, and sides of your knee. Diclofenac sodium should be applied without massaging the knee (See Figures D and E)." }

Figure D.

{ "type": "p", "children": [], "text": "\nFigure D.\n" }

Figure E.

{ "type": "p", "children": [], "text": "\nFigure E.\n" }

Step 4:       Repeat Steps 2 and 3 for your other knee if your healthcare provider has prescribed diclofenac sodium for both knees.

{ "type": "p", "children": [], "text": "Step 4:       Repeat Steps 2 and 3 for your other knee if your healthcare provider has prescribed diclofenac sodium for both knees. " }

Step 5:       Wash your hands with soap and water right away after applying diclofenac sodium.

{ "type": "p", "children": [], "text": "Step 5:       Wash your hands with soap and water right away after applying diclofenac sodium. " }

Step 6:       Replace the cap on the bottle and store in an upright position.

{ "type": "p", "children": [], "text": "Step 6:       Replace the cap on the bottle and store in an upright position." }

After you use diclofenac sodium: Do not:

{ "type": "p", "children": [], "text": "\nAfter you use diclofenac sodium:\nDo not: \n" }

{ "type": "ul", "children": [ "cover your knee with clothing until your knee is completely dry. ", "put sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medicines on your knee until it is completely dry. ", "take a shower or a bath for at least 30 minutes after you put diclofenac sodium on your knee(s). ", "use heating pads or cover the treated area with bandages where you have applied diclofenac sodium. ", "exercise following application of diclofenac sodium. ", "use sunlamp and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in the sunlight. " ], "text": "" }

How should I store diclofenac sodium?

{ "type": "p", "children": [], "text": "\nHow should I store diclofenac sodium? \n" }

{ "type": "ul", "children": [ "Store diclofenac sodium at room temperature between 68°F to 77°F (20°C to 25°C). " ], "text": "" }

Keep diclofenac sodium and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep diclofenac sodium and all medicines out of the reach of children. \n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "\nThis Instructions for Use has been approved by the U.S. Food and Drug Administration.\n" }

Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807

{ "type": "p", "children": [], "text": "Distributed by:\nAmneal Pharmaceuticals LLC\nBridgewater, NJ 08807" }

Rev. 08-2022-01

{ "type": "p", "children": [], "text": "Rev. 08-2022-01\n" }