Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in combination with omeprazole are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. The eradication of Helicobacter pylori has been shown to reduce the risk of duodenal ulcer recurrence.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and other antibacterial drugs, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Administer three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules after the morning and evening meal for 10 days (Table 1).

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<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Daily Dosing Schedule for Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules</span> </caption> <colgroup> <col align="left"/> <col align="center"/> <col align="center"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left"><span class="Bold">Time of dose</span></td><td align="center"><span class="Bold">Number of capsules of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride</span></td><td align="center"><span class="Bold">Number of capsules of omeprazole 20 mg</span></td> </tr> <tr> <td align="left">After morning meal</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left">After lunch</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left">After evening meal</td><td align="center">3</td><td align="center">1</td> </tr> <tr class="Last"> <td align="left">At bedtime</td><td align="center">3</td><td align="center">0</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 1: Daily Dosing Schedule for Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules</span>\n</caption>\n<colgroup>\n<col align=\"left\"/>\n<col align=\"center\"/>\n<col align=\"center\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\"><span class=\"Bold\">Time of dose</span></td><td align=\"center\"><span class=\"Bold\">Number of capsules of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride</span></td><td align=\"center\"><span class=\"Bold\">Number of capsules of omeprazole 20 mg</span></td>\n</tr>\n<tr>\n<td align=\"left\">After morning meal</td><td align=\"center\">3</td><td align=\"center\">1</td>\n</tr>\n<tr>\n<td align=\"left\">After lunch</td><td align=\"center\">3</td><td align=\"center\">0</td>\n</tr>\n<tr>\n<td align=\"left\">After evening meal</td><td align=\"center\">3</td><td align=\"center\">1</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\">At bedtime</td><td align=\"center\">3</td><td align=\"center\">0</td>\n</tr>\n</tbody>\n</table></div>" }

Instruct patients to swallow the bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride.

{ "type": "p", "children": [], "text": "Instruct patients to swallow the bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride." }

If a dose is missed, patients should continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted.

{ "type": "p", "children": [], "text": "If a dose is missed, patients should continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted." }

Each bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule contains 140 mg of bismuth subcitrate potassium, 125 mg of metronidazole, and a smaller capsule inside containing 125 mg of tetracycline hydrochloride. The capsules are hard gelatin capsules with a white opaque body and a white opaque cap, imprinted with “ING283” in black on both cap and body, filled with white to off-white powder and a smaller hard gelatin capsule.  

{ "type": "p", "children": [], "text": "Each bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule contains 140 mg of bismuth subcitrate potassium, 125 mg of metronidazole, and a smaller capsule inside containing 125 mg of tetracycline hydrochloride. The capsules are hard gelatin capsules with a white opaque body and a white opaque cap, imprinted with “ING283” in black on both cap and body, filled with white to off-white powder and a smaller hard gelatin capsule.  " }

Do not administer methoxyflurane to patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. The concurrent use of tetracycline hydrochloride, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule, with methoxyflurane has been reported to result in fatal renal toxicity [see Drug Interactions (7.1)].

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated in patients who have taken disulfiram within the last two weeks. Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, and disulfiram concurrently [see Drug Interactions (7.2)].

Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. A disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur due to the interaction between alcohol or propylene glycol and metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [see Drug Interactions (7.3)].

Bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride capsules are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome [see Adverse Reactions (6.3)].

Bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride capsules are contraindicated in patients with severe renal impairment. The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN) [see Adverse Reactions (6.3)]. In patients with significantly impaired renal function, higher serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis.

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated during pregnancy [see Use in Specific Populations (8.1)].

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated in patients with known hypersensitivity (e.g. urticaria, erythematous rash, flushing, and fever) to bismuth subcitrate potassium, metronidazole or other nitroimidazole derivatives, or tetracycline [see Adverse Reactions (6.3)].

Metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [see Nonclinical Toxicology (13)].  It is unknown whether metronidazole is associated with carcinogenicity in humans.

Tetracycline can cause fetal harm when administered to a pregnant woman. Based on animal data, use of drugs of the tetracycline class during the second and third trimester of pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development [see Warnings and Precautions (5.4)]. Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are used during pregnancy, or if the patient becomes pregnant while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, advise the patient of the potential risk to the fetus [see Contraindications (4.6) and Use in Specific Populations (8.1)].

Tetracycline, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, administered during pregnancy at high doses (> 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology [see Contraindications (4.6) and Use in Specific Populations (8.1)].

The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated [see Use in Specific Populations (8.4)].

Metronidazole: Convulsive seizures, encephalopathy, aseptic meningitis and peripheral neuropathy (including optic neuropathy) have been reported. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Aseptic meningitis symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

Tetracycline: Intracranial hypertension (IH), including pseudotumor cerebri, has been associated with the use of tetracyclines. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin should be avoided because isotretinoin is also known to cause IH.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize.

Bismuth-containing products: Cases of neurotoxicity associated with excessive doses of various bismuth-containing products have been reported. Effects have been reversible with discontinuation of bismuth therapy.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules therapy [see Adverse Reactions (6.3)].

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with an antifungal agent. As with other antibacterial drugs, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and institute appropriate therapy.

Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline [see Adverse Reactions (6.3)]. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Instruct patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema.

Bismuth subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped [see Adverse Reactions (6.1)]. Stool darkening should not be confused with melena.

Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy [see Adverse Reactions (6.3)].

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Clinical Pharmacology (12.3)].

Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract.

Bismuth subcitrate potassium may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood.

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ <=> NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Prescribing bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Skin and subcutaneous disorders including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with eosinophilia and systemic symptoms) have been reported. Discontinue treatment at the first evidence of a cutaneous reaction [see Adverse Reactions (6.2)].

Oral Contraceptives

Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [see Drug Interactions (7.4)]. 

Anticoagulants

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Drug Interactions (7.5)].

Lithium

In patients stabilized on relatively high doses of lithium, short-term use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations daily for several days after beginning treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules to detect any increase that may precede clinical symptoms of lithium toxicity [see Drug Interactions (7.6)].

Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly [see Drug Interactions (7.8)].

Drugs that Prolong the QT interval

QT prolongation has been reported with metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, particularly when administered with drugs with the potential for prolonging the QT interval.

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.

The safety of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole (OBMT) to eradicate Helicobacter pylori was assessed in an open-label, randomized, active-controlled clinical trial conducted in North America. The duration of treatment was 10 days with 147 patients exposed to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole (OBMT) and 152 exposed to control, consisting of omeprazole, amoxicillin, and clarithromycin (OAC). The age of the population in the study ranged from 18 to 75 years, with 59% male patients and 59% Caucasian patients.

Adverse drug reactions were reported in 58% of patients in the OBMT group and 59% of patients in the OAC group. There were no adverse reactions leading to discontinuation of the study during the clinical trial.

Adverse reactions with an incidence of ≥ 5% in OBMT group include abnormal feces, diarrhea, nausea, and headache. Adverse drug reactions with an incidence of ≥ 5% in OAC group include diarrhea, dysgeusia, dyspepsia, nausea and headache.

Table 2 lists adverse reactions with an incidence of ≥ 1%, in either groups (OBMT vs OAC) and in order of decreasing incidence for the OBMT group.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 2: Adverse reactions with an incidence of ≥ 1% from North American trial, [n (%)]</span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>OBMT = Omeprazole + Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>OAC = Omeprazole + Amoxicillin + Clarithromycin;</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Dark stools [see <span class="Italics">Warnings and Precautions (<a href="#section_5_7">5.8</a>)</span>]</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> Preferred Term</span></td><td><span class="Bold"> OBMT<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> (n = 147)</span></td><td><span class="Bold"> OAC<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> (n = 152)</span></td> </tr> <tr> <td colspan="3"><span class="Underline"><span class="Bold"> Gastrointestinal disorders</span></span></td> </tr> <tr> <td> Abnormal feces<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a></td><td> 23 (15.6%)</td><td> 7 (4.6%)</td> </tr> <tr> <td> Nausea </td><td> 12 (8.2%)</td><td> 14 (9.2%)</td> </tr> <tr> <td> Diarrhea</td><td> 10 (6.8%)</td><td> 20 (13.2%)</td> </tr> <tr> <td> Abdominal Pain</td><td> 7 (4.8%)</td><td> 2 (1.3%)</td> </tr> <tr> <td> Dyspepsia </td><td> 4 (2.7%)</td><td> 10 (6.6%)</td> </tr> <tr> <td> Constipation</td><td> 2 (1.4%)</td><td> 5 (3.3%)</td> </tr> <tr> <td> Dry Mouth</td><td> 2 (1.4%)</td><td>1 (0.7%)</td> </tr> <tr> <td> Flatulence</td><td> 0</td><td> 4 (2.6%)</td> </tr> <tr> <td>Glositis </td><td> 0</td><td> 2 (1.3%)</td> </tr> <tr> <td colspan="3"><span class="Underline"><span class="Bold"> General disorders and administration site conditions</span></span></td> </tr> <tr> <td> Asthenia </td><td> 5 (3.4%)</td><td> 2 (1.3%)</td> </tr> <tr> <td><span class="Underline"><span class="Bold">Infections and infestations </span></span></td><td></td><td></td> </tr> <tr> <td> Vaginal infection </td><td> 4 (2.7%)</td><td> 3 (2.0%)</td> </tr> <tr> <td colspan="3"><span class="Underline"><span class="Bold">Nervous system disorders</span></span></td> </tr> <tr> <td> Headache</td><td> 8 (5.4%)</td><td> 8 (5.3%)</td> </tr> <tr> <td> Dysgeusia</td><td> 6 (4.1%)</td><td> 18 (11.8%)</td> </tr> <tr> <td> Dizziness</td><td> 4 (2.7%)</td><td>4 (2.6%)</td> </tr> <tr> <td colspan="3"><span class="Underline"><span class="Bold">Investigations </span></span></td> </tr> <tr> <td> Laboratory test abnormal</td><td> 3 (2.0%)</td><td> 4 (2.6%)</td> </tr> <tr> <td> Alanine aminotransferase increased</td><td> 2 (1.4%)</td><td> 0</td> </tr> <tr> <td> Aspartate aminotransferase increased</td><td> 2 (1.4%)</td><td> 0</td> </tr> <tr> <td><span class="Bold"><span class="Underline"> Renal and urinary disorders</span></span></td><td></td><td></td> </tr> <tr> <td> Urine abnormality</td><td> 2 (1.4%)</td><td> 0</td> </tr> <tr> <td><span class="Underline"><span class="Bold">Skin and subcutaneous tissue disorders</span></span></td><td></td><td></td> </tr> <tr> <td> Rash Maculo-Papular</td><td>2 (1.4%)</td><td>0</td> </tr> <tr> <td> Rash</td><td>1 (0.7%)</td><td>3 (2.0%)</td> </tr> <tr class="Last"> <td> Pruritus</td><td>0</td><td>4 (2.6%)</td> </tr> </tbody> </table></div>

Adverse reactions with an incidence of <1% for OBMT group are: back pain, vomiting, tongue darkening [see Warnings and Precautions (5.8)], anxiety, gastritis, gastroenteritis, myalgia, chest pain, increased appetite, blood creatine phosphokinase increased, malaise, somnolence, tachycardia, duodenal ulcer, visual disturbance, weight increased.

Additionally, the following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. 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.

Metronidazole

Blood and Lymphatic system disorders: Reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent hematological abnormalities attributable to metronidazole have been observed [see Warnings and Precautions (5.9)].

Cardiac disorders: QT prolongation has been reported with metronidazole, particularly when administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings. 

Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, anorexia, metallic taste, furry tongue, glossitis, stomatitis and candida overgrowth. 

Hypersensitivity/Immune system disorders: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever [see Contraindications (4.6)].

Metabolism and nutrition disorders: Pancreatitis.  

Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia [see Warnings and Precautions (5.5)].

Dermatologic disorders: Erythematous rash and pruritus.

Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure.

Hepatic: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemtic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) [see Contraindications (4.4)].

Other: Dyspareunia, decrease of libido, proctitis, joint pains.

Tetracycline Hydrochloride

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia.

Gastrointestinal disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida overgrowth) in the anogenital region, esophagitis and esophageal ulceration. 

Nervous system disorders: Intracranial hypertension including pseudotumor cerebri, tinnitus, and myasthenic syndrome. 

Renal and urinary disorders: Increased BUN. 

Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes, onycholysis, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported [see Warnings and Precautions (5.13)].

Liver:Hepatotoxicity and liver failure.

Hypersensitivity reactions:Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

Do not administer methoxyflurane to patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. The concurrent use of tetracycline hydrochloride, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, with methoxyflurane has been reported to result in fatal renal toxicity [see Contraindications (4.1)].

Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and disulfiram concurrently. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should not be given to patients who have taken disulfiram within the last two weeks [see Contraindications (4.2)].

Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and for at least 3 days afterwards may cause a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) due to the interaction between alcohol or propylene glycol and metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [see Contraindications (4.3)].

Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [see Warnings and Precautions (5.14)].

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Warnings and Precautions (5.14)].

In patients stabilized on relatively high doses of lithium, short-term use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Serum lithium and serum creatinine concentrations should be monitored several days after beginning treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules to detect any increase that may precede clinical symptoms of lithium toxicity [see Warnings and Precautions (5.14)].

The absorption of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may be reduced if administered with antacids containing aluminum, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products due to the interaction between these products and tetracycline. These products should not be consumed concomitantly with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. However, the clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established.

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly [see Warnings and Precautions (5.14)].

The simultaneous administration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole.

The simultaneous administration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported in this situation. Monitor phenytoin concentrations during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules.

Risk Summary

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are contraindicated in women who are pregnant because treatment of Helicobacter pylori infection can be delayed in pregnant women, and the use of drugs of the tetracycline class during the second and third trimester pregnancy can also cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development [see Warnings and Precautions (5.2) and Data]. Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. There are maternal risks with high intravenous doses of tetracycline [see Clinical Considerations].

Metronidazole usage in pregnancy has been associated with certain congenital anomalies [see Data].  In animals, no fetotoxicity was observed when metronidazole was orally administered to pregnant mice at approximately 5% of the indicated human dose. There are no human or animal data on the use of bismuth subcitrate potassium during pregnancy. Although there are data on the separate components, there are no available data on the use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in pregnant women.

Clinical Considerations

Maternal Adverse Reactions

Tetracycline administered during pregnancy at high doses (> 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology [see Warnings and Precautions (5.3)].

Data

Human Data

Tetracycline

Published case reports have described the yellowing of bones and teeth in human infants exposed to tetracycline during the second and third trimester of pregnancy. The yellowing is caused by the direct deposition of tetracycline during the mineralization process. This discoloration is more common during long-term use of the drug but has also been observed following repeated short-term courses. All tetracyclines form a stable calcium complex in any bone forming tissue. A decrease in fibula growth rate was observed in premature infants given oral tetracycline in doses of 25 mg/kg every six hours. The effect resolved when the drug was discontinued. One long-term follow-up study in children exposed to tetracycline in-utero showed no adverse effects on bone growth and development.

Metronidazole

There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Bismuth subcitrate potassium

There are no human data on the use of bismuth subcitrate potassium during pregnancy.

Animal Data

Tetracycline

Results of animal studies indicate that tetracycline crosses the placenta, is found in fetal tissues, and can have toxic effects on the developing fetus (often related to reversible retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Multiple studies of limited design were conducted with pregnant and lactating female rats that resulted in fetuses and neonates with yellow discoloration of bones and teeth.

Metronidazole

Metronidazole crosses the placental barrier. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 10 mg/kg/day, approximately 5 percent of the indicated human dose (1500 mg/day) based on body surface area; however, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown.

Bismuth subcitrate potassium

Animal reproductive studies have not been conducted with bismuth subcitrate potassium.

Risk Summary

Two of the individual components of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, tetracycline and metronidazole, are present in human milk at concentrations similar to maternal serum levels.  It is not known whether bismuth subcitrate, the third component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules is present in human milk. It is not known what effect metronidazole, tetracycline or bismuth has on the breastfed infant or on milk production. Tetracycline binds with calcium in human milk [see Clinical Pharmacology (12.3)]. Data indicate that oral absorption of tetracycline in infants is low due to the calcium binding in human milk. Metronidazole transfers to human milk, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential risk of tumorigenicity shown in animal studies with metronidazole, a woman should pump and discard human milk for the duration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula.

Safety and effectiveness of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in pediatric patients infected with Helicobacter pylori have not been established.

Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should not be used in children up to 8 years of age [see Warnings and Precaution (5.4)].

Clinical studies of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, elderly patients may have a greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapies. Bismuth subcitrate potassium, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, additional monitoring may be required [see Contraindications (4.5)].

The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with severe renal impairment, higher serum concentrations of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis [see Contraindications (4.5)].

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events.  Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are not recommended in patients with severe hepatic impairment [see Warnings and Precautions (5.10) and Clinical Pharmacology (12.3)].

In case of an overdose, patients should contact a physician, poison control center, or emergency room. The available overdosage information for each of the individual components in Bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride capsules are summarized below:

{ "type": "p", "children": [], "text": "In case of an overdose, patients should contact a physician, poison control center, or emergency room. The available overdosage information for each of the individual components in Bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride capsules are summarized below:" }

Metronidazole:

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

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable.

{ "type": "p", "children": [], "text": "Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable." }

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

{ "type": "p", "children": [], "text": "Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day." }

Treatment of Overdosage

{ "type": "p", "children": [], "text": "\nTreatment of Overdosage\n" }

There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

{ "type": "p", "children": [], "text": "There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy." }

Tetracycline:

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

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage. 

{ "type": "p", "children": [], "text": "In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage. " }

Bismuth subcitrate potassium:

{ "type": "p", "children": [], "text": "\nBismuth subcitrate potassium:\n" }

Symptoms of a bismuth subcitrate potassium overdosage are not known.

{ "type": "p", "children": [], "text": "Symptoms of a bismuth subcitrate potassium overdosage are not known." }

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination antimicrobial product containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains:

{ "type": "p", "children": [], "text": "Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination antimicrobial product containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains:" }

{ "type": "ul", "children": [ "bismuth subcitrate potassium, 140 mg", "metronidazole, 125 mg", "smaller capsule (size 3) containing tetracycline hydrochloride, 125 mg" ], "text": "" }

Tetracycline hydrochloride is encapsulated within a smaller capsule to create a barrier to avoid contact with bismuth subcitrate potassium.

{ "type": "p", "children": [], "text": "Tetracycline hydrochloride is encapsulated within a smaller capsule to create a barrier to avoid contact with bismuth subcitrate potassium." }

Each bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule contains the following inactive ingredients: magnesium stearate NF, lactose monohydrate NF, talc USP, gelatin NF and titanium dioxide USP. The imprinting black ink contains ammonium hydroxide NF, ferrosoferric oxide NF, propylene glycol USP and shellac USP.

{ "type": "p", "children": [], "text": "Each bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule contains the following inactive ingredients: magnesium stearate NF, lactose monohydrate NF, talc USP, gelatin NF and titanium dioxide USP. The imprinting black ink contains ammonium hydroxide NF, ferrosoferric oxide NF, propylene glycol USP and shellac USP." }

Bismuth subcitrate potassium is a white to off-white powder. It is soluble, and a double salt of bismuth citrate and potassium citrate, containing an additional part of potassium hydroxide. The schematized empirical molecular formula of bismuth subcitrate potassium is BiK5(OH)2 (C6H5O7)2.H2O. The equivalent theoretical molecular formula is BiC12H14K5O17. The molecular mass of the theoretical molecular formula of a single unit of bismuth subcitrate potassium is 834.7.

{ "type": "p", "children": [], "text": "Bismuth subcitrate potassium is a white to off-white powder. It is soluble, and a double salt of bismuth citrate and potassium citrate, containing an additional part of potassium hydroxide. The schematized empirical molecular formula of bismuth subcitrate potassium is BiK5(OH)2 (C6H5O7)2.H2O. The equivalent theoretical molecular formula is BiC12H14K5O17. The molecular mass of the theoretical molecular formula of a single unit of bismuth subcitrate potassium is 834.7." }

Metronidazole is a white to pale yellow, odorless crystals or crystalline powder. Metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C6H9N3O3 and the following structural formula:

{ "type": "p", "children": [], "text": "Metronidazole is a white to pale yellow, odorless crystals or crystalline powder. Metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C6H9N3O3 and the following structural formula:" }

Molecular weight: 171.15

{ "type": "p", "children": [], "text": "Molecular weight: 171.15" }

Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-penta-hydroxy-6-methyl-1, 11-dioxo-2-napthacenecarboxamide monohydrochloride with a molecular formula of C22H24N2O8.HCl and the following structural formula:

{ "type": "p", "children": [], "text": "Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-penta-hydroxy-6-methyl-1, 11-dioxo-2-napthacenecarboxamide monohydrochloride with a molecular formula of C22H24N2O8.HCl and the following structural formula:" }

Molecular weight: 480.90

{ "type": "p", "children": [], "text": "Molecular weight: 480.90" }

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and bismuth subcitrate potassium [see Microbiology (12.4)].

The pharmacokinetics of the individual components of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are summarized below. In addition, two studies on bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules were conducted to determine the effect of co-administration on the pharmacokinetics of the components.

Bismuth Subcitrate Potassium (Bismuth)

Absorption and Distribution

Orally absorbed bismuth is distributed throughout the entire body. Bismuth is highly bound to plasma proteins (>90%).

Metabolism and Excretion

The elimination half-life of bismuth is approximately 5 days in both blood and urine. Elimination of bismuth is primarily through urinary and biliary routes. The rate of renal elimination appears to reach steady state 2 weeks after treatment discontinuation with similar rates of elimination at 6 weeks after discontinuation. The average urinary elimination of bismuth is 2.6% per day in the first two weeks after discontinuation (urine drug concentrations 24 to 250 mcg/mL) suggesting tissue accumulation and slow elimination.

Metronidazole

Absorption and Distribution

Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose, with oral administration of 500 mg producing a peak plasma concentration of 12 mcg/mL.

Metronidazole appears in the plasma mainly as unchanged compound with lesser quantities of the 2-hydroxymethyl metabolite also present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and breast milk in concentration similar to those found in plasma.

Metabolism and Excretion

The average elimination half-life of metronidazole in normal volunteers is 8 hours. The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl) 2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73m2.

Decreased renal function does not alter the single dose pharmacokinetics of metronidazole. In patients with decreased liver function, plasma clearance of metronidazole is decreased.

Tetracycline Hydrochloride

Absorption, Distribution, Metabolism and Excretion

Tetracycline hydrochloride is absorbed (60%-90%) in the stomach and upper small intestine. The presence of food, milk or cations may significantly decrease the extent of absorption. In the plasma, tetracycline is bound to plasma proteins in varying degrees. It is concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in biologically active form.

Tetracycline hydrochloride is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline hydrochloride tends to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation or tooth development. Tetracycline readily crosses the placenta and is excreted in high amounts in breast milk.

Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules

A comparative bioavailability study of metronidazole (375 mg), tetracycline hydrochloride (375 mg) and bismuth subcitrate potassium (420 mg, equivalent to 120 mg Bi2O3) administered as bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules or as 3 separate capsule formulations administered simultaneously was conducted in healthy male volunteers. The pharmacokinetic parameters for the individual drugs, when administered as separate capsule formulations or as bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, are similar as shown in Table 3.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Mean (%CV) Pharmacokinetic Parameters for Metronidazole, Tetracycline hydrochloride, and Bismuth Subcitrate Potassium in Healthy Volunteers (N=18) </span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>C.V. - Coefficient Variation</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules given as a single dose of 3 capsules</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td></td><td></td><td><span class="Bold"> C<span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span> <br/> <span class="Bold">(%C.V.<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a>)</span></td><td><span class="Bold"> AUC<span class="Sub">T</span> (ng · h/mL)</span> <br/> <span class="Bold">(%C.V.<span class="Sup">*</span>)</span></td><td><span class="Bold"> AUC<span class="Sub">∞</span> (ng · h/mL)</span> <br/> <span class="Bold">(%C.V.<span class="Sup">*</span>)</span></td> </tr> <tr> <td><span class="Bold"> Metronidazole</span></td><td> Metronidazole Capsules</td><td> 9044 (20)</td><td> 80289 (15)</td><td> 81849 (16)</td> </tr> <tr> <td></td><td> Bismuth Subcitrate, Metronidazole and Tetracycline Hydrochloride Capsules<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a></td><td> 8666.3 (22) </td><td> 83018 (17)</td><td> 84413 (17)</td> </tr> <tr> <td><span class="Bold"> Tetracycline</span></td><td> Tetracycline Capsules</td><td> 748.0 (40)</td><td> 9544 (55)</td><td> 9864 (53)</td> </tr> <tr> <td></td><td> Bismuth Subcitrate, Metronidazole and Tetracycline Hydrochloride Capsules<span class="Sup">†</span></td><td> 774 (47)</td><td> 9674 (50)</td><td> 9987 (49)</td> </tr> <tr> <td><span class="Bold"> Bismuth</span></td><td> Bismuth Capsule</td><td> 22 (123)</td><td> 47 (129)</td><td> 65.4 (113)</td> </tr> <tr class="Last"> <td></td><td> Bismuth Subcitrate, Metronidazole and Tetracycline Hydrochloride Capsules<span class="Sup">†</span></td><td> 17 (202)</td><td> 43 (191)</td><td> 57 (178)</td> </tr> </tbody> </table></div>

Effect of Bismuth on the Bioavailability of Tetracycline Hydrochloride

There is an anticipated reduction in tetracycline hydrochloride systemic absorption due to an interaction with bismuth. The effect of a reduced tetracycline hydrochloride systemic exposure, due to an interaction with bismuth, on the clinical efficacy of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules is not thought to be clinically meaningful as the contribution of systemic, as compared to local, antimicrobial activity against Helicobacter pylori has not been established.

Effect of Food on the Bioavailability of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules

The pharmacokinetic parameters for metronidazole, tetracycline hydrochloride and bismuth were also determined when bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules were administered under fasting and fed conditions, as shown in Table 4. Food reduced the systemic absorption of all three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule components, with AUC values for metronidazole, tetracycline hydrochloride and bismuth being reduced by 6%, 34% and 60%, respectively. Reduction in the absorption of all three bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule components in the presence of food is not considered to be clinically significant. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should be given after meals and at bedtime, in combination with omeprazole twice a day.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 4: Mean Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Pharmacokinetic Parameters in Fasted and Fed States (N=18)<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules given as a single dose of 3 capsules</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>T<span class="Sub">max</span> is expressed as median (range)</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td></td><td align="center" colspan="3"><span class="Bold"> FED</span></td><td align="center" colspan="3"><span class="Bold"> FASTED</span></td> </tr> <tr> <td></td><td><span class="Bold"> Metronidazole</span></td><td><span class="Bold"> Tetracycline</span></td><td><span class="Bold"> Bismuth</span></td><td><span class="Bold"> Metronidazole</span></td><td><span class="Bold"> Tetracycline</span></td><td><span class="Bold"> Bismuth</span></td> </tr> <tr> <td><span class="Bold"> C<span class="Sub">max</span> (ng/mL)</span> <br/> <span class="Bold">(%C.V.)</span></td><td> 6835.0 (13)</td><td> 515.8 (36)</td><td> 1.7 (61)</td><td> 8666.3 (22)</td><td> 773.8 (47)</td><td> 16.7 (202)</td> </tr> <tr> <td><span class="Bold"> T<span class="Sub">max</span> (hours)<a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a></span> <br/> <span class="Bold">(range)</span></td><td> 3.0 (1.3-4.0)</td><td> 4.0 (2.5 – 5.0)</td><td>3.5 (0.8 – 6.0) </td><td> 0.75 (0.5-3.5)</td><td> 3.3 (1.3 –  5.0)</td><td> 0.6 (0.5-1.7)</td> </tr> <tr class="Last"> <td><span class="Bold"> AUC<span class="Sub">∞</span></span> <br/> <span class="Bold">(ng · h/mL)</span> <br/> <span class="Bold">(%C.V.)</span></td><td> 79225.6 (18)</td><td> 5840.1 (312)</td><td> 18.4 (116)</td><td> 84413.6 (17)</td><td> 9986.7 (49)</td><td> 56.5 (178)</td> </tr> </tbody> </table></div>

Effect of Omeprazole on the Bioavailability of Bismuth

The effect of omeprazole on bismuth absorption was assessed in 34 healthy volunteers given bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules (four times daily) with or without omeprazole (20 mg twice daily) for 6 days. In the presence of omeprazole, the extent of absorption of bismuth from bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules was significantly increased, compared to when no omeprazole was given (Table 5). Concentration-dependent neurotoxicity is associated with long-term use of bismuth and not likely to occur with short-term administration or at steady state concentrations below 50 ng/mL. One subject transiently achieved a maximum bismuth concentration (Cmax) higher than 50 ng/mL (73 ng/mL) following multiple dosing of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules with omeprazole. The patient did not exhibit symptoms of neurotoxicity during the study. There is no clinical evidence to suggest that short-term exposure to bismuth Cmax concentrations above 50 ng/mL is associated with neurotoxicity.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 5: Mean Bismuth Pharmacokinetic Parameters following Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Administration<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a> With and Without Omeprazole (N=34)</span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules given as 3 capsules four times daily for 6 days with or without 20 mg omeprazole twice daily</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>C.V. - Coefficient Variation</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> Parameter</span></td><td colspan="2"><span class="Bold"> Without Omeprazole </span></td><td colspan="2"><span class="Bold"> With Omeprazole </span></td> </tr> <tr> <td></td><td><span class="Bold"> Mean</span></td><td><span class="Bold"> %C.V.<a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></span></td><td><span class="Bold"> Mean</span></td><td><span class="Bold"> %C.V.<span class="Sup">†</span></span></td> </tr> <tr> <td><span class="Bold"> C<span class="Sub">max</span> (ng/mL)</span></td><td> 8.1</td><td>84</td><td> 25.5</td><td> 69</td> </tr> <tr class="Last"> <td><span class="Bold"> AUC<span class="Sub">T</span> (ng · h/mL)</span></td><td> 48.5</td><td> 28</td><td> 140.9</td><td> 42</td> </tr> </tbody> </table></div>

Mechanism of Action

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and bismuth subcitrate potassium. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. Metronidazole’s antibacterial mechanism of action in an anaerobic environment is not fully understood but a possible mechanism includes reduction by intracellular electron transport proteins after entry into the organism. Because of this alteration to the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of bacteria. The antibacterial action of bismuth salts is not well understood.

Antimicrobial Activity

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole therapy has been shown to be active against most isolates of Helicobacter pylori both in vitro and in clinical infections [see Clinical Studies (14)].

Susceptibility Testing 

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

No long-term studies have been performed to evaluate the effect of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules on carcinogenesis, mutagenesis, or impairment of fertility.

Bismuth Subcitrate Potassium

No carcinogenicity or reproductive toxicity studies have been conducted with bismuth subcitrate potassium. Bismuth subsalicylate did not show mutagenic potential in the NTP Salmonella plate assay.

Metronidazole

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was an increased incidence of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At the highest dose levels, (approximately 500 mg/kg/day, which is approximately 1.6 times the indicated human dose for a 60 kg adult based on body surface area) there was a statistically significant increase in the incidence of malignant liver tumors in male mice. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Long-term, oral-dosing studies in the rat showed statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.

Fertility studies have been conducted with male rats and mice with divergent results. Metronidazole, at doses up to 400 mg/kg/day (approximately 3 times the indicated human dose based on mg/m2) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. Rats treated with up to 400 mg/kg/day for 6 weeks or longer, showed severe degeneration of the seminiferous epithelium in the testes which was associated with a marked decrease in testicular spermatid counts and epididymal sperm counts and a marked decrease in fecundity. These effects were partially reversible.

Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based upon mg/m2 and have revealed no evidence of impaired fertility. Another fertility study was performed in male mice at oral doses of 500 mg/kg/day (approximately 2 times the indicated human dose based on mg/m²) for 14 days. Metronidazole significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm. The viability of sperm was normal by 2 months after the start of the treatment.

Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Tetracycline hydrochloride

There has been no evidence of carcinogenicity for tetracycline hydrochloride in studies conducted with rats and mice. Some related antibiotics (oxytetracycline, minocycline) have shown evidence of oncogenic activity in rats.

There was evidence of mutagenicity by tetracycline hydrochloride in two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells).

Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose.

An open-label, parallel group, active-controlled, multicenter study in Helicobacter pylori positive patients with current duodenal ulcer or a history of duodenal ulcer disease was conducted in the United States and Canada (the North American Study).

Patients were randomized to one of the following 10-day treatment regimens:

H. pylori eradication rates, defined as two negative 13C-urea breath tests performed at 4 and 8 weeks post-therapy are shown in Table 6 for OBMT and OAC. The eradication rates for both groups were found to be similar using either the Per Protocol (PP) or Modified Intent-to-Treat (MITT) populations.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6: Helicobacter pylori Eradication at 8 Weeks after 10 Day Treatment Regimen Percent (%) of Patients Cured [95% Confidence Interval] (Number of Patients) </span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd> <span class="Bold">OBMT</span>: Omeprazole + Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">†</a> </dt> <dd>Results for OAC treatment represent all isolates regardless of clarithromycin susceptibility. Eradication rates for clarithromycin susceptible organisms, as defined by an MIC ≤ 0.25 mcg/mL, were 94.6% and 92.1% for the PP and MITT analysis, respectively. Eradication rates for clarithromycin non-susceptible organisms, as defined by an MIC ≥ 0.5 mcg/mL, were 23.1% and 21.4% for the PP and MITT analysis, respectively.</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">‡</a> </dt> <dd> <span class="Bold">OAC</span>: Omeprazole + amoxicillin + clarithromycin</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">§</a> </dt> <dd>Patients were included in the PP analysis if they had <span class="Italics">H. pylori</span> infection documented at baseline, defined as a positive <span class="Sup">13</span>C-UBT plus histology or culture, had at least one endoscopically verified duodenal ulcer ≥ 0.3 cm at baseline or had a documented history of duodenal ulcer disease, and were not protocol violators. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">¶</a> </dt> <dd>Patients were included in the MITT analysis if they had documented <span class="Italics">H. pylori</span> infection at baseline as defined above, and had at least one documented duodenal ulcer at baseline or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts were included as failures of therapy.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td></td><td align="center" colspan="2"><span class="Bold"> Treatment Group </span></td><td align="center"><span class="Bold"> Difference</span></td> </tr> <tr> <td></td><td align="center"><span class="Bold"> OBMT<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></span></td><td align="center"><span class="Bold"> OAC<a class="Sup" href="#footnote-11" name="footnote-reference-11">†</a><a class="Sup" href="#footnote-12" name="footnote-reference-12">‡</a></span></td><td></td> </tr> <tr> <td align="center"> Per Protocol<a class="Sup" href="#footnote-13" name="footnote-reference-13">§</a></td><td align="center"> 92.5%<br/>[87.8, 97.2]<br/>(n=120)</td><td align="center"> 85.7%<br/>[76.9, 91.8]<br/>(n=126)</td><td align="center"> 6.8%<br/>[-0.9, 14.5]</td> </tr> <tr class="Last"> <td align="center"> Modified<br/>Intent-to-Treat<a class="Sup" href="#footnote-14" name="footnote-reference-14">¶</a></td><td align="center"> 87.7%<br/>[82.2, 93.2]<br/>(n=138)</td><td align="center"> 83.2%<br/>[77.0, 89.5]<br/>(n=137)</td><td align="center"> 4.5%<br/>[-3.9, 12.8]</td> </tr> </tbody> </table></div>

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are supplied as a hard gelatin capsule with a white opaque body and a white opaque cap, imprinted with “ING283” in black on both body and cap, filled with white to off-white powder and a smaller hard gelatin capsule. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are supplied as bottles of 120 capsules and as the 10 day Therapy pack containing 10 blister cards, with each card containing 12 bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules for a total of 120 capsules. 

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NDC Number: 50742-283-12, Bottles of 120.

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NDC Number: 50742-283-13, Blister pack of 120.

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Storage

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Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

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Lactation

Advise the lactating women to pump and discard their milk during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and for 2 days after the therapy ends [see Use in Specific Populations (8.2)].

Hypersensitivity

Inform patients that bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may cause allergic reactions and to discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules at the first sign of urticaria, erythematous rash, flushing, and fever or other symptoms of an allergic reaction [see Contraindications (4.7)].

Central Nervous System Effects

Inform patients of the risk of central and peripheral nervous system effects with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and to discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and report immediately to their health-care provider if any neurologic symptoms occur [see Warnings and Precautions (5.5)].

Photosensitivity

Avoid exposure to sun or sun lamps while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [see Warnings and Precautions (5.7)].

Drug Interactions

Advise patients to report to their health-care provider the use of any other medications while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. The administration of any of the following drugs with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may result in clinically significant adverse reactions or insufficient drug efficacies [see Contraindications (4) and Drug Interactions (7)]:

Darkening of the Tongue and/or Stool

Inform patients that bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may cause temporary and harmless darkening of the tongue and/or black stool generally reversible within several days after treatment is stopped. Stool darkening should not be confused with melena (blood in the stool) [see Warnings and Precautions (5.8)].

Dosing Information

Inform patients that each dose of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules includes 3 capsules. All 3 capsules should be taken 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules after the morning and evening meal for 10 days.

If a dose is missed, advise patient not to make up the dose, but to continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, advise the patient to contact their health-care provider [see Dosage and Administration (2)]. 

Administration with Fluids

Instruct patients to swallow the bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride [see Dosage and Administration (2)].

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules or other antibacterial drugs in the future.

555000

Manufactured for:

Ingenus Pharmaceuticals, LLC

Orlando, FL 32811

 ingenus

Revised: 12/2022

NDC 50742-283-13

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Rx only

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Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules

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140 mg/125 mg/125 mg

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NDC 50742-283-13

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Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules

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140 mg/125 mg/125 mg

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10 Day Therapy PAK

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Combination therapy indicated for the eradication of Helicobacter pylori

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One blister card=1 day of therapy

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Rx only

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120 Capsules in 10 blister cards

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Each card contains 4 blisters.

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Each blister contains 3 capsules.

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 LIKMEZ is indicated for the treatment of:

Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, treat sexual partners of patients simultaneously to prevent re-infection.

LIKMEZ is indicated for the treatment of acute intestinal amebiasis (amoebic dysentery) and amebic liver abscess in adults and pediatric patients. In amebic liver abscess, treatment with LIKMEZ does not obviate the need for aspiration or drainage of pus.

 LIKMEZ is indicated in the treatment of the following serious infections caused by susceptible anaerobic bacteria in adults:

Indicated surgical procedures should be performed in conjunction with LIKMEZ therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of aerobic infection should be used in addition to LIKMEZ.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of LIKMEZ and other antibacterial drugs, LIKMEZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Adult Female and Male Patients:

The dosage regimen should be individualized. Single-dose treatment may help improve compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen.

A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. There are some data from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen.  Further, some patients may tolerate one treatment regimen better than the other.

When repeat courses of LIKMEZ are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment.

Adult Patients:

Pediatric Patients:

In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially.

Adult Patients: Administer 7.5 mg/kg of LIKMEZ orally every six hours (approx. 500 mg (5 mL) for a 70 kg adult) for 7 days to 10 days. Infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment.

Do not exceed a maximum of 4 g (40 mL) during a 24-hour period.

For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of LIKMEZ by 50% [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)].

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of LIKMEZ cannot be separated from the hemodialysis session, consider a supplemental dose of LIKMEZ following the hemodialysis session, depending on the patient’s clinical situation [see Clinical Pharmacology (12.3)] .

No adjustment in LIKMEZ dose is needed in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [see Clinical Pharmacology (12.3)] .

Shake the bottle well before administering the recommended dosage.

Use a calibrated oral dosing device to correctly measure the prescribed dose of medication. Do not use household teaspoons or tablespoons to measure doses. Calibrated oral dosing devices may be obtained from the pharmacy.

Oral Suspension:500 mg/5 mL white to slightly brown suspension with a characteristic strawberry peppermint flavor.

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LIKMEZ is contraindicated in patients with known hypersensitivity to metronidazole or other nitroimidazole derivatives [see  Adverse Reactions (6.1)] .

LIKMEZ is contraindicated in patients who have used disulfiram within the last two weeks. Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently [see Drug Interactions (7.1)] .

LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least three days after LIKMEZ therapy. Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing [see Drug Interactions (7.2)] .

LIKMEZ is contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome [see Adverse Reactions (6.2)] .

Metronidazole has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [see Nonclinical Toxicology (13.1)] .  Avoid unnecessary use of LIKMEZ. Reserve LIKMEZ for use in the following indications: trichomoniasis [see  Indications and Usage (1.1)] , amebiasis [see Indications and Usage (1.2)] and anaerobic bacterial infections [see  Indications and Usage (1.3)].

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue LIKMEZ immediately and institute appropriate therapy.

Encephalopathy, aseptic meningitis, peripheral neuropathy (including optic neuropathy) and convulsive seizures have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Cases of aseptic meningitis have been reported with metronidazole [ see Adverse Reactions (6.1)]. Symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurological signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with LIKMEZ and requires treatment with an antifungal agent.

LIKMEZ is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during metronidazole administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy [see Adverse Reactions (6.1)] .

Prescribing LIKMEZ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of thedevelopment of drug-resistant bacteria.

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.

The following reactions have been reported during treatment with metronidazole:

Central and Peripheral Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity.  Persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole. In addition, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia have been reported.

Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation.

Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candidawhich may occur during therapy.

Dermatologic: Erythematous rash and pruritus.

Hematopoietic: Reversible neutropenia (leukopenia); reversible thrombocytopenia.

Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T‑wave may be seen in electrocardiographic tracings.

Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

Other: Proliferation of Candidain the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.

Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause-and-effect relationship has not been established. Crohn’s disease is not an approved indication for LIKMEZ.

The following adverse reactions have been identified during post-approval use of metronidazole. 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.

The cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) [ see Contraindications (4.4)] .

Central and Peripheral Nervous System: Tinnitus, hearing impairment, and hearing loss.

Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) [ see Warnings and Precautions (5.2)] .

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. LIKMEZ is contraindicated in patients who have taken disulfiram within the last two weeks [see Contraindications (4.2)] .

LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least 3 days after therapy with LIKMEZ. Use of LIKMEZ with alcohol or other products containing propylene glycol is associated with a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) [see Contraindications (4.3)] .

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When LIKMEZ is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.

In patients stabilized on relatively high doses of lithium, short-term use of LIKMEZ has been associated with elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations for several days after beginning treatment with LIKMEZ to detect any increase that may precede clinical symptoms of lithium toxicity.

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer LIKMEZ concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to LIKMEZ are available, and concomitant administration with busulfan is medically needed, monitor for busulfan plasma concentrations and adjust the busulfan dose accordingly.

The simultaneous administration of LIKMEZ and drugs that decrease microsomal liver enzymes, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

The simultaneous administration of LIKMEZ and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported.

QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD +⇌ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Risk Summary

While available studies cannot definitively establish the absence of risk, published data from case-control studies, cohort studies and meta-analyses have not established an association with metronidazole use during pregnancy and major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data).

The 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. 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.

Data

Human Data

There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5,000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5,000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Animal Data

Metronidazole crosses the placental barrier. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Risk Summary

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. There are no data on the effects of metronidazole on milk production. Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice [see  Nonclinical Toxicology (13.1)]. This drug is not intended to be administered chronically; therefore, the clinical relevance of the findings of the animal studies is unclear.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LIKMEZ and any potential adverse effects on the breastfed infant from LIKMEZ or from the underlying maternal condition. Alternatively, a lactating woman may choose to pump and discard human milk for the duration of LIKMEZ therapy, and for 48 hours after the last dose and feed her infant stored human milk or formula.

The safety and effectiveness of LIKMEZ for the treatment of amebiasis have been established in pediatric patients.

The safety and effectiveness of LIKMEZ for the treatment of trichomoniasis and anaerobic bacterial infections have not been established in pediatric patients.

In elderly geriatric patients, monitoring for LIKMEZ associated adverse reactions is recommended  [see  Clinical Pharmacology (12.3)] . Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage  [see  Dosage and Administration (2.4)].

Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitor for LIKMEZ associated adverse reactions [see Clinical Pharmacology (12.3)] .

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of LIKMEZ by 50%. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for LIKMEZ associated adverse reactions [ see Clinical Pharmacology (12.3)and Dosage and Administration (2.4)] .

General

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

Single oral doses of metronidazole, up to 15 g (7.5 times the maximum recommended single dose), have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable.

{ "type": "p", "children": [], "text": "Single oral doses of metronidazole, up to 15 g (7.5 times the maximum recommended single dose), have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable." }

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 days to 7 days of doses of 6 g to 10.4 g every other day (3 times to 5.2 times the maximum recommended single dose).

{ "type": "p", "children": [], "text": "Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 days to 7 days of doses of 6 g to 10.4 g every other day (3 times to 5.2 times the maximum recommended single dose)." }

Treatment of Overdosage

{ "type": "p", "children": [], "text": "\nTreatment of Overdosage\n" }

There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

{ "type": "p", "children": [], "text": "There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy." }

LIKMEZ (metronidazole) oral suspension is a nitroimidazole antimicrobial. The chemical name of metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The structural formula is shown as:

{ "type": "p", "children": [], "text": "LIKMEZ (metronidazole) oral suspension is a nitroimidazole antimicrobial. The chemical name of metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The structural formula is shown as:" }

Metronidazole is a white to pale yellow crystalline powder with a molecular formula of C 6H 9N 3O 3and a molecular weight of 171.2 g/mole. The pKa of metronidazole is 14.44 ± 0.10. The pH of a 1% aqueous solution of metronidazole is 5.5-7.5. It is slightly soluble in water, acetone, alcohol, and methylene chloride.

{ "type": "p", "children": [], "text": "Metronidazole is a white to pale yellow crystalline powder with a molecular formula of C 6H 9N 3O 3and a molecular weight of 171.2 g/mole. The pKa of metronidazole is 14.44 ± 0.10. The pH of a 1% aqueous solution of metronidazole is 5.5-7.5. It is slightly soluble in water, acetone, alcohol, and methylene chloride." }

LIKMEZ is an oral suspension containing 500 mg of metronidazole per 5 mL, and the following inactive ingredients: Glycerin, magnesium aluminum silicate, methylparaben, microcrystalline cellulose, natural peppermint flavor, natural strawberry flavor, propylparaben, purified water, sodium phosphate dibasic, sodium phosphate monobasic, sucralose, and sucrose.

{ "type": "p", "children": [], "text": "LIKMEZ is an oral suspension containing 500 mg of metronidazole per 5 mL, and the following inactive ingredients: Glycerin, magnesium aluminum silicate, methylparaben, microcrystalline cellulose, natural peppermint flavor, natural strawberry flavor, propylparaben, purified water, sodium phosphate dibasic, sodium phosphate monobasic, sucralose, and sucrose." }

Metronidazole is a nitroimidazole antimicrobial drug [see  Microbiology (12.4)] .

Metronidazole pharmacokinetics are similar for both oral and intravenous dosage forms. The C maxis dose proportional between 250 mg, 500 mg, and 2,000 mg for metronidazole oral tablets, producing peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively.

Absorption

Following oral administration, LIKMEZ is well absorbed, with peak plasma concentrations occurring between 0.25 and 6 hours after administration.

Two pharmacokinetic studies (Study 1 and Study 2) performed in healthy adult volunteers evaluated the bioavailability of LIKMEZ under fasting and fed conditions.

Effect of Food

Food delays T maxand lowers C maxwhen compared to fasted conditions, but systemic exposure (AUC) is similar in fed and fasted state (see Table 1).

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 1: Mean (± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 500 mg LIKMEZ in Healthy Adults Under Fed and Fasting Conditions</span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Median (min max)</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Fed study administered LIKMEZ following a high-fat, high-calorie breakfast (approximately 1,000 calories, 26.5% carbohydrates, 16.5% protein, and 57% fat).</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center"><span class="Bold">Formulation</span></td><td align="center"><span class="Bold">C <span class="Sub">max</span></span> <br/> <span class="Bold">(mcg/mL)</span></td><td align="center"><span class="Bold">AUC <span class="Sub">0-∞</span></span> <br/> <span class="Bold">(mcg.h/mL)</span></td><td align="center"><span class="Bold">Tmax <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> <br/> <span class="Bold">(h)</span></td> </tr> <tr> <td colspan="4"><span class="Bold">Study 1- Fasting state (n = 44)</span></td> </tr> <tr> <td><span class="Bold">LIKMEZ</span></td><td align="center">13 ± 3</td><td align="center">146 ± 36</td><td align="center">0.75 <br/> (0.25 to 6) </td> </tr> <tr> <td colspan="4"><span class="Bold">Study 2- Fed State <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> (n = 46) </span></td> </tr> <tr class="Last"> <td><span class="Bold">LIKMEZ</span></td><td align="center">10 ± 1</td><td align="center">144 ± 30</td><td align="center">2.33 <br/> (0.25 to 4) </td> </tr> </tbody> </table></div>

Distribution

Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Elimination

Metabolism

The metabolites of metronidazole that appear in the urine result primarily from side-chain oxidation [1-(-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitroantimicrobial activity.

Excretion

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose.

Renal clearance of metronidazole is approximately 10 mL/min/1.73 m 2. The average elimination half-life of LIKMEZ in healthy adult subjects is nine hours.

Specific Populations

Geriatric Patients

Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy‑metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls <40 years old  [see Use in Specific Populations (8.5)] .

Pediatric Patients

In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first 3 days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 weeks and 40 weeks, the corresponding elimination half-lives ranged from 109 hours to 22.5 hours.

Male and Female Patients

Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower.

Patients with Renal Impairment

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.

Subjects with end-stage renal disease (ESRD; CL CR= 8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher C maxof hydroxy-metronidazole and 5‑fold higher C maxof metronidazole acetate, compared to healthy subjects with normal renal function (CL CR= 126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse reactions are recommended [see Use in Specific Populations (8.6)] .

Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 hours to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered [see  Dosage and Administration (2.5)]. A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.

Patients with Hepatic Impairment

Following a single intravenous infusion of 500 mg metronidazole, the mean AUC 24of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC 24of hydroxyl-metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment. No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse reactions [see Use in Specific Populations (8.7)and Dosage and Administration (2.4)].

Mechanism of Action

Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear.

Resistance

A potential for development of resistance exists against metronidazole.

Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair.

Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.

Antimicrobial Activity

Metronidazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see  Indications and Usage(1)].

Gram-positive anaerobes

      Clostridiumspecies Eubacterium species

      Peptococcus species

      Peptostreptococcus species

Gram-negative anaerobes

      Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, B. vulgatus)

      Parabacteroides distasonis

      Fusobacterium species

Protozoal parasites

      Entamoeba histolytica

      Trichomonas vaginalis

The following in vitrodata are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for metronidazole against isolates of similar genus or organism group. However, the efficacy of metronidazole in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative anaerobes

      Bacteroides fragilisgroup (B. caccae, B. uniformis)

      Prevotellaspecies (P. bivia, P. buccae, P. disiens)

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis

Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters. Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1,500 mg/m 2(similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Mutagenesis

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Impairment of Fertility

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up at 400 mg/kg/day (similar to the maximum recommended clinical dose, based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight-week, drug-free recovery period.

How Supplied

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

LIKMEZ 500 mg/5 mL is a white to slightly brown suspension with characteristic strawberry peppermint flavor packed in white HDPE round bottles with a child-resistant cap and supplied as follows:

{ "type": "p", "children": [], "text": "LIKMEZ 500 mg/5 mL is a white to slightly brown suspension with characteristic strawberry peppermint flavor packed in white HDPE round bottles with a child-resistant cap and supplied as follows:" }

NDC 71656-066-75   Bottles of 75 mL 

{ "type": "p", "children": [], "text": "NDC 71656-066-75   Bottles of 75 mL " }

NDC 71656-066-20   Bottles of 200 mL 

{ "type": "p", "children": [], "text": "NDC 71656-066-20   Bottles of 200 mL " }

Storage

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

Store between 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted [See USP Controlled Room Temperature]. Do not freeze.

{ "type": "p", "children": [], "text": "Store between 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted [See USP Controlled Room Temperature].\n \n Do not freeze.\n\n " }

Dispense in a tight container as defined in USP. Discard 60 days after opening container.

{ "type": "p", "children": [], "text": "Dispense in a tight container as defined in USP. Discard 60 days after opening container." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

Administration Instructions

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

Instruct the patients and caregivers to: • Ensure the prescribed dose of LIKMEZ oral suspension is taken as directed [ see Dosage and Administration (2)]. • Use a calibrated oral dosing device to correctly measure the prescribed dose of medication. Do not use a household teaspoon or tablespoon to measure doses. Calibrated oral dosing devices may be obtained from the pharmacy. • Shake LIKMEZ oral suspension well before use each time.

{ "type": "p", "children": [], "text": "Instruct the patients and caregivers to: \n • Ensure the prescribed dose of LIKMEZ oral suspension is taken as directed\n \n [\n \n see Dosage and Administration (2)]. \n • Use a calibrated oral dosing device to correctly measure the prescribed dose of medication. Do not use a household teaspoon or tablespoon to measure doses. Calibrated oral dosing devices may be obtained from the pharmacy. \n • Shake LIKMEZ oral suspension well before use each time.\n\n " }

Severe Cutaneous Adverse Reactions

{ "type": "p", "children": [], "text": "\nSevere Cutaneous Adverse Reactions\n" }

Advise patients that LIKMEZ may increase the risk of serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS). Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop LIKMEZ immediately if they develop any type of rash and seek medical attention [ see Warnings and Precautions (5.2)] .

{ "type": "p", "children": [], "text": "Advise patients that LIKMEZ may increase the risk of serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS). Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop LIKMEZ immediately if they develop any type of rash and seek medical attention\n \n [\n \n see Warnings and Precautions (5.2)]\n \n .\n\n " }

Alcohol or Products Containing Propylene Glycol

{ "type": "p", "children": [], "text": "\nAlcohol or Products Containing Propylene Glycol\n" }

Advise patients to avoid consumption of alcoholic beverages and preparations containing ethanol or propylene glycol during LIKMEZ therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur [ see Contraindications (4.3)and Drug Interactions (7.2)] .

{ "type": "p", "children": [], "text": "Advise patients to avoid consumption of alcoholic beverages and preparations containing ethanol or propylene glycol during LIKMEZ therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur\n \n [\n \n see Contraindications (4.3)and\n \n Drug Interactions (7.2)]\n \n .\n\n " }

Lactation

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

Advise lactating women that they may choose to pump and discard human milk for the duration of LIKMEZ therapy and for 48 hours after the last dose and feed her infant stored human milk or formula [see Use in Specific Populations (8.2)] .

{ "type": "p", "children": [], "text": "Advise lactating women that they may choose to pump and discard human milk for the duration of LIKMEZ therapy and for 48 hours after the last dose and feed her infant stored human milk or formula\n \n [see\n \n Use in Specific Populations (8.2)]\n \n .\n\n " }

Central and Peripheral Nervous System Effects

{ "type": "p", "children": [], "text": "\nCentral and Peripheral Nervous System Effects\n" }

Inform patients of the risk of central and peripheral nervous system effects while taking LIKMEZ. Advise patients to stop taking LIKMEZ and report immediately to their healthcare provider if any neurological symptoms occur [see Warnings and Precautions (5.3)] .

{ "type": "p", "children": [], "text": "Inform patients of the risk of central and peripheral nervous system effects while taking LIKMEZ. Advise patients to stop taking LIKMEZ and report immediately to their healthcare provider if any neurological symptoms occur\n \n [see\n \n Warnings and Precautions (5.3)]\n \n .\n\n " }

Drug Interactions

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

Advise patients to report the use of any other medications while taking LIKMEZ. Theadministration of any of the following drugs with LIKMEZ may result in clinically significant adverse reactions or reduced effectiveness of the drug [see Contraindications (4.2)and Drug Interactions (7.1to 7.7)] :

{ "type": "p", "children": [], "text": "Advise patients to report the use of any other medications while taking LIKMEZ. Theadministration of any of the following drugs with LIKMEZ may result in clinically significant adverse reactions or reduced effectiveness of the drug\n \n [see\n \n Contraindications (4.2)and\n \n Drug Interactions (7.1to\n \n 7.7)]\n \n :\n\n " }

{ "type": "ul", "children": [ "Disulfiram", "Warfarin and other oral Anticoagulants", "Lithium", " Busulfan", "Cimetidine", "Phenytoin and Phenobarbital" ], "text": "" }

Antibacterial Resistance Patients should be counseled that antibacterial drugs including LIKMEZ should only be usedto treat bacterial infections. They do not treat viral infections (e.g., the common cold). WhenLIKMEZ is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by LIKMEZ or other antibacterial drugs in the future.

{ "type": "p", "children": [], "text": "\nAntibacterial Resistance\n Patients should be counseled that antibacterial drugs including LIKMEZ should only be usedto treat bacterial infections. They do not treat viral infections (e.g., the common cold). WhenLIKMEZ is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by LIKMEZ or other antibacterial drugs in the future.\n\n " }

Distributed by: Saptalis Pharmaceuticals LLC Hauppauge, NY 11788 Made in USA

{ "type": "p", "children": [], "text": "Distributed by: \n Saptalis Pharmaceuticals LLC \n Hauppauge, NY 11788 \n Made in USA\n " }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="55%"/> <col align="left" valign="top" width="43%"/> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="2">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="center"> <p class="First">Issued: 07/2024</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="center" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">PATIENT INFORMATION</span> </p> <p> <span class="Bold">LIKMEZ <span class="Sup">®</span>(lik mez) </span> </p> <p> <span class="Bold">(metronidazole)</span> </p> <p> <span class="Bold">oral suspension</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">What is LIKMEZ?</span> </p> <p>LIKMEZ is an antibiotic medicine used to treat:</p> <ul> <li>trichomoniasis (a sexually transmitted infection) in adults</li> <li>amebiasis (an infection caused by a parasite) in adults and children</li> <li>anaerobic bacterial infections (infections caused by bacteria that do not need oxygen to survive) in adults</li> </ul>It is not known if LIKMEZ is safe and effective in children, except for the treatment of amebiasis. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">Do not take LIKMEZ if you:</span> </p> <ul> <li>are allergic to metronidazole or other nitroimidazole medicines.</li> <li>have taken disulfiram (medicine used to help people stop drinking alcohol) in the last 2 weeks. Taking LIKMEZ with disulfiram can cause psychotic symptoms (seeing or hearing things that are not really there) in people who drink alcohol.</li> <li>drink alcohol or use products with propylene glycol during treatment with LIKMEZ and for at least 3 days after you stop taking LIKMEZ, because this can cause side effects including abdominal cramps, nausea, vomiting, headaches, and flushing.</li> <li>have Cockayne Syndrome (a rare genetic disorder that affects growth and development).</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">Before taking LIKMEZ, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <ul> <li>have liver problems.</li> <li>have kidney problems.</li> <li>have medical problems that affect the brain.</li> <li>have a yeast infection.</li> <li>have a history of blood problems.  </li> <li>are breastfeeding or plan to breastfeed. LIKMEZ can pass into your breastmilk. Talk to your healthcare provider about the best way to feed your baby while taking LIKMEZ. If you are breastfeeding, you may consider pumping and throwing away your breast milk during treatment with LIKMEZ and for 48 hours after your last dose of LIKMEZ and feeding your infant stored human milk or formula.</li> </ul> <p>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. LIKMEZ and other medicines can affect each other causing side effects.</p> <p> <span class="Bold">Especially tell your healthcare provider if you take</span>: </p> <ul> <li>warfarin or other blood thinners (anticoagulants)</li> <li>lithium</li> <li>busulfan</li> <li>cimetidine</li> <li>phenytoin and phenobarbital</li> </ul> <p>You can ask your pharmacist for a list of medicines that interact with LIKMEZ.</p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">How should I take LIKMEZ?</span> </p> <ul> <li>Take LIKMEZ exactly as your healthcare provider tells you to.</li> <li>Shake LIKMEZ oral suspension well before each use.</li> <li>Always use an accurate measuring device to measure the correct amount of LIKMEZ. <span class="Bold">Do not</span>use a household teaspoon or tablespoon to measure your medicine. You can ask your pharmacist for the measuring device you should use and how to measure the correct dose. </li> <li>Do not skip any doses of LIKMEZ or stop taking it, even if you begin to feel better, until you have finished your prescribed treatment. Taking all of your LIKMEZ doses will help make sure that all of the bacteria are killed. Taking all of your LIKMEZ doses will help lower the chance that the bacteria will become resistant to LIKMEZ. If you become resistant to LIKMEZ, LIKMEZ and other antibacterial medicines may not work for you in the future.</li> </ul>If you take too much LIKMEZ, call your healthcare provider or go to the nearest emergency room right away. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">What are the possible side effects of LIKMEZ?</span> </p> <p> <span class="Bold">LIKMEZ may cause serious side effects including</span>: </p> <ul> <li> <span class="Bold">Severe skin reactions </span>Serious skin reactions that may affect any part of the body and can lead to death, including toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have happened in some people taking metronidazole (the active ingredient in LIKMEZ). These severe skin reactions may be life threatening and you may need to be treated in a hospital. Stop taking LIKMEZ right away and call your healthcare provider or get emergency help if you have any of the following symptoms: </li> </ul> <ul> <li>skin rash or acne                                                                                       • blisters or sores in your mouth</li> <li>dry skin                                                                                                     • peeling of your skin </li> <li>itching                                                                                                       • fever</li> <li>blisters on your skin                                                                                  • muscle or joint aches</li> <li>redness or swelling of your face, hands, or soles of your feet                  •  swollen glands                                                   </li> </ul> <ul> <li> <span class="Bold">Nervous system problems</span>, including brain disorder (encephalopathy), inflammation of the brain and spinal cord membranes (aseptic meningitis), numbness or tingling in the hands or feet (peripheral neuropathy) and seizures (convulsions). Tell your healthcare provider right away if you have any nervous system problems while taking LIKMEZ. </li> <li> <span class="Bold">Worsening yeast infection (candidiasis) symptoms</span>in people with a known yeast infection or a yeast infection they were not aware of.  </li> <li> <span class="Bold">Low white blood cell count (leukopenia) in people with a history of blood problems</span>. This can affect how well the body fights infection. </li> </ul> <p> <span class="Bold">The most common side effects of LIKMEZ include:</span> nausea, headache, anorexia, vomiting, diarrhea, pain in the upper abdomen, abdominal cramping, and constipation. </p> <p class="Default"> <span class="Bold">Other side effects of LIKMEZ include:</span> </p> <ul> <li>allergic reactions: such as itching, hives (urticaria), flushing of the skin, red skin rash that can be widespread, blisters and separation of skin layers, nasal congestion, dryness of the mouth and vagina, and fever</li> <li>abnormal heart rhythm (QT prolongation)</li> </ul>These are not all the possible side effects of LIKMEZ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA-1088. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">How should I store LIKMEZ?</span> </p> <ul> <li>Store LIKMEZ oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Do not freeze.</li> <li>Throw away (discard) any unused LIKMEZ 60 days after opening the container.</li> </ul> <span class="Bold">Keep LIKMEZ and all medicines out of the reach of children</span>. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">General information about the safe and effective use of LIKMEZ.</span> </p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LIKMEZ for a condition for which it was not prescribed. Do not give LIKMEZ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LIKMEZ that is written for health professionals. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">What are the ingredients in LIKMEZ?</span> </p> <p> <span class="Bold">Active ingredient:</span>metronidazole </p> <span class="Bold">Inactive ingredients:</span>glycerin, magnesium aluminum silicate, methylparaben, microcrystalline cellulose, natural peppermint flavor, natural strawberry flavor, propylparaben, purified water, sodium phosphate dibasic, sodium phosphate monobasic, sucralose, and sucrose. </td> </tr> <tr class="Botrule Last Last"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First">Manufactured by:</p> <p>Saptalis Pharmaceuticals LLC</p> <p>Hauppauge, NY 11788</p> <p>Made in USA</p>For more information, call 1-833-727-8254. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"55%\"/>\n<col align=\"left\" valign=\"top\" width=\"43%\"/>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" colspan=\"2\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"center\">\n<p class=\"First\">Issued: 07/2024</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">PATIENT INFORMATION</span>\n</p>\n<p>\n<span class=\"Bold\">LIKMEZ\n \n <span class=\"Sup\">®</span>(lik mez)\n \n </span>\n</p>\n<p>\n<span class=\"Bold\">(metronidazole)</span>\n</p>\n<p>\n<span class=\"Bold\">oral suspension</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">What is LIKMEZ?</span>\n</p>\n<p>LIKMEZ is an antibiotic medicine used to treat:</p>\n<ul>\n<li>trichomoniasis (a sexually transmitted infection) in adults</li>\n<li>amebiasis (an infection caused by a parasite) in adults and children</li>\n<li>anaerobic bacterial infections (infections caused by bacteria that do not need oxygen to survive) in adults</li>\n</ul>It is not known if LIKMEZ is safe and effective in children, except for the treatment of amebiasis.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take LIKMEZ if you:</span>\n</p>\n<ul>\n<li>are allergic to metronidazole or other nitroimidazole medicines.</li>\n<li>have taken disulfiram (medicine used to help people stop drinking alcohol) in the last 2 weeks. Taking LIKMEZ with disulfiram can cause psychotic symptoms (seeing or hearing things that are not really there) in people who drink alcohol.</li>\n<li>drink alcohol or use products with propylene glycol during treatment with LIKMEZ and for at least 3 days after you stop taking LIKMEZ, because this can cause side effects including abdominal cramps, nausea, vomiting, headaches, and flushing.</li>\n<li>have Cockayne Syndrome (a rare genetic disorder that affects growth and development).</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking LIKMEZ, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<ul>\n<li>have liver problems.</li>\n<li>have kidney problems.</li>\n<li>have medical problems that affect the brain.</li>\n<li>have a yeast infection.</li>\n<li>have a history of blood problems.  </li>\n<li>are breastfeeding or plan to breastfeed. LIKMEZ can pass into your breastmilk. Talk to your healthcare provider about the best way to feed your baby while taking LIKMEZ. If you are breastfeeding, you may consider pumping and throwing away your breast milk during treatment with LIKMEZ and for 48 hours after your last dose of LIKMEZ and feeding your infant stored human milk or formula.</li>\n</ul>\n<p>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. LIKMEZ and other medicines can affect each other causing side effects.</p>\n<p>\n<span class=\"Bold\">Especially tell your healthcare provider if you take</span>:\n \n </p>\n<ul>\n<li>warfarin or other blood thinners (anticoagulants)</li>\n<li>lithium</li>\n<li>busulfan</li>\n<li>cimetidine</li>\n<li>phenytoin and phenobarbital</li>\n</ul>\n<p>You can ask your pharmacist for a list of medicines that interact with LIKMEZ.</p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take LIKMEZ?</span>\n</p>\n<ul>\n<li>Take LIKMEZ exactly as your healthcare provider tells you to.</li>\n<li>Shake LIKMEZ oral suspension well before each use.</li>\n<li>Always use an accurate measuring device to measure the correct amount of LIKMEZ.\n \n <span class=\"Bold\">Do not</span>use a household teaspoon or tablespoon to measure your medicine. You can ask your pharmacist for the measuring device you should use and how to measure the correct dose.\n \n </li>\n<li>Do not skip any doses of LIKMEZ or stop taking it, even if you begin to feel better, until you have finished your prescribed treatment. Taking all of your LIKMEZ doses will help make sure that all of the bacteria are killed. Taking all of your LIKMEZ doses will help lower the chance that the bacteria will become resistant to LIKMEZ. If you become resistant to LIKMEZ, LIKMEZ and other antibacterial medicines may not work for you in the future.</li>\n</ul>If you take too much LIKMEZ, call your healthcare provider or go to the nearest emergency room right away.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of LIKMEZ?</span>\n</p>\n<p>\n<span class=\"Bold\">LIKMEZ may cause serious side effects including</span>:\n \n </p>\n<ul>\n<li>\n<span class=\"Bold\">Severe skin reactions </span>Serious skin reactions that may affect any part of the body and can lead to death, including toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have happened in some people taking metronidazole (the active ingredient in LIKMEZ). These severe skin reactions may be life threatening and you may need to be treated in a hospital. Stop taking LIKMEZ right away and call your healthcare provider or get emergency help if you have any of the following symptoms:\n \n </li>\n</ul>\n<ul>\n<li>skin rash or acne                                                                                       • blisters or sores in your mouth</li>\n<li>dry skin                                                                                                     • peeling of your skin </li>\n<li>itching                                                                                                       • fever</li>\n<li>blisters on your skin                                                                                  • muscle or joint aches</li>\n<li>redness or swelling of your face, hands, or soles of your feet                  •  swollen glands                                                   </li>\n</ul>\n<ul>\n<li>\n<span class=\"Bold\">Nervous system problems</span>, including brain disorder (encephalopathy), inflammation of the brain and spinal cord membranes (aseptic meningitis), numbness or tingling in the hands or feet (peripheral neuropathy) and seizures (convulsions). Tell your healthcare provider right away if you have any nervous system problems while taking LIKMEZ.\n \n </li>\n<li>\n<span class=\"Bold\">Worsening yeast infection (candidiasis) symptoms</span>in people with a known yeast infection or a yeast infection they were not aware of. \n \n </li>\n<li>\n<span class=\"Bold\">Low white blood cell count (leukopenia) in people with a history of blood problems</span>. This can affect how well the body fights infection.\n \n </li>\n</ul>\n<p>\n<span class=\"Bold\">The most common side effects of LIKMEZ include:</span> nausea, headache, anorexia, vomiting, diarrhea, pain in the upper abdomen, abdominal cramping, and constipation.\n \n </p>\n<p class=\"Default\">\n<span class=\"Bold\">Other side effects of LIKMEZ include:</span>\n</p>\n<ul>\n<li>allergic reactions: such as itching, hives (urticaria), flushing of the skin, red skin rash that can be widespread, blisters and separation of skin layers, nasal congestion, dryness of the mouth and vagina, and fever</li>\n<li>abnormal heart rhythm (QT prolongation)</li>\n</ul>These are not all the possible side effects of LIKMEZ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA-1088.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store LIKMEZ?</span>\n</p>\n<ul>\n<li>Store LIKMEZ oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Do not freeze.</li>\n<li>Throw away (discard) any unused LIKMEZ 60 days after opening the container.</li>\n</ul>\n<span class=\"Bold\">Keep LIKMEZ and all medicines out of the reach of children</span>.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of LIKMEZ.</span>\n</p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LIKMEZ for a condition for which it was not prescribed. Do not give LIKMEZ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LIKMEZ that is written for health professionals.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in LIKMEZ?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span>metronidazole\n \n </p>\n<span class=\"Bold\">Inactive ingredients:</span>glycerin, magnesium aluminum silicate, methylparaben, microcrystalline cellulose, natural peppermint flavor, natural strawberry flavor, propylparaben, purified water, sodium phosphate dibasic, sodium phosphate monobasic, sucralose, and sucrose.\n \n </td>\n</tr>\n<tr class=\"Botrule Last Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">Manufactured by:</p>\n<p>Saptalis Pharmaceuticals LLC</p>\n<p>Hauppauge, NY 11788</p>\n<p>Made in USA</p>For more information, call 1-833-727-8254.\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

71656-066-20

{ "type": "p", "children": [], "text": "\n71656-066-20\n" }

LIKMEZ ®

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

(metronidazole) Oral Supension

{ "type": "p", "children": [], "text": "\n(metronidazole) Oral Supension\n" }

500 mg/mL

{ "type": "p", "children": [], "text": "\n500 mg/mL\n" }

(100 mg/mL)

{ "type": "p", "children": [], "text": "\n(100 mg/mL)\n" }

Strawberry Peppermint Flavor

{ "type": "p", "children": [], "text": "\nStrawberry Peppermint Flavor\n" }

For Oral Use Only

{ "type": "p", "children": [], "text": "\nFor Oral Use Only\n" }

Rx only

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

200 mL

{ "type": "p", "children": [], "text": "\n200 mL\n" }

71656-066-75

{ "type": "p", "children": [], "text": "\n71656-066-75\n" }

LIKMEZ ®

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

(metronidazole) Oral Supension

{ "type": "p", "children": [], "text": "\n(metronidazole) Oral Supension\n" }

500 mg/mL

{ "type": "p", "children": [], "text": "\n500 mg/mL\n" }

(100 mg/mL)

{ "type": "p", "children": [], "text": "\n(100 mg/mL)\n" }

Strawberry Peppermint Flavor

{ "type": "p", "children": [], "text": "\nStrawberry Peppermint Flavor\n" }

For Oral Use Only

{ "type": "p", "children": [], "text": "\nFor Oral Use Only\n" }

Rx only

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

75 mL

{ "type": "p", "children": [], "text": "\n75 mL\n" }

Metronidazole Gel, 1% is indicated for the topical treatment of inflammatory lesions of rosacea. 

{ "type": "p", "children": [], "text": "Metronidazole Gel, 1% is indicated for the topical treatment of inflammatory lesions of rosacea. " }

{ "type": "ul", "children": [ "Cleanse treated areas before the application of Metronidazole Gel.", "Apply and rub in a thin film of Metronidazole Gel once daily to affected area(s). ", "Cosmetics may be applied after the application of Metronidazole Gel. ", "For topical use only, not for oral, ophthalmic, or intravaginal use." ], "text": "" }

Gel, 1%. Metronidazole Gel is a clear, colorless to pale yellow gel. Each gram of Metronidazole Gel contains 10 mg (1%) of metronidazole.

{ "type": "p", "children": [], "text": "Gel, 1%. Metronidazole Gel is a clear, colorless to pale yellow gel. Each gram of Metronidazole Gel contains 10 mg (1%) of metronidazole.\n" }

Metronidazole Gel is contraindicated in patients with a history of hypersensitivity to metronidazole or to any other ingredient in the formulation.

{ "type": "p", "children": [], "text": "Metronidazole Gel is contraindicated in patients with a history of hypersensitivity to metronidazole or to any other ingredient in the formulation." }

Peripheral neuropathy, characterized by numbness or paresthesia of an extremity, has been reported in patients treated with systemic metronidazole. Peripheral neuropathy has been reported with the post approval use of topical metronidazole. Immediately reevaluate Metronidazole Gel therapy if abnormal neurologic signs appear. Administer metronidazole with caution to patients with central nervous system diseases.

Metronidazole is a nitroimidazole; use with care in patients with evidence of, or history of, blood dyscrasia.

Irritant and allergic contact dermatitis have been reported with Metronidazole Gel. If dermatitis occurs, patients may need to discontinue use.

Topical metronidazole has been reported to cause tearing of the eyes.  Avoid contact with the eyes.

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. In a controlled clinical trial, 557 subjects used Metronidazole Gel and 189 subjects used the gel vehicle once daily for up to 10 weeks. The following table summarizes selected adverse reactions that occurred at a rate of ≥1% and at a higher rate than vehicle:

<div class="scrollingtable"><table class="Noautorules" width="90%"> <caption> <span>Table 1: Adverse Reactions That Occurred at a Rate of ≥1% and Higher Than Vehicle in Subjects Treated with Metronidazole Gel for Up to 10 Weeks</span> </caption> <colgroup> <col width="50%"/> <col width="25%"/> <col width="25%"/> </colgroup> <thead> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Preferred Term</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Metronidazole Gel</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Gel Vehicle</span></td> </tr> </thead> <tbody> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Influenza</td><td align="center" class="Botrule Lrule Rrule Toprule">8 (1.4)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Upper respiratory tract infection</td><td align="center" class="Botrule Lrule Rrule Toprule">14 (2.5)</td><td align="center" class="Botrule Lrule Rrule Toprule">4 (2.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Urinary tract infection</td><td align="center" class="Botrule Lrule Rrule Toprule">6 (1.1)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Headache</td><td align="center" class="Botrule Lrule Rrule Toprule">12 (2.2)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Contact dermatitis</td><td align="center" class="Botrule Lrule Rrule Toprule">7 (1.3)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Hypertension</td><td align="center" class="Botrule Lrule Rrule Toprule">6 (1.1)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline in Subjects Treated with Metronidazole Gel for Up to 10 Weeks</span> </caption> <colgroup> <col width="50%"/> <col width="25%"/> <col width="25%"/> </colgroup> <thead> <tr class="First Last"> <td align="left" class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Metronidazole Gel</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Gel Vehicle</span></td> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Sign/Symptom</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">N= 544 N (%)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">N= 184 N (%)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Dryness</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">138 (25.4)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">63 (34.2)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Mild</td><td align="center" class="Botrule Lrule Rrule Toprule">93 (17.1)</td><td align="center" class="Botrule Lrule Rrule Toprule">41 (22.3)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Moderate</td><td align="center" class="Botrule Lrule Rrule Toprule">42 (7.7)</td><td align="center" class="Botrule Lrule Rrule Toprule">20 (10.9)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Severe</td><td align="center" class="Botrule Lrule Rrule Toprule">3 (0.6)</td><td align="center" class="Botrule Lrule Rrule Toprule">2 (1.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Scaling</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">134 (24.6)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">60 (32.6)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Mild</td><td align="center" class="Botrule Lrule Rrule Toprule">88 (16.2)</td><td align="center" class="Botrule Lrule Rrule Toprule">32 (17.4)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Moderate</td><td align="center" class="Botrule Lrule Rrule Toprule">43 (7.9)</td><td align="center" class="Botrule Lrule Rrule Toprule">27 (14.7)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Severe</td><td align="center" class="Botrule Lrule Rrule Toprule">3 (0.6)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Pruritus</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">86 (15.8)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">35 (19.0)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Mild</td><td align="center" class="Botrule Lrule Rrule Toprule">53 (9.7)</td><td align="center" class="Botrule Lrule Rrule Toprule">21 (11.4)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Moderate</td><td align="center" class="Botrule Lrule Rrule Toprule">27 (5.0)</td><td align="center" class="Botrule Lrule Rrule Toprule">13 (7.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Severe</td><td align="center" class="Botrule Lrule Rrule Toprule">6 (1.1)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Stinging/burning</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">56 (10.3)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">28 (15.2)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Mild</td><td align="center" class="Botrule Lrule Rrule Toprule">39 (7.2)</td><td align="center" class="Botrule Lrule Rrule Toprule">18 (9.8)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">   Moderate</td><td align="center" class="Botrule Lrule Rrule Toprule">7 (1.3)</td><td align="center" class="Botrule Lrule Rrule Toprule">9 (4.9)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule">   Severe</td><td align="center" class="Botrule Lrule Rrule Toprule">10 (1.8)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.5)</td> </tr> </tbody> </table></div>

The following additional adverse experiences have been reported with the topical use of metronidazole: transient redness, metallic taste, tingling or numbness of extremities, and nausea.

The following adverse reaction has been identified during post- approval use of topical metronidazole. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Nervous System Disorders: Peripheral neuropathy  Ophthalmic Adverse Reactions: Tearing of the eyes

Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Use caution when prescribing for patients who are receiving anticoagulant treatment.

{ "type": "p", "children": [], "text": "Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Use caution when prescribing for patients who are receiving anticoagulant treatment." }

Risk Summary Available data have not established an association with metronidazole use during pregnancy and major birth defects, miscarriage or other adverse maternal or fetal outcomes. No fetotoxicity was observed after oral administration of metronidazole in pregnant rats or mice. The available data do not allow the calculation of relevant comparisons between the systemic exposures of metronidazole observed in animal studies to the systemic exposures that would be expected in humans after topical use of Metronidazole Gel. The 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary It is not known whether metronidazole is present in human milk after topical administration. Published literature reports the presence of metronidazole in human milk after oral administration. There are no data on the effects of metronidazole on milk production. Because of the potential for serious adverse reactions, advise patients that breastfeeding is not recommended during treatment with Metronidazole Gel.

Safety and effectiveness of Metronidazole Gel have not been established in pediatric patients.

Sixty-six subjects aged 65 years and older were treated with Metronidazole Gel in the clinical study. 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..

Metronidazole topical gel, 1% is a nitroimidazole for topical use. Metronidazole Gel is a clear, colorless to pale yellow, aqueous gel. Each gram contains 10 mg of metronidazole. Chemically, metronidazole is 2-methyl-5-nitro-1 H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. It has the following structural formula:

{ "type": "p", "children": [], "text": "Metronidazole topical gel, 1% is a nitroimidazole for topical use. Metronidazole Gel is a clear, colorless to pale yellow, aqueous gel. Each gram contains 10 mg of metronidazole. Chemically, metronidazole is 2-methyl-5-nitro-1 H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. It has the following structural formula:" }

Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has solubility in water of 10 mg/mL at 20˚C. Metronidazole belongs to the nitroimidazole class of compounds.The inactive ingredients are betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.

{ "type": "p", "children": [], "text": "Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has solubility in water of 10 mg/mL at 20˚C. Metronidazole belongs to the nitroimidazole class of compounds.The inactive ingredients are betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water." }

The mechanism of action of metronidazole in the treatment of rosacea is unknown.

The pharmacodynamics of metronidazole in association with the treatment of rosacea are unknown. Cardiac Electrophysiology: The effect of Metronidazole Gel on the QTc interval has not been adequately characterized.

Topical administration of a one gram dose of Metronidazole Gel to the face of 13 patients with moderate to severe rosacea once daily for 7 days resulted in a mean ± SD Cmax of metronidazole of 32 ± 9 ng/mL.  The mean ± SD AUC(0-24) was 595 ± 154 ng*hr/mL. The mean Cmax and AUC(0-24) are less than 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) was 6-10 hours after topical application.

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats, but not in studies involving hamsters. In several long-term studies in mice, oral doses of approximately 225 mg/m2/day or greater were associated with an increase in pulmonary tumors and lymphomas. Several long-term oral studies in the rat have shown statistically significant increases in mammary and hepatic tumors at doses >885 mg/m2/day. Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-related increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in patients with Crohn’s disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohn’s disease treated with the drug for 8 months.

In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with Metronidazole Gel or vehicle once daily for 10 weeks. Most subjects had a disease severity score of 3 (“moderate”) on the 5-point Investigator Global Assessment (IGA) scale, with 8 to 50 inflammatory lesions and no more than two nodules at baseline. The co-primary efficacy endpoints were the percent reduction in inflammatory lesion counts and percentage of subjects with success on IGA, defined as an IGA score of 0 (“clear”) or 1 ( “almost clear”) at Week 10. The efficacy results are shown in the following table:

{ "type": "p", "children": [], "text": "In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with Metronidazole Gel or vehicle once daily for 10 weeks. Most subjects had a disease severity score of 3 (“moderate”) on the 5-point Investigator Global Assessment (IGA) scale, with 8 to 50 inflammatory lesions and no more than two nodules at baseline. The co-primary efficacy endpoints were the percent reduction in inflammatory lesion counts and percentage of subjects with success on IGA, defined as an IGA score of 0 (“clear”) or 1 ( “almost clear”) at Week 10. \nThe efficacy results are shown in the following table:\n" }

<div class="scrollingtable"><table frame="box" width="90%"> <caption> <span>Table 3: Inflammatory Lesion Counts and Global Scores in Subjects with Rosacea at Week 10 in a Clinical Trial </span> </caption> <thead> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2"> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2">Metronidazole Gel</td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2">Vehicle</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule">N</td><td align="center" class="Botrule Lrule Rrule Toprule">Results N (%)</td><td align="center" class="Botrule Lrule Rrule Toprule">N</td><td align="center" class="Botrule Lrule Rrule Toprule">Results N (%)</td> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Inflammatory lesions</span></td><td align="center" class="Botrule Lrule Rrule Toprule">557</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">189</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Baseline, mean count</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">18.3</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">18.4</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Week-10, mean count</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">8.9</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">12.8</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Reduction</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">9.4 (50.7)</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">5.6 (32.6)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Investigator Global Assessment</span></td><td align="center" class="Botrule Lrule Rrule Toprule">557</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">189</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Subject clear or almost clear</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">214 (38.42)</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">52 (27.51)</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule">Subject with no change</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">159 (28.5)</td><td align="center" class="Botrule Lrule Rrule Toprule"> </td><td align="center" class="Botrule Lrule Rrule Toprule">77 (40.7)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table frame=\"box\" width=\"90%\">\n<caption>\n<span>Table 3: Inflammatory Lesion Counts and Global Scores in Subjects with Rosacea at Week 10 in a Clinical Trial </span>\n</caption>\n<thead>\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">Metronidazole Gel</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">Vehicle</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">N</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Results N (%)</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">N</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Results N (%)</td>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Inflammatory lesions</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">557</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">189</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Baseline, mean count</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">18.3</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">18.4</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Week-10, mean count</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">8.9</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">12.8</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Reduction</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">9.4 (50.7)</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">5.6 (32.6)</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Investigator Global Assessment</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">557</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">189</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Subject clear or almost clear</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">214 (38.42)</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">52 (27.51)</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">Subject with no change</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">159 (28.5)</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">77 (40.7)</td>\n</tr>\n</tbody>\n</table></div>" }

Subjects treated with Metronidazole Gel experienced a mean reduction of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to a reduction of 5.6 for those treated with vehicle, or a difference in means of 3.8 lesions.

{ "type": "p", "children": [], "text": "Subjects treated with Metronidazole Gel experienced a mean reduction of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to a reduction of 5.6 for those treated with vehicle, or a difference in means of 3.8 lesions." }

How Supplied Metronidazole Gel is clear, colorless to pale yellow in color, and supplied as follows: 55 gram pump – NDC 68308-663-55 60 gram tube – NDC 68308-663-60 Storage and Handling Store at controlled room temperature: 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F).

{ "type": "p", "children": [], "text": "\nHow Supplied\nMetronidazole Gel is clear, colorless to pale yellow in color, and supplied as follows: 55 gram pump – NDC 68308-663-55 60 gram tube – NDC 68308-663-60 \n\nStorage and Handling\nStore at controlled room temperature: 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F)." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

Administration Instructions Use as directed. Avoid contact with the eyes [see Warnings and Precautions (5.4)]. Cleanse treated areas before the application of Metronidazole Gel [see Dosage and Administration (2)] Advise patients to report any adverse reaction to their healthcare providers. Neurologic Disease Advise patients to immediately report any abnormal neurologic signs to their healthcare provider [see Warnings and Precautions (5.1)]. Lactation Advise women not to breastfeed during treatment with Metronidazole Gel [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "\nAdministration Instructions\nUse as directed. Avoid contact with the eyes [see Warnings and Precautions (5.4)].\nCleanse treated areas before the application of Metronidazole Gel [see Dosage and Administration (2)] \nAdvise patients to report any adverse reaction to their healthcare providers.\n\nNeurologic Disease\nAdvise patients to immediately report any abnormal neurologic signs to their healthcare provider [see Warnings and Precautions (5.1)].\n\n\nLactation\nAdvise women not to breastfeed during treatment with Metronidazole Gel [see Use in Specific Populations (8.2)].\n" }

Rx Only US Patent No. 6,881,726 and 7,348,317Distributed by: Mayne Pharma Raleigh, NC 27609 P58252-0Product of CanadaAll trademarks are the property of their respective owners.

{ "type": "p", "children": [], "text": "\nRx Only\nUS Patent No. 6,881,726 and 7,348,317Distributed by:\nMayne Pharma\nRaleigh, NC 27609 P58252-0Product of CanadaAll trademarks are the property of their respective owners. \n\n" }

Metronidazole Gel

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

Important: Metronidazole Gel is for use on the skin only (topical use). Do not use Metronidazole Gel in your mouth, eyes, or vagina.

{ "type": "p", "children": [], "text": "\nImportant: Metronidazole Gel is for use on the skin only (topical use). Do not use Metronidazole Gel in your mouth, eyes, or vagina." }

What is Metronidazole Gel? Metronidazole Gel is a prescription medicine used on the skin (topical) to treat pimples and bumps (inflammatory lesions) caused by a condition called rosacea. It is not known if Metronidazole Gel is safe and effective in children.

{ "type": "p", "children": [], "text": "\nWhat is Metronidazole Gel?\nMetronidazole Gel is a prescription medicine used on the skin (topical) to treat pimples and bumps (inflammatory lesions) caused by a condition called rosacea. It is not known if Metronidazole Gel is safe and effective in children." }

Do not use Metronidazole Gel if you are allergic to metronidazole or any of the ingredients in Metronidazole Gel. See the end of this leaflet for a complete list of ingredients in Metronidazole Gel.

{ "type": "p", "children": [], "text": "\nDo not use Metronidazole Gel if you are allergic to metronidazole or any of the ingredients in Metronidazole Gel. See the end of this leaflet for a complete list of ingredients in Metronidazole Gel." }

Before using Metronidazole Gel, tell your healthcare provider about all your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore using Metronidazole Gel, tell your healthcare provider about all your medical conditions, including if you:\n" }

{ "type": "ul", "children": [ "have tingling or numbness in your hands or feet", "have or have had a blood disorder or disease", "are pregnant or plan to become pregnant. It is not known if Metronidazole Gel will harm your unborn baby.", "are breastfeeding or plan to breastfeed. It is not known if Metronidazole Gel passes into your breast milk. Do not breastfeed during treatment with Metronidazole Gel. Talk to your healthcare provider about the best way to feed your baby during treatment with Metronidazole Gel." ], "text": "" }

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

{ "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. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine." }

How should I use Metronidazole Gel?

{ "type": "p", "children": [], "text": "\nHow should I use Metronidazole Gel?\n" }

{ "type": "ul", "children": [ "Use Metronidazole Gel exactly as your healthcare provider tells you to.", "Cleanse the treated area before applying Metronidazole Gel.", "Apply and rub in a thin film of Metronidazole Gel 1 time a day to the affected area(s).", "You can apply cosmetics after applying Metronidazole Gel. \n", "Avoid contact of Metronidazole Gel with your eyes." ], "text": "" }

What are the possible side effects of Metronidazole Gel? Metronidazole Gel may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of Metronidazole Gel? \nMetronidazole Gel may cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nPeripheral neuropathy. Tingling, burning, pain or numbness in the hands or feet (peripheral neuropathy) have happened in people treated with metronidazole used on the skin. Tell your healthcare provider if you experience tingling, burning, pain or numbness in your hands or feet during treatment with Metronidazole Gel.", "\nSkin reactions, including allergic reactions. Tell your healthcare provider if you develop any skin reactions, including rash, itching, redness, swelling, or blisters during treatment with Metronidazole Gel. ", "\nEye irritation. Tearing from eye irritation has happened in people treated with metronidazole used on the skin. Tell your healthcare provider if you experience tearing, redness or discomfort of the eyes during treatment with Metronidazole Gel." ], "text": "" }

The most common side effects of Metronidazole Gel include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of Metronidazole Gel include:\n" }

{ "type": "ul", "children": [ "sore throat and nasal congestion", "upper respiratory tract infections", "headache" ], "text": "" }

Tell your healthcare provider if you get any side effects during treatment with Metronidazole Gel.

{ "type": "p", "children": [], "text": "Tell your healthcare provider if you get any side effects during treatment with Metronidazole Gel." }

These are not all of the possible side effects of Metronidazole Gel. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Mayne Pharma at 1-844-825-8500.

{ "type": "p", "children": [], "text": "These are not all of the possible side effects of Metronidazole Gel. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Mayne Pharma at 1-844-825-8500." }

How should I store Metronidazole Gel?

{ "type": "p", "children": [], "text": "\nHow should I store Metronidazole Gel?\n" }

{ "type": "ul", "children": [ "Store Metronidazole Gel at room temperature between 68°F to 77°F (20°C to 25°C). " ], "text": "" }

Keep Metronidazole Gel and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep Metronidazole Gel and all medicines out of the reach of children.\n" }

General information about the safe and effective use of Metronidazole Gel. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Metronidazole Gel for a condition for which it was not prescribed. Do not give Metronidazole Gel to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Metronidazole Gel that is written for health professionals.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of Metronidazole Gel. \nMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Metronidazole Gel for a condition for which it was not prescribed. Do not give Metronidazole Gel to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Metronidazole Gel that is written for health professionals." }

What are the ingredients in Metronidazole Gel? Active ingredient: metronidazole Inactive ingredients: betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water Distributed by: Mayne Pharma Raleigh, NC 27609P58252-0Product of Canada US Patent No. 6,881,726 and 7,348,317 This Patient Information has been approved by the U.S. Food and Drug Administration. Revised 10/2024

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in Metronidazole Gel?\n Active ingredient: metronidazole\n Inactive ingredients: betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water\nDistributed by: \nMayne Pharma \nRaleigh, NC 27609P58252-0Product of Canada US Patent No. 6,881,726 and 7,348,317 \nThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised 10/2024" }

NDC 68308-663-55 Metronidazole Gel 1% Pump For topical use only Rx Only NET WT. 55gmaynepharma For topical use only. Not for oral, ophthalmic or intravaginal use. Store at controlled room temperature, 68° to 77°F (20° - 25°C), excursions permitted between 59° to 86°F (15° - 30°C).Keep out of reach of children. Usual dosage: Apply a thin film once a day to the affected areas.  See package insert for complete prescribing instructions. Each gram contains: 10 mg (1%) metronidazole as active ingredient in a gel base consisting of betadex, edetate disodium, hydroxyethl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparben, and purified water.

{ "type": "p", "children": [], "text": "\nNDC 68308-663-55\nMetronidazole Gel 1%\n\nPump\n\nFor topical use only\n\nRx Only\nNET WT. 55gmaynepharma\n\n\nFor topical use only. Not for oral, ophthalmic or intravaginal use.\n\nStore at controlled room temperature, 68° to 77°F (20° - 25°C), excursions permitted between 59° to 86°F (15° - 30°C).Keep out of reach of children.\n\nUsual dosage: Apply a thin film once a day to the affected areas.  See package insert for complete prescribing instructions.\n\n\nEach gram contains: 10 mg (1%) metronidazole as active ingredient in a gel base consisting of betadex, edetate disodium, hydroxyethl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparben, and purified water.\n\n\n\n" }

Distributed by: Mayne Pharma Raleigh, NC 27609Product of Canada. P57418-0

{ "type": "p", "children": [], "text": "Distributed by:\nMayne Pharma\nRaleigh, NC 27609Product of Canada.\nP57418-0" }

NDC 68308-663-60 Metronidazole Gel 1%  For Topical Use Only Rx OnlyNet Wt. 60 g maynepharma Product of CanadaDistributed by: MaynePharma Raleigh, NC 27609 P58251-0 FOR TOPICAL USE ONLY. NOT FOR ORAL, OPHTHALMIC OR INTRAVAGINAL USE.STORE AT CONTROLLED ROOM TEMPERATURE 68º TO 77ºF(20º - 25º C)EXCURSIONS PERMITTED BETWEEN 59º AND 86ºF (15º - 30ºC) Usual dosage: Apply a thin film once a day to the affected areas.  See package insert for complete prescribing instructions. Each gram contains: Active: 10 mg (1%) metronidazole as active ingredient in a gel base consisting of betadex, edetate disodium, hydroxyethl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparben, and purified water. See crimp of tube for lot number and expiration date.

{ "type": "p", "children": [], "text": "NDC 68308-663-60\nMetronidazole Gel\n\n 1% \n\nFor Topical Use Only\n\nRx OnlyNet Wt. 60 g\nmaynepharma\nProduct of CanadaDistributed by:\nMaynePharma\nRaleigh, NC 27609\nP58251-0\n\n\nFOR TOPICAL USE ONLY. NOT FOR ORAL, OPHTHALMIC OR INTRAVAGINAL USE.STORE AT CONTROLLED ROOM TEMPERATURE 68º TO 77ºF(20º - 25º C)EXCURSIONS PERMITTED BETWEEN 59º AND 86ºF (15º - 30ºC)\n\n\nUsual dosage: Apply a thin film once a day to the affected areas.  See package insert for complete prescribing instructions.\n\nEach gram contains: Active: 10 mg (1%) metronidazole as active ingredient in a gel base consisting of betadex, edetate disodium, hydroxyethl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparben, and purified water.\nSee crimp of tube for lot number and expiration date.\n\n\n" }