LUTRATE DEPOT 22.5 mg for 3-month administration (leuprolide acetate) is indicated for treatment of advanced prostate cancer.

{ "type": "p", "children": [], "text": "LUTRATE DEPOT 22.5 mg for 3-month administration (leuprolide acetate) is indicated for treatment of advanced prostate cancer." }

LUTRATE DEPOT must be administered under the supervision of a physician.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration-resistant prostate cancer.

<div class="scrollingtable"><table> <caption> <span>Table 1. LUTRATE DEPOT Recommended Dosing</span> </caption> <colgroup> <col width="50%"/> <col width="50%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule">Dosage</td><td align="left" class="Lrule Rrule Toprule">22.5 mg for 3-Month Administration</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule Toprule">Recommended Dose</td><td align="left" class="Lrule Rrule Toprule">1 injection every 12 weeks</td> </tr> </tbody> </table></div>

The recommended dose of LUTRATE DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different release characteristics.

Incorporated in a depot formulation, the lyophilized microspheres must be reconstituted and administered every 12 weeks as a single intramuscular injection.

LUTRATE DEPOT is packaged in a commercial kit. Each kit contains:

Please read the instructions completely before you begin.

MIXJECT Preparation

Wash your hands with soap and hot water and put on gloves1 immediately prior to preparing the injection. Place the tray on a clean, flat surface that is covered with a sterile pad or cloth. Remove the MIXJECT device, the backstop, the prefilled syringe containing the solvent for reconstitution and the LUTRATE DEPOT vial.

Remove the Flip-Off button from the top of the vial, revealing the rubber stopper. Place the vial in a standing upright position on the prepared surface. Disinfect the rubber stopper with the alcohol wipe. Discard the alcohol wipe and allow the stopper to dry. Insert the backstop to the flange of the syringe until you feel it snap in place. Proceed to MIXJECT Activation.

MIXJECT Activation

LUTRATE DEPOT

{ "type": "p", "children": [], "text": "LUTRATE DEPOT" }

For Injection: 22.5 mg of leuprolide acetate for 3-month administration as lyophilized microspheres in a single dose vial as a kit with a prefilled syringe containing 2mL 0.8% mannitol solution and a MIXJECT transfer device for a single dose injection.

{ "type": "p", "children": [], "text": "For Injection: 22.5 mg of leuprolide acetate for 3-month administration as lyophilized microspheres in a single dose vial as a kit with a prefilled syringe containing 2mL 0.8% mannitol solution and a MIXJECT transfer device for a single dose injection." }

LUTRATE DEPOT is contraindicated in:

{ "type": "p", "children": [], "text": "\nLUTRATE DEPOT is contraindicated in:\n" }

{ "type": "ul", "children": [ "\nHypersensitivity\n LUTRATE DEPOT is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the excipients in LUTRATE DEPOT. Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature." ], "text": "" }

Initially, LUTRATE DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first weeks of treatment. Ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. Patients may experience a temporary increase in bone pain, which can be managed symptomatically.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.

The use of GnRH agonists may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving a GnRH agonist, and manage according to current treatment guidelines.

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Patients receiving a GnRH agonist who experience convulsion should be managed according to current clinical practice.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), may occur in patients receiving LUTRATE DEPOT; including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions (6.2)].

Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).

If a SCAR is suspected, interrupt LUTRATE DEPOT until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue LUTRATE DEPOT.

Monitor serum levels of testosterone following injection of LUTRATE DEPOT 22.5 mg for 3-month administration. In the majority of patients, testosterone levels increased above baseline during the first week, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks. [see Clinical Studies (14) and Adverse Reactions (6)].

Based on findings in animal studies, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose, based on body surface area, using an estimated daily dose. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)].

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.

LUTRATE DEPOT 22.5 mg for 3-Month Administration

In a clinical trial of LUTRATE DEPOT 22.5 mg for 3-month administration, patients were treated for 24 weeks with 157/163 receiving two injections. The table includes adverse reactions were reported in 5% or more of the patients during the treatment period as well as the incidence of these adverse reaction that were considered, by the treating physician, to be at least possibly related to LUTRATE DEPOT. Grade 3-4 adverse reactions reported as treatment-emergent in 13% of patients and treatment-related 4% of patients.

<div class="scrollingtable"><table> <colgroup> <col width="40%"/> <col width="30%"/> <col width="30%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" class="Footnote" colspan="3"> <p class="First">CTCAE v.3</p> <p> <span class="Sup">1</span><span>Includes cold sweat, flushing, hot flush, hyperhidrosis, and night sweats</span> </p> <span class="Sup">2</span>Includes influenza, influenza-like illness, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection and congestion</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">Table 2. Adverse Reactions Reported in ≥ 5% of Patients</span></td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">LUTRATE DEPOT 22.5 mg for 3-Month Administration</span> <p class="First"> <span class="Bold">N = 163 (%)</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Grade 1-4</span></td> </tr> <tr> <td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule">Treatment-Emergent</td><td align="center" class="Lrule Rrule Toprule">Treatment-Related</td> </tr> <tr> <td class="Lrule Rrule Toprule">Hot Flush/Flushing<span class="Sup">1</span></td><td align="center" class="Lrule Rrule Toprule">128 (79)</td><td align="center" class="Lrule Rrule Toprule">127 (78)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Upper Respiratory Infection<span class="Sup">2</span></td><td align="center" class="Lrule Rrule Toprule">28 (17)</td><td align="center" class="Lrule Rrule Toprule">0</td> </tr> <tr> <td class="Lrule Rrule Toprule">Fatigue/Asthenia</td><td align="center" class="Lrule Rrule Toprule">24 (15)</td><td align="center" class="Lrule Rrule Toprule">22 (13)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Diarrhea</td><td align="center" class="Lrule Rrule Toprule">21 (13)</td><td align="center" class="Lrule Rrule Toprule">2 (1)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Pollakiuria</td><td align="center" class="Lrule Rrule Toprule">20 (12)</td><td align="center" class="Lrule Rrule Toprule">3 (2)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Arthralgia/Arthritis</td><td align="center" class="Lrule Rrule Toprule">18 (11)</td><td align="center" class="Lrule Rrule Toprule">2 (1)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Injection Site Pain/Discomfort</td><td align="center" class="Lrule Rrule Toprule">18 (11)</td><td align="center" class="Lrule Rrule Toprule">15 (9)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Constipation</td><td align="center" class="Lrule Rrule Toprule">15 (9)</td><td align="center" class="Lrule Rrule Toprule">1 (0.6)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Extremity Pain</td><td align="center" class="Lrule Rrule Toprule">14 (9)</td><td align="center" class="Lrule Rrule Toprule">0</td> </tr> <tr> <td class="Lrule Rrule Toprule">Nausea</td><td align="center" class="Lrule Rrule Toprule">14 (9)</td><td align="center" class="Lrule Rrule Toprule">4 (2)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Nocturia</td><td align="center" class="Lrule Rrule Toprule">14 (9)</td><td align="center" class="Lrule Rrule Toprule">3 (2)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Abdominal Pain/Discomfort</td><td align="center" class="Lrule Rrule Toprule">13 (8)</td><td align="center" class="Lrule Rrule Toprule">1 (0.6)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Urinary Tract Pain</td><td align="center" class="Lrule Rrule Toprule">13 (8)</td><td align="center" class="Lrule Rrule Toprule">2 (1)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Dizziness</td><td align="center" class="Lrule Rrule Toprule">12 (7)</td><td align="center" class="Lrule Rrule Toprule">2 (1)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Headache/Sinus Headache</td><td align="center" class="Lrule Rrule Toprule">12 (7)</td><td align="center" class="Lrule Rrule Toprule">1 (0.6)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Urinary Tract Infection</td><td align="center" class="Lrule Rrule Toprule">12 (7)</td><td align="center" class="Lrule Rrule Toprule">0</td> </tr> <tr> <td class="Lrule Rrule Toprule">Bone Pain</td><td align="center" class="Lrule Rrule Toprule">11 (7)</td><td align="center" class="Lrule Rrule Toprule">4 (2)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Back Pain</td><td align="center" class="Lrule Rrule Toprule">10 (6)</td><td align="center" class="Lrule Rrule Toprule">1 (0.6)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Hypertension/Blood Pressure Increased</td><td align="center" class="Lrule Rrule Toprule">10 (6)</td><td align="center" class="Lrule Rrule Toprule">0</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">Pruritus/Generalized Pruritus</td><td align="center" class="Lrule Rrule Toprule">9 (6)</td><td align="center" class="Lrule Rrule Toprule">3 (2)</td> </tr> </tbody> </table></div>

In the same study, erectile dysfunction and testicular atrophy were reported in patients on LUTRATE DEPOT 22.5 mg.

Laboratory abnormalities

During the treatment period, at least a one grade change in laboratory values was seen (>10%) in the following: anemia, increased triglyceride, hyperglycemia, increased cholesterol, increased creatine kinase, leukopenia, increased AST, increased creatinine, and increased ALT.

The following adverse reactions have been identified during post approval use of gonadotropin-releasing hormone agonists. 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.

Mood swings, including depression, have been reported. There have been very rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with LUTRATE DEPOT.

Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.

Pituitary apoplexy: During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Localized reactions including induration and abscess have been reported at the site of injection.

Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide acetate-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density.

Immune Disorders: Anaphylaxis

Psychiatric Disorders: Depression

Cardiovascular System - hypotension, myocardial infarction, pulmonary embolism

Respiratory, Thoracic and Mediastinal disorder - Pneumonitis, interstitial lung disease

Hepato-biliary disorder - serious drug-induced liver injury, non-alcoholic fatty liver disease

Skin reactions – rash, urticaria, photosensitivity, erythema multiforme, bullous dermatitis, exfoliative dermatitis, DRESS, SJS/TEN, and AGEP

Blood and Lymphatic System - decreased WBC

Central/Peripheral Nervous System - convulsion, peripheral neuropathy, spinal fracture/paralysis

Endocrine System - diabetes mellitus

Musculoskeletal System - tenosynovitis-like symptoms

Urogenital System - prostate pain

Administration of LUTRATE DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUTRATE DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUTRATE DEPOT may be affected.

Risk summary

Based on findings in animal studies and mechanism of action, LUTRATE DEPOT may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose based on body surface area using an estimated daily dose (see data). Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Animal Data

Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy at doses of 0.00024, 0.0024, and 0.024 mg/kg (approximately 1/1600 to 1/16 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot formulation was utilized in the study, a sustained exposure to leuprolide acetate was expected throughout the period of organogenesis and to the end of gestation. Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.

The safety and efficacy of LUTRATE DEPOT have not been established in females. There is no information regarding the presence of LUTRATE DEPOT in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfed child from LUTRATE DEPOT, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Infertility

Males

Based on findings in animals and mechanism of action, LUTRATE DEPOT may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of LUTRATE DEPOT in pediatric patients have not been established.

In the clinical trials for LUTRATE DEPOT in prostate cancer 74% of the patients studied were at least 65 years of age. Hot flushes occurred with equal frequency in those less than or at least 65 years of age.

There is no experience of overdosage in clinical trials. In rats, a single subcutaneous dose of 100 mg/kg (approximately 4,000 times the estimated daily human dose based on body surface area), resulted in dyspnea, decreased activity, and excessive scratching.

{ "type": "p", "children": [], "text": "There is no experience of overdosage in clinical trials. In rats, a single subcutaneous dose of 100 mg/kg (approximately 4,000 times the estimated daily human dose based on body surface area), resulted in dyspnea, decreased activity, and excessive scratching." }

In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up two years caused no adverse effects differing from those observed with the 1 mg/day dose.

{ "type": "p", "children": [], "text": "In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up two years caused no adverse effects differing from those observed with the 1 mg/day dose." }

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:

{ "type": "p", "children": [], "text": "Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:" }

Where: n=1 or 2

{ "type": "p", "children": [], "text": "Where: n=1 or 2" }

Leuprolide acetate has a molecular weight of 1209.41 as "free base”. Leuprolide is freely soluble in water.

{ "type": "p", "children": [], "text": "Leuprolide acetate has a molecular weight of 1209.41 as \"free base”. Leuprolide is freely soluble in water." }

LUTRATE DEPOT 22.5 mg for 3-month administration is available in a vial containing white to off white sterile lyophilized microspheres together with the corresponding sterile reconstitution diluent in a pre-filled syringe. When LUTRATE DEPOT and the diluent are mixed together they become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS as a single dose.

{ "type": "p", "children": [], "text": "LUTRATE DEPOT 22.5 mg for 3-month administration is available in a vial containing white to off white sterile lyophilized microspheres together with the corresponding sterile reconstitution diluent in a pre-filled syringe. When LUTRATE DEPOT and the diluent are mixed together they become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS as a single dose." }

Each vial of LUTRATE DEPOT 22.5 mg for 3-month administration delivers leuprolide acetate (22.5 mg), polylactic acid (188.4 mg), triethylcitrate (10.4 mg), polysorbate 80 (3.8 mg), mannitol (88.4 mg) and carmellose sodium (25 mg). The prefilled syringe containing the clear reconstitution diluent (2 mL) contains mannitol (16 mg), water for injection, and sodium hydroxide and hydrochloric acid to control pH.

{ "type": "p", "children": [], "text": "Each vial of LUTRATE DEPOT 22.5 mg for 3-month administration delivers leuprolide acetate (22.5 mg), polylactic acid (188.4 mg), triethylcitrate (10.4 mg), polysorbate 80 (3.8 mg), mannitol (88.4 mg) and carmellose sodium (25 mg). The prefilled syringe containing the clear reconstitution diluent (2 mL) contains mannitol (16 mg), water for injection, and sodium hydroxide and hydrochloric acid to control pH." }

LUTRATE DEPOT is an extended release sterile, single dose injection in suspension form for intramuscular administration.

{ "type": "p", "children": [], "text": "LUTRATE DEPOT is an extended release sterile, single dose injection in suspension form for intramuscular administration." }

Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy.

Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostate tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for more than five years.

Leuprolide acetate is not active when given orally.

Absorption

Following two sequential injections of LUTRATE DEPOT 22.5 mg administered with a 3-month interval, plasma leuprolide acetate  concentrations were similar among both cycles. After first administration, mean plasma leuprolide concentration of 46.8 ng/mL was observed at approximately 2 hours and the mean concentration then declined until next injection.

Distribution

The mean steady-state volume of distribution of leuprolide acetate following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.

Elimination

The mean systemic clearance of leuprolide acetate following intravenous bolus administration to healthy male volunteers was 7.6 L/h, and terminal elimination half-life was approximately 3 hours based on a two-compartment model.

Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M- 1) metabolite.

Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with LUTRATE DEPOT.

Genotoxicity studies were conducted with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of mutagenic effects or chromosomal aberrations.

Leuprolide acetate may reduce male and female fertility. Administration of leuprolide acetate to male and female rats at dose of 0.024, 0.24, and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive function. These changes were reversible upon cessation of treatment.

The efficacy of LUTRATE DEPOT 22.5 mg was evaluated in an open-label, multicenter, non-controlled, multiple dose clinical trial which enrolled 162 evaluable patients with prostate cancer. Patients were administered LUTRATE DEPOT 22.5 mg intramuscularly in 2 doses (157 received 2 injections) with a 3-month interval.

The median age was 71 years (range; 47-91), 62% White, and 30% Black or African-American.

Castrate levels of serum testosterone (<50 ng/dL) were achieved and maintained from Day 28 to 168 in 94.3% (95% CI:89.4, 97.0) of patients. On Day 28, 160 of the 162 (98.8%) patients had castrate testosterone levels. One patient did not achieve a castrate level and one had a missing value. Testosterone escapes (any value > 50 ng/dL after castrate levels were achieved) occurred in four patients. In addition, three patients had a single unevaluable testosterone level after Day 28 that was considered to be non-castrate in this analysis.

Figure 1. Mean testosterone plasma levels during treatment with two three-month IM injections of LUTRATE DEPOT 22.5 mg

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

{ "type": "p", "children": [], "text": "1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html\n" }

LUTRATE® DEPOT is supplied as a kit consisting of a LEUPROLIDE ACETATE MIXJECT single-dose delivery system consisting of a vial with a Flip-Off seal containing sterile, white to off white lyophilized leuprolide acetate microspheres incorporated in a biodegradable polymer, a MIXJECT vial adapter containing the needle, and a pre-filled syringe containing clear sterile mannitol solution for injection, USP, 2 mL, pH 4.5 to 7.0.

{ "type": "p", "children": [], "text": "LUTRATE® DEPOT is supplied as a kit consisting of a LEUPROLIDE ACETATE MIXJECT single-dose delivery system consisting of a vial with a Flip-Off seal containing sterile, white to off white lyophilized leuprolide acetate microspheres incorporated in a biodegradable polymer, a MIXJECT vial adapter containing the needle, and a pre-filled syringe containing clear sterile mannitol solution for injection, USP, 2 mL, pH 4.5 to 7.0." }

LUTRATE® DEPOT (leuprolide acetate for depot suspension) 22.5 mg – NDC 83831-134-01

{ "type": "p", "children": [], "text": "LUTRATE® DEPOT (leuprolide acetate for depot suspension) 22.5 mg – NDC 83831-134-01" }

Storage

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

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

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

Hypersensitivity

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

{ "type": "ul", "children": [ "Inform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like LUTRATE DEPOT, LUTRATE DEPOT is contraindicated [see Contraindications (4)].\n" ], "text": "" }

Tumor Flare

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

{ "type": "ul", "children": [ "Inform patients that LUTRATE DEPOT can cause tumor flare during the first weeks of treatment. Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if ureteral obstruction, spinal cord compression, paralysis, or new or worsened symptoms occur after beginning LUTRATE DEPOT treatment [see Warnings and Precautions (5.1)].\n" ], "text": "" }

Metabolic Syndrome

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

{ "type": "ul", "children": [ "Advise patients that there is an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease with LUTRATE DEPOT therapy. Inform patients that periodic monitoring for metabolic changes is required when being treated with LUTRATE DEPOT [see Warnings and Precautions (5.2)].\n" ], "text": "" }

Cardiovascular Disease

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

{ "type": "ul", "children": [ "Inform patients that there is an increased risk of myocardial infarction, sudden cardiac death, and stroke with LUTRATE DEPOT treatment. Advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.3)].\n" ], "text": "" }

Urogenital Disorders

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

{ "type": "ul", "children": [ "Advise patients that LUTRATE DEPOT may cause impotence [see Use In Specific Populations (8.3)]." ], "text": "" }

Infertility

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

{ "type": "ul", "children": [ "Inform patients that LUTRATE DEPOT may cause infertility [see Use In Specific Populations (8.3)].\n" ], "text": "" }

Continuation of LUTRATE DEPOT Treatment

{ "type": "p", "children": [], "text": "\nContinuation of LUTRATE DEPOT Treatment \n" }

{ "type": "ul", "children": [ "Inform patients that LUTRATE DEPOT is usually continued, often with additional medication, after the development of metastatic castration-resistant prostate cancer [see Dosage and Administration (2.1)].\n" ], "text": "" }

Trademarks are property of their respective owners and are not of Avyxa Pharma, LLC

{ "type": "p", "children": [], "text": "Trademarks are property of their respective owners and are not of Avyxa Pharma, LLC" }

For more information on how to use, call 1-888-520-0954. 

{ "type": "p", "children": [], "text": "For more information on how to use, call 1-888-520-0954. " }

Manufactured for: Avyxa Pharma, LLCNew Jersey 07054, USA Made in Spain 99355081                                                                                                                                       

{ "type": "p", "children": [], "text": "\nManufactured for:\nAvyxa Pharma, LLCNew Jersey 07054, USA\nMade in Spain\n99355081                                                                                                                                       " }

NDC 83831-134-01                     Rx Only

{ "type": "p", "children": [], "text": "\nNDC 83831-134-01                     Rx Only\n" }

Lutrate® Depot(Leuprolide acetate for depot suspension)

{ "type": "p", "children": [], "text": "\nLutrate® Depot(Leuprolide acetate for depot suspension)\n" }

22.5 mg

{ "type": "p", "children": [], "text": "\n22.5 mg\n" }

For intramuscular injection

{ "type": "p", "children": [], "text": "\nFor intramuscular injection\n" }

See package insert for reconstitution and administration procedures Recommended dose: one intramuscular injection every three months

{ "type": "p", "children": [], "text": "See package insert for reconstitution and administration procedures Recommended dose: one intramuscular injection every three months" }

Sterile Must be reconstituted before use

{ "type": "p", "children": [], "text": "\nSterile Must be reconstituted before use\n" }

AVYXA

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

BRONCHITOL is indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years and older with Cystic Fibrosis. Use BRONCHITOL only for adults who have passed the BRONCHITOL Tolerance Test [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "BRONCHITOL is indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years and older with Cystic Fibrosis. Use BRONCHITOL only for adults who have passed the BRONCHITOL Tolerance Test [see Dosage and Administration (2.1)]." }

Prior to prescribing BRONCHITOL for treatment of cystic fibrosis, the BRONCHITOL Tolerance Test (BTT) must be administered and performed under the supervision of a healthcare practitioner who is able to manage acute bronchospasm, to identify patients who are suitable candidates for BRONCHITOL maintenance therapy.

See the BTT Healthcare Practitioner (HCP) Instructions for Use (IFU) for complete instructions and to avoid medication errors associated with BTT dosing and procedures.

Do not use BRONCHITOL add-on maintenance therapy in patients who fail the BTT [see Contraindications (4)].

For patients who have passed the BTT, the recommended dosage of BRONCHITOL is 400 mg twice a day by oral inhalation (the contents of 10 capsules administered individually) via the inhaler [see Dosage and Administration (2.1)].

A short-acting bronchodilator should be administered by oral inhalation, 5-15 minutes before every dose of BRONCHITOL.

BRONCHITOL should be taken once in the morning and once in the evening, with the later dose taken at least 2-3 hours before bedtime.

Instruct patients on safe hygiene practices (clean and dry hands thoroughly) and correct inhaler use, including loading of capsules and proper inhalation technique per the Patient Instructions for Use.

The BRONCHITOL inhaler should be discarded and replaced after 7 days of use. If the inhaler does need to be washed, the patient should allow the inhaler to thoroughly air dry before next use.

Inhalation powder: 40 mg mannitol per capsule; clear, colorless hard gelatin capsule imprinted with “PXS 40 mg”

{ "type": "p", "children": [], "text": "Inhalation powder: 40 mg mannitol per capsule; clear, colorless hard gelatin capsule imprinted with “PXS 40 mg”" }

BRONCHITOL is contraindicated in the following conditions:

{ "type": "p", "children": [], "text": "BRONCHITOL is contraindicated in the following conditions:" }

{ "type": "ul", "children": [ "Hypersensitivity to mannitol or to any of the capsule components", "Failure to pass the BRONCHITOL Tolerance Test (BTT)" ], "text": "" }

BRONCHITOL Tolerance Test BRONCHITOL can cause bronchospasm, which can be severe in susceptible individuals. Because of the risk of bronchospasm, prior to prescribing BRONCHITOL, perform the BRONCHITOL Tolerance Test (BTT), to identify patients who are appropriate for maintenance treatment with BRONCHITOL. The BTT must be administered under the supervision of a healthcare practitioner who can treat severe bronchospasm. In clinical trials, 896 adult patients with cystic fibrosis underwent the BTT and 72 patients (8%) failed or did not complete the BTT. Do not prescribe BRONCHITOL if the patient fails the BTT.

Maintenance Therapy Bronchospasm may occur during inhalation of BRONCHITOL, even in patients who have passed the BTT. An inhaled short-acting bronchodilator must be administered 5-15 minutes before administration of each dose during maintenance therapy. In clinical studies, bronchospasm or bronchial hyperreactivity was reported in 4 of 414 adult patients (1.0%) receiving BRONCHITOL as maintenance therapy and in 2 of 347 adult patients (0.6%) receiving control (50 mg inhaled mannitol), even though these patients had passed the BTT. If bronchospasm occurs following dosing of BRONCHITOL, it should immediately be discontinued and treated with an inhaled short-acting bronchodilator or as medically appropriate.

Hemoptysis may occur with BRONCHITOL use. Hemoptysis was reported in 43 (10.4%) adult patients receiving BRONCHITOL and in 33 (9.5%) adult patients receiving control (50 mg inhaled mannitol) during clinical studies. In patients aged 6 years to 17 years, hemoptysis was reported in 12 of 154 (7.8%) patients who received BRONCHITOL and in 2 of 105 (1.9%) patients who received control. BRONCHITOL has not been studied in patients with a history of episodes of significant hemoptysis (volume greater than 60 mL) in the previous 3 months. BRONCHITOL should be discontinued in the event of hemoptysis. BRONCHITOL is not indicated for use in children and adolescents.

The following clinically significant adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following clinically significant adverse reactions are described elsewhere in the labeling:" }

Bronchospasm [see Warnings and Precautions (5.1)] Hemoptysis [see Warnings and Precautions (5.2)]

{ "type": "p", "children": [], "text": "Bronchospasm [see Warnings and Precautions (5.1)]\n \nHemoptysis [see Warnings and Precautions (5.2)]\n " }

No formal drug interaction studies have been conducted with mannitol, the active ingredient in BRONCHITOL.

{ "type": "p", "children": [], "text": "No formal drug interaction studies have been conducted with mannitol, the active ingredient in BRONCHITOL." }

Risk Summary

There are no adequate and well-controlled studies of BRONCHITOL in pregnant women. The available data on BRONCHITOL use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. Based on animal reproduction studies, no evidence of structural alterations was observed when mannitol was administered to pregnant rats and mice during organogenesis at doses up to approximately 20 and 10 times, respectively, the maximum recommended daily inhalation dose (MRDID) in humans [ see Data]. There are risks to the mother associated with cystic fibrosis in pregnancy [see Clinial Considerations]. BRONCHITOL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

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

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Cystic fibrosis may increase the risk for preterm delivery. Data

Animal Data

In animal reproduction studies, oral administration of mannitol to pregnant rats and mice during the period of organogenesis did not cause fetal structural alterations. The mannitol dose in rats and mice was approximately 20 and 10 times the maximum recommended human daily inhalation dose (MRDID) in humans, respectively, (on a mg/m 2 basis at maternal doses of 1600 mg/kg/day in both species).

Risk Summary

It is not known whether BRONCHITOL is excreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BRONCHITOL and any potential adverse effects on the breastfed child from BRONCHITOL or from the underlying maternal condition.

BRONCHITOL is not indicated for use in children and adolescents. The safety and effectivenss of BRONCHITOL have not been established in pediatric patients for cystic fibrosis. Patients aged 6 years to 17 years were included in two 26- week, double-blind clinical trials (Trials 2 and 3). In these trials, 154 patients under 18 years of age received BRONCHITOL and 105 patients received control (50 mg inhaled mannitol). Hemoptysis was reported in 12 of 154 (7.8%) patients who received BRONCHITOL and in 2 of 105 (1.9%) patients who received control.

Clinical trials of BRONCHITOL did not include sufficient numbers of patients with cystic fibrosis who were 65 years of age and older to allow evaluation of safety and efficacy in this population.

Clinical trials of BRONCHITOL did not include patients with hepatic or renal impairment. No specific dose recommendations for these patient populations are available. However, an increase in systemic exposure of mannitol can be expected in patients with renal impairment based on the kidney being its primary route of elimination.

Susceptible persons may experience bronchoconstriction from an overdosage. If excessive coughing and bronchoconstriction occurs, immediately administer an inhaled short-acting bronchodilator and other medical treatments as necessary.

{ "type": "p", "children": [], "text": "Susceptible persons may experience bronchoconstriction from an overdosage. If excessive coughing and bronchoconstriction occurs, immediately administer an inhaled short-acting bronchodilator and other medical treatments as necessary." }

BRONCHITOL (mannitol) inhalation powder contains D-Mannitol (referred to throughout as mannitol) as the active ingredient. Mannitol is a hexahydric sugar alcohol, with the following chemical name hexane-1,2,3,4,5,6-hexol and chemical structure:

{ "type": "p", "children": [], "text": "BRONCHITOL (mannitol) inhalation powder contains D-Mannitol (referred to throughout as mannitol) as the active ingredient. Mannitol is a hexahydric sugar alcohol, with the following chemical name hexane-1,2,3,4,5,6-hexol and chemical structure:" }

Mannitol is a white or almost white crystalline powder or free-flowing granules with an empirical formula of C6H14O6 and molecular weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism.

{ "type": "p", "children": [], "text": "Mannitol is a white or almost white crystalline powder or free-flowing granules with an empirical formula of C6H14O6 and molecular weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism." }

BRONCHITOL contains mannitol powder spray dried into particles of respirable size filled into clear, colorless hard gelatin capsules. There are no inactive ingredients in BRONCHITOL.

{ "type": "p", "children": [], "text": "BRONCHITOL contains mannitol powder spray dried into particles of respirable size filled into clear, colorless hard gelatin capsules. There are no inactive ingredients in BRONCHITOL." }

The accompanying white plastic inhaler is comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. A blister pack consists of 10 capsules, each containing 40 mg mannitol. After a capsule is placed in the

{ "type": "p", "children": [], "text": "The accompanying white plastic inhaler is comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. A blister pack consists of 10 capsules, each containing 40 mg mannitol. After a capsule is placed in the" }

capsule chamber and pierced by firmly pressing and releasing the buttons on the side of the device, the powder within the capsule becomes exposed and ready for dispersion into the airstream generated by the patient upon inhalation through the mouthpiece. Under standardized in vitro test conditions, the inhaler delivers 32.2 mg of mannitol per inhalation when tested at a flow rate of 60 L/min for 2 seconds. The actual amount of drug delivered to the lungs will depend on patient factors, such as inspiratory flow profile.

{ "type": "p", "children": [], "text": "capsule chamber and pierced by firmly pressing and releasing the buttons on the side of the device, the powder within the capsule becomes exposed and ready for dispersion into the airstream generated by the patient upon inhalation through the mouthpiece. Under standardized in vitro test conditions, the inhaler delivers 32.2 mg of mannitol per inhalation when tested at a flow rate of 60 L/min for 2 seconds. The actual amount of drug delivered to the lungs will depend on patient factors, such as inspiratory flow profile." }

The precise mechanism of action of BRONCHITOL in improving pulmonary function in cystic fibrosis patients is unknown.

The pharmacodynamics of mannitol are unknown.

Absorption

Following oral inhalation of 635 mg, the mean mannitol peak plasma concentration (Cmax) was 13.71 mcg/mL while the mean extent of systemic exposure (AUC) was 73.15 mcg•hr/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour.

Distribution

Based on intravenous administration, the volume of distribution of mannitol was 34.3 L.

Elimination

Metabolism

Mannitol is metabolized in a CYP-independent manner through the glycolytic pathway via dehydrogenation to fructose. The extent of metabolism of mannitol appears to be small. This is evident from a urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy patients.

Excretion

Following oral inhalation, the elimination half-life of mannitol was 4.7 hours. The mean terminal elimination half-life for mannitol in plasma remained unchanged regardless of the route of administration (oral, inhalation, and intravenous). The urinary excretion rate versus time profile for mannitol was consistent for all routes of administration. The total clearance after intravenous administration was 5.1 L/hr while the renal clearance was 4.4 L/hr. Therefore, the clearance of mannitol was predominately via the kidney. Following inhalation of 635 mg of mannitol in 18 healthy patients, about 55% of the total dose was excreted in the urine as unchanged mannitol. Following oral or intravenous administration of a 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively.

Specific Populations

Patients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using BRONCHITOL have not been conducted in patients with hepatic or renal impairment. Since the drug is eliminated primarily via the kidney, an increase in systemic exposure can be expected in renally impaired patients.

Drug Interaction Studies

No formal drug interaction studies have been conducted with BRONCHITOL.

Carcinogenesis

In 2-year carcinogenicity studies in rats and mice mannitol did not show evidence of carcinogenicity at oral dietary concentrations up to 5% (or 7,500 mg/kg on a mg/kg basis). These doses were approximately 55 and 30 times the

MRHDID, respectively, on a mg/m 2 basis.

Mutagenesis

Mannitol tested negative in the following assays: bacterial gene mutation assay, in vitro mouse lymphoma assay, in vitro chromosomal aberration assay in WI-38 human cells, in vivo chromosomal aberration assay in rat bone marrow, in vivo dominant lethal assay in rats, and in vivo mouse micronucleus assay.

Impairment of Fertility

The effect of inhaled mannitol on fertility has not been investigated.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="First"> <td> <p class="First"></p> </td><td> <p class="First">Control (N=214)</p> </td><td> <p class="First">BRONCHITOL (N=209)</p> </td> </tr> <tr> <td> <p class="First">Adjusted mean change from baseline</p> </td><td> <p class="First">12 mL</p> </td><td> <p class="First">63 mL</p> </td> </tr> <tr class="Last"> <td> <p class="First">Adjusted mean difference (95% CI), p-value</p> </td><td colspan="2"> <p class="First">51 mL (6 to 97 mL), p=0.028</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>\n<p class=\"First\"></p>\n</td><td>\n<p class=\"First\">Control (N=214)</p>\n</td><td>\n<p class=\"First\">BRONCHITOL (N=209)</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">Adjusted mean change from baseline</p>\n</td><td>\n<p class=\"First\">12 mL</p>\n</td><td>\n<p class=\"First\">63 mL</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td>\n<p class=\"First\">Adjusted mean difference (95% CI), p-value</p>\n</td><td colspan=\"2\">\n<p class=\"First\">51 mL (6 to 97 mL), p=0.028</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

intention-to-treat population of adults of 78 mL (95% CI: 2 to 153 mL).

{ "type": "p", "children": [], "text": "intention-to-treat population of adults of 78 mL (95% CI: 2 to 153 mL)." }

BRONCHITOL (mannitol) inhalation powder:

{ "type": "p", "children": [], "text": "BRONCHITOL (mannitol) inhalation powder:" }

{ "type": "ul", "children": [ "40 mg of mannitol per capsule", "capsules are clear, colorless and imprinted in black with “PXS” on cap and “40 mg” on body", "supplied in cartons containing 10, 140 or 560 capsules in blister packs co-packaged with 1, 1, and 4 inhalers respectively in a carton" ], "text": "" }

BRONCHITOL is provided in 3 commercial presentations:

{ "type": "p", "children": [], "text": "BRONCHITOL is provided in 3 commercial presentations:" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="First"> <td> <p class="First">Pack Quantities</p> </td><td> <p class="First">Inhalers</p> </td><td> <p class="First">Capsules</p> </td><td> <p class="First">NDC Number</p> </td> </tr> <tr> <td> <p class="First">4-week Treatment Pack (4 x 7-day treatment packs)</p> </td><td> <p class="First">4</p> </td><td> <p class="First">560</p> </td><td> <p class="First">84639-212-56</p> </td> </tr> <tr> <td> <p class="First">7-day Treatment Pack</p> </td><td> <p class="First">1</p> </td><td> <p class="First">140</p> </td><td> <p class="First">84639-212-14</p> </td> </tr> <tr class="Last"> <td> <p class="First">Bronchitol Tolerance Test</p> </td><td> <p class="First">1</p> </td><td> <p class="First">10</p> </td><td> <p class="First">84639-212-04</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>\n<p class=\"First\">Pack Quantities</p>\n</td><td>\n<p class=\"First\">Inhalers</p>\n</td><td>\n<p class=\"First\">Capsules</p>\n</td><td>\n<p class=\"First\">NDC Number</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">4-week Treatment Pack (4 x 7-day treatment packs)</p>\n</td><td>\n<p class=\"First\">4</p>\n</td><td>\n<p class=\"First\">560</p>\n</td><td>\n<p class=\"First\">84639-212-56</p>\n</td>\n</tr>\n<tr>\n<td>\n<p class=\"First\">7-day Treatment Pack</p>\n</td><td>\n<p class=\"First\">1</p>\n</td><td>\n<p class=\"First\">140</p>\n</td><td>\n<p class=\"First\">84639-212-14</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td>\n<p class=\"First\">Bronchitol Tolerance Test</p>\n</td><td>\n<p class=\"First\">1</p>\n</td><td>\n<p class=\"First\">10</p>\n</td><td>\n<p class=\"First\">84639-212-04</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

BRONCHITOL should be stored between 68°F-77°F (20°C-25°C) with excursions permitted between 59°F-86°F (15°C- 30°C). [See USP Controlled Room Temperature]. Do not refrigerate. Do not freeze.

{ "type": "p", "children": [], "text": "BRONCHITOL should be stored between 68°F-77°F (20°C-25°C) with excursions permitted between 59°F-86°F (15°C- 30°C). [See USP Controlled Room Temperature]. Do not refrigerate. Do not freeze." }

BRONCHITOL should only be used with the provided inhaler, which is a white plastic inhaler comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. All remaining unused (opened and unopened) blister packs and the inhalers should be properly discarded. Be sure to read the accompanying BRONCHITOL instructions completely before administration. If you have any questions, contact the supplier at 1-888-276-2144.

{ "type": "p", "children": [], "text": "BRONCHITOL should only be used with the provided inhaler, which is a white plastic inhaler comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. All remaining unused (opened and unopened) blister packs and the inhalers should be properly discarded. Be sure to read the accompanying BRONCHITOL instructions completely before administration. If you have any questions, contact the supplier at 1-888-276-2144." }

Advise the patient to read the FDA-approved patient labeling (Patient Information and Patient Instructions for Use).

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

BRONCHITOL Tolerance Test

{ "type": "p", "children": [], "text": "\nBRONCHITOL Tolerance Test\n" }

Inform patients that a BRONCHITOL Tolerance Test is required prior to beginning treatment with BRONCHITOL. The

{ "type": "p", "children": [], "text": "Inform patients that a BRONCHITOL Tolerance Test is required prior to beginning treatment with BRONCHITOL. The" }

BRONCHITOL Tolerance Test must be performed by a healthcare practitioner equipped to monitor oxygen saturation (SpO 2), perform spirometry (FEV 1), and manage acute bronchospasm.

{ "type": "p", "children": [], "text": "BRONCHITOL Tolerance Test must be performed by a healthcare practitioner equipped to monitor oxygen saturation (SpO\n 2), perform spirometry (FEV\n 1), and manage acute bronchospasm.\n " }

Inhaled Short-Acting Bronchodilator Use

{ "type": "p", "children": [], "text": "\nInhaled Short-Acting Bronchodilator Use \n" }

Instruct patients that an inhaled short-acting bronchodilator such as albuterol must always be administered 5 to 15 minutes prior to every dose of BRONCHITOL.

{ "type": "p", "children": [], "text": "Instruct patients that an inhaled short-acting bronchodilator such as albuterol must always be administered 5 to 15 minutes prior to every dose of BRONCHITOL." }

Bronchospasm

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

Prior to administration, inform patients that bronchospasm can occur with inhalation of BRONCHITOL. If patient experiences bronchospasm, instruct the patient to discontinue BRONCHITOL and contact their healthcare practitioner right away.

{ "type": "p", "children": [], "text": "Prior to administration, inform patients that bronchospasm can occur with inhalation of BRONCHITOL. If patient experiences bronchospasm, instruct the patient to discontinue BRONCHITOL and contact their healthcare practitioner right away." }

Hemoptysis

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

Inform patients that hemoptysis can occur with inhalation of BRONCHITOL. If a patient experiences hemoptysis, instruct patients to discontinue BRONCHITOL and contact their healthcare practitioner right away.

{ "type": "p", "children": [], "text": "Inform patients that hemoptysis can occur with inhalation of BRONCHITOL. If a patient experiences hemoptysis, instruct patients to discontinue BRONCHITOL and contact their healthcare practitioner right away." }

Administration

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

Instruct patients on the proper administration of BRONCHITOL with the inhaler. The recommended dosage is 10 capsules (400 mg) twice a day. This requires inhaling the contents of 10 capsules administered individually once in the morning and once at least 2-3 hours before bed.

{ "type": "p", "children": [], "text": "Instruct patients on the proper administration of BRONCHITOL with the inhaler. The recommended dosage is 10 capsules (400 mg) twice a day. This requires inhaling the contents of 10 capsules administered individually once in the morning and once at least 2-3 hours before bed." }

Manufactured by:

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

Arna Pharma Pty Ltd.

{ "type": "p", "children": [], "text": "Arna Pharma Pty Ltd." }

20 Rodborough Rd Frenchs Forest NSW 2086 AUSTRALIA

{ "type": "p", "children": [], "text": "20 Rodborough Rd Frenchs Forest NSW 2086 AUSTRALIA" }

Manufactured for:

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

Pharmaxis Europe Limited

{ "type": "p", "children": [], "text": "Pharmaxis Europe Limited" }

108 Q House Furze Road,

{ "type": "p", "children": [], "text": "108 Q House Furze Road," }

Sandyford Dublin 18,

{ "type": "p", "children": [], "text": "Sandyford Dublin 18," }

D18AY29 Ireland

{ "type": "p", "children": [], "text": "D18AY29 Ireland" }

BRONCHITOL® is a registered trademark of Pharmaxis Europe Limited.

{ "type": "p", "children": [], "text": " BRONCHITOL® is a registered trademark of Pharmaxis Europe Limited. \n " }

BRONCHITOL® (mannitol) inhalation powder for oral inhalation use

{ "type": "p", "children": [], "text": "BRONCHITOL® (mannitol) inhalation powder for oral inhalation use" }

This Patient Instructions for Use contains information on how to take BRONCHITOL.

{ "type": "p", "children": [], "text": "This Patient Instructions for Use contains information on how to take BRONCHITOL." }

Each BRONCHITOL box contains:

{ "type": "p", "children": [], "text": "Each BRONCHITOL box contains:" }

<div class="scrollingtable"><table border="0"> <tbody class="Headless"> <tr class="First"> <td> <p class="First">7-day Treatment Pack</p> </td><td> <p class="First">4-week Treatment Pack</p> </td> </tr> <tr> <td> <ul> <li>140 Capsules (14 blister packs)</li> </ul> </td><td> <ul> <li>560 Capsules (56 blister packs)</li> </ul> </td> </tr> <tr> <td> <ul> <li>1 Inhaler</li> </ul> </td><td> <ul> <li>4 Inhalers</li> </ul> </td> </tr> <tr class="Last"> <td> <ul> <li>Prescribing Information</li> </ul> </td><td> <ul> <li>Prescribing Information</li> </ul> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\">\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>\n<p class=\"First\">7-day Treatment Pack</p>\n</td><td>\n<p class=\"First\">4-week Treatment Pack</p>\n</td>\n</tr>\n<tr>\n<td>\n<ul>\n<li>140 Capsules (14 blister packs)</li>\n</ul>\n</td><td>\n<ul>\n<li>560 Capsules (56 blister packs)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td>\n<ul>\n<li>1 Inhaler</li>\n</ul>\n</td><td>\n<ul>\n<li>4 Inhalers</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td>\n<ul>\n<li>Prescribing Information</li>\n</ul>\n</td><td>\n<ul>\n<li>Prescribing Information</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Important Information You Need to Know Before Using BRONCHITOL

{ "type": "p", "children": [], "text": "Important Information You Need to Know Before Using BRONCHITOL" }

{ "type": "ul", "children": [ "Do not use BRONCHITOL until your healthcare provider has performed the BRONCHITOL Tolerance Test (BTT) and approved you for treatment. This is to make sure you get the right treatment if you have a severe reaction.", "For oral inhalation only", "Do not swallow BRONCHITOL capsules.", "Use an inhaled short-acting bronchodilator 5 to15 minutes before every dose of BRONCHITOL.", "Use BRONCHITOL 2 times each day. Inhale through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules:\n\t\n \n1 time in the morning\n1 time at least 2 to 3 hours before bedtime\n\n" ], "text": "" }

Preparing to use BRONCHITOL

{ "type": "p", "children": [], "text": "Preparing to use BRONCHITOL" }

BRONCHITOL is supplied to people in cartons containing 140 or 560 capsules in blister packs. Supplies you will need to use BRONCHITOL:

{ "type": "p", "children": [], "text": "BRONCHITOL is supplied to people in cartons containing 140 or 560 capsules in blister packs. Supplies you will need to use BRONCHITOL:" }

{ "type": "ul", "children": [ "1 Blister pack", "1 Inhaler", "Bronchodilator (and spacer for bronchodilator if needed)", "Sink or hand washing station" ], "text": "" }

Before using BRONCHITOL:

{ "type": "p", "children": [], "text": "Before using BRONCHITOL:" }

Use an inhaled bronchodilator 5 to15 minutes before using BRONCHITOL (See Figure A).

{ "type": "p", "children": [], "text": "Use an inhaled bronchodilator 5 to15 minutes before using BRONCHITOL (See Figure A)." }

Clean and dry hands well (See Figure B).

{ "type": "p", "children": [], "text": "Clean and dry hands well (See Figure B)." }

Inhaler use steps for inhalation of the contents of a single capsule: Step 1. Remove cap (See Figure C).

{ "type": "p", "children": [], "text": "Inhaler use steps for inhalation of the contents of a single capsule: Step 1. Remove cap (See Figure C)." }

Step 2. Twist open inhaler by turning the mouthpiece to the right. (See Figure D).

{ "type": "p", "children": [], "text": "Step 2. Twist open inhaler by turning the mouthpiece to the right. (See Figure D)." }

Step 3. Take 1 capsule out of the blister pack and put it in the chamber. (See Figure E).

{ "type": "p", "children": [], "text": "Step 3. Take 1 capsule out of the blister pack and put it in the chamber. (See Figure E)." }

Do not place capsule into the mouthpiece of the inhaler.

{ "type": "p", "children": [], "text": "Do not place capsule into the mouthpiece of the inhaler." }

Step 4. Hold inhaler upright and turn the mouthpiece to the left until it locks in place. (See Figure F).

{ "type": "p", "children": [], "text": "Step 4. Hold inhaler upright and turn the mouthpiece to the left until it locks in place. (See Figure F)." }

Step 5. Push both piercing buttons at the same time. Release both piercing buttons at the same time (See Figure G).

{ "type": "p", "children": [], "text": "Step 5. Push both piercing buttons at the same time. Release both piercing buttons at the same time (See Figure G)." }

Keep inhaler upright. Never keep piercing buttons pressed.

{ "type": "p", "children": [], "text": "Keep inhaler upright. Never keep piercing buttons pressed." }

Step 6. Breathe out (exhale) fully (See Figure H).

{ "type": "p", "children": [], "text": "Step 6. Breathe out (exhale) fully (See Figure H)." }

Do not breathe out into inhaler.

{ "type": "p", "children": [], "text": "Do not breathe out into inhaler." }

Step 7. Close lips around the mouthpiece and take a steady deep breath in through your mouth. Do not breathe through your nose. Remove inhaler from mouth. Hold breath for 5 seconds before exhaling, do not breathe out (exhale) into inhaler (See Figure I).

{ "type": "p", "children": [], "text": "Step 7. Close lips around the mouthpiece and take a steady deep breath in through your mouth. Do not breathe through your nose. Remove inhaler from mouth. Hold breath for 5 seconds before exhaling, do not breathe out (exhale) into inhaler (See Figure I)." }

You should hear a rattling sound while breathing in. If you do not, tap bottom of inhaler firmly and repeat steps 6 and 7.

{ "type": "p", "children": [], "text": "You should hear a rattling sound while breathing in. If you do not, tap bottom of inhaler firmly and repeat steps 6 and 7." }

Step 8. Open the inhaler by turning the cap to the right. If powder is left in capsule, repeat steps 6 and 7. After the capsule is empty, throw away. (See Figure J).

{ "type": "p", "children": [], "text": "Step 8. Open the inhaler by turning the cap to the right. If powder is left in capsule, repeat steps 6 and 7. After the capsule is empty, throw away. (See Figure J)." }

Step 9. Repeat steps 3 to 8 for all 10 capsules in 1 blister pack (See Figure K).

{ "type": "p", "children": [], "text": "Step 9. Repeat steps 3 to 8 for all 10 capsules in 1 blister pack (See Figure K)." }

Breathe in (inhale) contents of each capsule one after another until all 10 capsules in the blister pack are used.

{ "type": "p", "children": [], "text": "Breathe in (inhale) contents of each capsule one after another until all 10 capsules in the blister pack are used." }

Step 10. After inhaling contents of all 10 capsules, close mouthpiece and place cap on inhaler (See Figure L).

{ "type": "p", "children": [], "text": "Step 10. After inhaling contents of all 10 capsules, close mouthpiece and place cap on inhaler (See Figure L)." }

Step 11. Continue using BRONCHITOL for 7 days then throw away (discard) the inhaler (See Figure M).

{ "type": "p", "children": [], "text": "Step 11. Continue using BRONCHITOL for 7 days then throw away (discard) the inhaler (See Figure M)." }

How should I store BRONCHITOL?

{ "type": "p", "children": [], "text": "How should I store BRONCHITOL?" }

{ "type": "ul", "children": [ "Store BRONCHITOL at room temperature between 68°F to77°F (20°C to 25°C).", "If your BRONCHITOL capsules are stored at temperatures more than 86°F (30°C), throw them away.", "Do not freeze BRONCHITOL.", "Do not refrigerate BRONCHITOL.", "Keep BRONCHITOL and all medicines out of the reach of children." ], "text": "" }

Cleaning your BRONCHITOL inhaler.

{ "type": "p", "children": [], "text": "Cleaning your BRONCHITOL inhaler." }

{ "type": "ul", "children": [ "Your inhaler should give you the correct dose of medicine for 7 days without needing cleaning. However, if your inhaler does need cleaning:\n\t\n \nMake sure your inhaler is empty.\nWash your inhaler in warm water with the mouthpiece open.\nShake it until there are no large water droplets left in the inhaler.\nLeave it to dry in the air by laying it on its side with the mouthpiece open.\nAllow the inhaler to dry fully (or completely) after it has been washed.\n\n" ], "text": "" }

Caring for your BRONCHITOL inhaler.

{ "type": "p", "children": [], "text": "Caring for your BRONCHITOL inhaler." }

{ "type": "ul", "children": [ "Keep your inhaler dry and always make sure your hands are completely dry before using it.", "Do not breathe or cough into your inhaler.", "Do not take your inhaler apart.", "Do not place a capsule directly into the mouthpiece of your inhaler.", "Do not leave a used capsule in your inhaler chamber.", "Use a new inhaler after 7 days.", "If your inhaler breaks, call to your healthcare provider." ], "text": "" }

For more information about BRONCHITOL or how to use your inhaler, call 1-888-276-2144.

{ "type": "p", "children": [], "text": "For more information about BRONCHITOL or how to use your inhaler, call 1-888-276-2144." }

Manufactured by:

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

Arna Pharma Pty Ltd.

{ "type": "p", "children": [], "text": "Arna Pharma Pty Ltd." }

20 Rodborough Road

{ "type": "p", "children": [], "text": "20 Rodborough Road" }

Frenchs Forest NSW

{ "type": "p", "children": [], "text": "Frenchs Forest NSW" }

2086 AUSTRALIA

{ "type": "p", "children": [], "text": "2086 AUSTRALIA" }

Manufactured for:

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

Pharmaxis Europe Limited

{ "type": "p", "children": [], "text": "Pharmaxis Europe Limited" }

108 Q House Furze Road,

{ "type": "p", "children": [], "text": "108 Q House Furze Road," }

Sandyford Dublin 18,

{ "type": "p", "children": [], "text": "Sandyford Dublin 18," }

D18AY29 Ireland

{ "type": "p", "children": [], "text": "D18AY29 Ireland" }

1-888-276-2144

{ "type": "p", "children": [], "text": "1-888-276-2144" }

BRONCHITOL is registered in the US Patent and Trademark Office.

{ "type": "p", "children": [], "text": "BRONCHITOL is registered in the US Patent and Trademark Office." }

This Patient Instructions for Use has been approved by the U.S. Food and Drug Administration.

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

Revised: 06/2024

{ "type": "p", "children": [], "text": "Revised: 06/2024" }

Principal Display Panel - 40 mg 4 Week Carton Label

{ "type": "p", "children": [], "text": "Principal Display Panel - 40 mg 4 Week Carton Label" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 84639-212-56

{ "type": "p", "children": [], "text": "NDC 84639-212-56" }

Caution: Federal Law Prohibits Dispensing Without A Prescription

{ "type": "p", "children": [], "text": "Caution: Federal Law Prohibits Dispensing Without A Prescription" }

Bronchitol®

{ "type": "p", "children": [], "text": "Bronchitol®" }

(mannitol) inhalation powder

{ "type": "p", "children": [], "text": "(mannitol) inhalation powder" }

40 mg per capsule

{ "type": "p", "children": [], "text": "40 mg per capsule" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION ONLY" }

Do Not Swallow Bronchitol Capsules

{ "type": "p", "children": [], "text": "Do Not Swallow Bronchitol Capsules" }

Complete entire package (56 Blister Packs) for 28 days treatment

{ "type": "p", "children": [], "text": "Complete entire package (56 Blister Packs) for 28 days treatment" }

Contents:

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

56 Blister Cards: 560 capsules (40 mg each)

{ "type": "p", "children": [], "text": "56 Blister Cards: 560 capsules (40 mg each)" }

4 Bronchitol devices: For use with enclosed capsules only

{ "type": "p", "children": [], "text": "4 Bronchitol devices: For use with enclosed capsules only" }

See package insert for complete dosage information

{ "type": "p", "children": [], "text": "See package insert for complete dosage information" }

For more information, call 1-888-661-9260.

{ "type": "p", "children": [], "text": "For more information, call 1-888-661-9260." }

Principal Display Panel - 40 mg 7 Day Carton Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - 40 mg 7 Day Carton Label\n" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 84639-212-14

{ "type": "p", "children": [], "text": "NDC 84639-212-14" }

Bronchitol®

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

(mannitol) inhalation powder

{ "type": "p", "children": [], "text": "(mannitol) inhalation powder" }

40 mg per capsule

{ "type": "p", "children": [], "text": "\n40 mg per capsule\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION ONLY" }

Do Not Swallow Bronchitol Capsules

{ "type": "p", "children": [], "text": "Do Not Swallow Bronchitol Capsules" }

Complete entire package (14 Blister Packs) for 7 days treatment

{ "type": "p", "children": [], "text": "Complete entire package (14 Blister Packs) for 7 days treatment" }

Contents:

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

{ "type": "ul", "children": [ "14 Blister Packs: 140 capsules (40 mg each)", "1 Bronchitol inhaler: For use with enclosed capsules only", "Quick reference guide", "Package Insert" ], "text": "" }

See package insert for complete dosage information

{ "type": "p", "children": [], "text": "See package insert for complete dosage information" }

For more information, call 1-888-276-0618.

{ "type": "p", "children": [], "text": "For more information, call 1-888-276-0618." }

Principal Display Panel - 40 mg Tolerance Test Carton Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - 40 mg Tolerance Test Carton Label\n" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 84639-212-04

{ "type": "p", "children": [], "text": "NDC 84639-212-04" }

Bronchitol®

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

(mannitol) inhalation powder

{ "type": "p", "children": [], "text": "(mannitol) inhalation powder" }

Tolerance Test

{ "type": "p", "children": [], "text": "Tolerance Test" }

40 mg per capsule

{ "type": "p", "children": [], "text": "40 mg per capsule" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION ONLY" }

Contents:

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

{ "type": "ul", "children": [ "1 Blister Pack: 10 capsules", "1 Bronchitol inhaler:" ], "text": "" }

For use with enclosed capsules only

{ "type": "p", "children": [], "text": "For use with enclosed capsules only" }

{ "type": "ul", "children": [ "Tolerance Test Instructions", "Package Insert" ], "text": "" }

The Bronchitol Tolerance Test MUST be completed to identify bronchial hyperresponsiveness to mannitol prior to prescribing Bronchitol. Read Tolerance Test instructions for detailed procedure.

{ "type": "p", "children": [], "text": "The Bronchitol Tolerance Test MUST be completed to\n \nidentify bronchial hyperresponsiveness to mannitol\n \nprior to prescribing Bronchitol. Read Tolerance Test\n \ninstructions for detailed procedure.\n " }

Do Not Swallow Bronchitol Capsules

{ "type": "p", "children": [], "text": "Do Not Swallow Bronchitol Capsules" }

These highlights do not include all the information needed to use MANNITOL INJECTION safely and effectively. See full prescribing information for MANNITOL INJECTION.

{ "type": "p", "children": [], "text": "These highlights do not include all the information needed to use MANNITOL INJECTION safely and effectively. See full prescribing information for MANNITOL INJECTION." }

MANNITOL injection, for intravenous useInitial U.S. Approval: 1964

{ "type": "p", "children": [], "text": "MANNITOL injection, for intravenous useInitial U.S. Approval: 1964" }

Mannitol Injection is indicated for the reduction of:

{ "type": "p", "children": [], "text": "Mannitol Injection is indicated for the reduction of:" }

{ "type": "ul", "children": [ "intracranial pressure and treatment of cerebral edema.", "elevated intraocular pressure." ], "text": "" }

2.1 Important Preparation and Administration Instructions

{ "type": "p", "children": [], "text": "2.1 Important Preparation and Administration Instructions" }

Mannitol Injection is for intravenous infusion preferably through a central venous catheter [see WARNINGS AND PRECAUTIONS (5.6), DESCRIPTION (11)].Prior to the administration of Mannitol Injection, evaluate renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances [see DOSAGE AND ADMINISTRATION (2.2)].Do not administer Mannitol Injection simultaneously with blood products or through the same administration set because of the possibility of pseduoagglutination or hemolysis. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination.Do not transfer Mannitol Injection into polyvinylchloride (PVC) bags; a white flocculent precipitate may form from contact with PVC surfaces.Administer Mannitol Injection using an administration set with a filter to ensure against infusion of mannitol crystals.Preparation

{ "type": "p", "children": [], "text": "Mannitol Injection is for intravenous infusion preferably through a central venous catheter [see WARNINGS AND PRECAUTIONS (5.6), DESCRIPTION (11)].Prior to the administration of Mannitol Injection, evaluate renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances [see DOSAGE AND ADMINISTRATION (2.2)].Do not administer Mannitol Injection simultaneously with blood products or through the same administration set because of the possibility of pseduoagglutination or hemolysis. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination.Do not transfer Mannitol Injection into polyvinylchloride (PVC) bags; a white flocculent precipitate may form from contact with PVC surfaces.Administer Mannitol Injection using an administration set with a filter to ensure against infusion of mannitol crystals.Preparation" }

Visually inspect the container before preparation and again before administration. Do not administer unless solution is clear, the container undamaged, and the fliptop vial seal intact.Crystals may form in Mannitol Injection, especially if the solution is exposed to low temperatures. If crystallization occurs, warm the vial in water at 80°C and periodically shake vigorously to dissolve the crystals. Mannitol Injection may be autoclaved at 121°C for 20 minutes at 15 psi. Cool to body temperature or less before administering. Re-inspect Mannitol Injection for crystals prior to administration. Discard the solution if all the crystals cannot be dissolved.Remove cover from fliptop vial and cleanse stopper with antiseptic before use.Additives may be incompatible. Consult with pharmacist, if available.For single use only; discard unused portion.2.2 Recommended DosagePrior to administration of Mannitol Injection, evaluate renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances.

{ "type": "p", "children": [], "text": "Visually inspect the container before preparation and again before administration. Do not administer unless solution is clear, the container undamaged, and the fliptop vial seal intact.Crystals may form in Mannitol Injection, especially if the solution is exposed to low temperatures. If crystallization occurs, warm the vial in water at 80°C and periodically shake vigorously to dissolve the crystals. Mannitol Injection may be autoclaved at 121°C for 20 minutes at 15 psi. Cool to body temperature or less before administering. Re-inspect Mannitol Injection for crystals prior to administration. Discard the solution if all the crystals cannot be dissolved.Remove cover from fliptop vial and cleanse stopper with antiseptic before use.Additives may be incompatible. Consult with pharmacist, if available.For single use only; discard unused portion.2.2 Recommended DosagePrior to administration of Mannitol Injection, evaluate renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances." }

The total dosage, concentration, and rate of administration depend on the age, weight, and condition of the patient being treated, including fluid requirement, electrolyte balance, serum osmolality, urinary output, and concomitant therapy.

{ "type": "p", "children": [], "text": "The total dosage, concentration, and rate of administration depend on the age, weight, and condition of the patient being treated, including fluid requirement, electrolyte balance, serum osmolality, urinary output, and concomitant therapy." }

The following outline of administration and dosage is only a general guide to therapy.

{ "type": "p", "children": [], "text": "The following outline of administration and dosage is only a general guide to therapy." }

Reduction of Intracranial Pressure and Treatment of Cerebral Edema

{ "type": "p", "children": [], "text": "Reduction of Intracranial Pressure and Treatment of Cerebral Edema" }

Usually a maximum reduction in intracranial pressure can be achieved with a dose of 0.25 g/kg administered as an intravenous infusion over at least 30 minutes, which may be repeated every six to eight hours. During and following infusion of Mannitol Injection, monitor fluid and electrolytes, serum osmolarity, and renal, cardiac, and pulmonary function. Discontinue Mannitol Injection if renal, cardiac, or pulmonary status worsens or CNS toxicity develops [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4, 5.5)].

{ "type": "p", "children": [], "text": "Usually a maximum reduction in intracranial pressure can be achieved with a dose of 0.25 g/kg administered as an intravenous infusion over at least 30 minutes, which may be repeated every six to eight hours. During and following infusion of Mannitol Injection, monitor fluid and electrolytes, serum osmolarity, and renal, cardiac, and pulmonary function. Discontinue Mannitol Injection if renal, cardiac, or pulmonary status worsens or CNS toxicity develops [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4, 5.5)]." }

Reduction of Intraocular Pressure

{ "type": "p", "children": [], "text": "Reduction of Intraocular Pressure" }

The recommended dosage is 1.5 to 2 g/kg as a single dose administered as an intravenous infusion over at least 30 minutes. When used preoperatively, administer Mannitol Injection 60 to 90 minutes before surgery to achieve maximal reduction of intraocular pressure before operation.

{ "type": "p", "children": [], "text": "The recommended dosage is 1.5 to 2 g/kg as a single dose administered as an intravenous infusion over at least 30 minutes. When used preoperatively, administer Mannitol Injection 60 to 90 minutes before surgery to achieve maximal reduction of intraocular pressure before operation." }

Mannitol Injection 25%, USP: 12.5 g/50 mL (0.25 g/mL) of mannitol as a clear and colorless solution in a single-dose vial.

{ "type": "p", "children": [], "text": "Mannitol Injection 25%, USP: 12.5 g/50 mL (0.25 g/mL) of mannitol as a clear and colorless solution in a single-dose vial." }

Mannitol Injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Mannitol Injection is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Known hypersensitivity to mannitol [see WARNINGS AND PRECAUTIONS (5.1)].", "Anuria [see WARNINGS AND PRECAUTIONS (5.2)].", "Severe hypovolemia [see WARNINGS AND PRECAUTIONS (5.4)].", "Pre-existing severe pulmonary vascular congestion or pulmonary edema [see WARNINGS AND PRECAUTIONS (5.5)].", "Active intracranial bleeding except during craniotomy." ], "text": "" }

5.1 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylaxis, hypotension, and dyspnea resulting in cardiac arrest and death have been reported with Mannitol Injection [see ADVERSE REACTIONS (6)]. Stop the infusion immediately if signs or symptoms of a suspected hypersensitivity reaction develop. Initiate appropriate therapeutic countermeasures as clinically indicated.

{ "type": "p", "children": [], "text": "5.1 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylaxis, hypotension, and dyspnea resulting in cardiac arrest and death have been reported with Mannitol Injection [see ADVERSE REACTIONS (6)]. Stop the infusion immediately if signs or symptoms of a suspected hypersensitivity reaction develop. Initiate appropriate therapeutic countermeasures as clinically indicated." }

5.2 Renal Complications Including Renal FailureRenal complications, including irreversible renal failure, have been reported in patients receiving mannitol.

{ "type": "p", "children": [], "text": "5.2 Renal Complications Including Renal FailureRenal complications, including irreversible renal failure, have been reported in patients receiving mannitol." }

Reversible, oliguric acute kidney injury has occurred in patients with normal pretreatment renal function who received large intravenous doses of mannitol. Although the osmotic nephrosis associated with mannitol administration is in principle reversible, osmotic nephrosis in general is known to potentially proceed chronic or even end-stage renal failure. Monitor renal function closely, including signs of urine output reduction, during mannitol injection.

{ "type": "p", "children": [], "text": "Reversible, oliguric acute kidney injury has occurred in patients with normal pretreatment renal function who received large intravenous doses of mannitol. Although the osmotic nephrosis associated with mannitol administration is in principle reversible, osmotic nephrosis in general is known to potentially proceed chronic or even end-stage renal failure. Monitor renal function closely, including signs of urine output reduction, during mannitol injection." }

Patients with pre-existing renal disease, patients with conditions that put them at risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk for renal failure following administration of Mannitol Injection. Avoid concomitant administration of nephrotoxic drugs (e.g., aminoglycosides) or other diuretics with Mannitol Injection, if possible [see DRUG INTERACTIONS (7)].

{ "type": "p", "children": [], "text": "Patients with pre-existing renal disease, patients with conditions that put them at risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk for renal failure following administration of Mannitol Injection. Avoid concomitant administration of nephrotoxic drugs (e.g., aminoglycosides) or other diuretics with Mannitol Injection, if possible [see DRUG INTERACTIONS (7)]." }

Patients with oliguric acute kidney injury who subsequently develop anuria while receiving mannitol are at risk of congestive heart failure, pulmonary edema, hypertensive crisis, coma, and death.

{ "type": "p", "children": [], "text": "Patients with oliguric acute kidney injury who subsequently develop anuria while receiving mannitol are at risk of congestive heart failure, pulmonary edema, hypertensive crisis, coma, and death." }

During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue Mannitol Injection if renal function worsens [see WARNINGS AND PRECAUTIONS (5.5)].

{ "type": "p", "children": [], "text": "During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue Mannitol Injection if renal function worsens [see WARNINGS AND PRECAUTIONS (5.5)]." }

5.3 Central Nervous System (CNS) ToxicityCNS toxicity manifested by, e.g., confusion, lethargy, coma, has been reported in patients treated with mannitol, some resulting in death, in particular in the presence of impaired renal function CNS toxicity may result from high serum mannitol concentrations, serum hyperosmolarity resulting in intracellular dehydration within CNS, hyponatremia or other disturbances of electrolyte and acid/base balance secondary to mannitol administration [see WARNINGS AND PRECAUTIONS (5.4)].

{ "type": "p", "children": [], "text": "5.3 Central Nervous System (CNS) ToxicityCNS toxicity manifested by, e.g., confusion, lethargy, coma, has been reported in patients treated with mannitol, some resulting in death, in particular in the presence of impaired renal function CNS toxicity may result from high serum mannitol concentrations, serum hyperosmolarity resulting in intracellular dehydration within CNS, hyponatremia or other disturbances of electrolyte and acid/base balance secondary to mannitol administration [see WARNINGS AND PRECAUTIONS (5.4)]." }

At high concentrations, mannitol may cross the blood brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis.

{ "type": "p", "children": [], "text": "At high concentrations, mannitol may cross the blood brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis." }

In patients with pre-existing compromise of the blood brain barrier, the risk of increasing cerebral edema (general and focal) associated with repeated or continued use of Mannitol Injection must be individually weighed against the expected benefits.

{ "type": "p", "children": [], "text": "In patients with pre-existing compromise of the blood brain barrier, the risk of increasing cerebral edema (general and focal) associated with repeated or continued use of Mannitol Injection must be individually weighed against the expected benefits." }

A rebound increase of intracranial pressure may occur several hours after the infusion. Patients with a compromised blood brain barrier are at increased risk.

{ "type": "p", "children": [], "text": "A rebound increase of intracranial pressure may occur several hours after the infusion. Patients with a compromised blood brain barrier are at increased risk." }

Concomitant administration of neurotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate neurotoxicity. Avoid concomitant use of neurotoxic drugs, if possible [see DRUG INTERACTIONS (7.3)].

{ "type": "p", "children": [], "text": "Concomitant administration of neurotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate neurotoxicity. Avoid concomitant use of neurotoxic drugs, if possible [see DRUG INTERACTIONS (7.3)]." }

During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue Mannitol Injection if CNS toxicity develops [see WARNINGS AND PRECAUTIONS (5.5)].

{ "type": "p", "children": [], "text": "During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue Mannitol Injection if CNS toxicity develops [see WARNINGS AND PRECAUTIONS (5.5)]." }

5.4 Fluid and Electrolyte Imbalances, HyperosmolarityDepending on dosage and duration, administration of Mannitol Injection may result in hypervolemia leading to or exacerbating existing congestive heart failure. Accumulation of mannitol due to insufficient renal excretion increases the risk of hypervolemia. Mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolemia and hemoconcentration. Administration of Mannitol Injection may also cause hyperosmolarity [see DESCRIPTION (11)].

{ "type": "p", "children": [], "text": "5.4 Fluid and Electrolyte Imbalances, HyperosmolarityDepending on dosage and duration, administration of Mannitol Injection may result in hypervolemia leading to or exacerbating existing congestive heart failure. Accumulation of mannitol due to insufficient renal excretion increases the risk of hypervolemia. Mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolemia and hemoconcentration. Administration of Mannitol Injection may also cause hyperosmolarity [see DESCRIPTION (11)]." }

Depending on dosage and duration of administration, electrolyte and acid/base imbalances may also result from transcellular shifts in water and electrolytes, osmotic diuresis, and/or other mechanisms. Such imbalances may be severe and potentially fatal.

{ "type": "p", "children": [], "text": "Depending on dosage and duration of administration, electrolyte and acid/base imbalances may also result from transcellular shifts in water and electrolytes, osmotic diuresis, and/or other mechanisms. Such imbalances may be severe and potentially fatal." }

Imbalances that may result from administration of Mannitol Injection include:

{ "type": "p", "children": [], "text": "Imbalances that may result from administration of Mannitol Injection include:" }

{ "type": "ul", "children": [ "Hypernatremia, dehydration, and hemoconcentration", "Hyponatremia, which can lead to headache, nausea, seizures, lethargy, coma, cerebral edema, and death. Acute symptomatic hyponatremic encephalopathy is considered a medical emergency.", "Hypo/hyperkalemia. The development of electrolyte imbalances (e.g., hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs that are sensitive to such imbalances (e.g., digoxin, agents that may cause QT prolongation, neuromuscular blocking agents) [see DRUG INTERACTIONS (7.4)].", "Other electrolyte disturbances", "Metabolic acidosis/alkalosis", "Pediatric patients less than two years of age, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following administration of Mannitol Injection due to decreased glomerular filtration rate and limited ability to concentrate urine [see USE IN SPECIFIC POPULATIONS (8.4)].", "During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor fluid and electrolyte status and discontinue Mannitol Injection if imbalances occur [see WARNINGS AND PRECAUTIONS (5.5)]." ], "text": "" }

5.5 Monitoring/Laboratory TestsDuring and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor:

{ "type": "p", "children": [], "text": "5.5 Monitoring/Laboratory TestsDuring and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor:" }

{ "type": "ul", "children": [ "serum osmolarity, serum electrolytes (including sodium, potassium, calcium and phosphate) and acid/base balance,", "the osmol gap", "signs of hypo- or hypervolemia, including urine output", "renal, cardiac, and pulmonary function", "intracranial pressure", "Discontinue Mannitol Injection if renal, cardiac, or pulmonary status worsens or CNS toxicity develops [see CONTRAINDICATIONS (4)]." ], "text": "" }

5.6 Infusion Site ReactionsThe infusion of hypertonic solutions through a peripheral vein, including Mannitol Injection, may result in peripheral venous irritation, including phlebitis. Other severe infusion site reactions, such as compartment syndrome and swelling associated with extravasation, can occur with administration of Mannitol Injection [see ADVERSE REACTIONS (6)]. Mannitol Injection is preferably administered through a central venous catheter [see DOSAGE AND ADMINISTRATION (2.1)].

{ "type": "p", "children": [], "text": "5.6 Infusion Site ReactionsThe infusion of hypertonic solutions through a peripheral vein, including Mannitol Injection, may result in peripheral venous irritation, including phlebitis. Other severe infusion site reactions, such as compartment syndrome and swelling associated with extravasation, can occur with administration of Mannitol Injection [see ADVERSE REACTIONS (6)]. Mannitol Injection is preferably administered through a central venous catheter [see DOSAGE AND ADMINISTRATION (2.1)]." }

5.7 Interference with Laboratory TestsHigh concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations [see DRUG INTERACTIONS (7.6)].

{ "type": "p", "children": [], "text": "5.7 Interference with Laboratory TestsHigh concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations [see DRUG INTERACTIONS (7.6)]." }

Mannitol may produce false positive results in tests for blood ethylene glycol concentrations [see DRUG INTERACTIONS (7.6)].

{ "type": "p", "children": [], "text": "Mannitol may produce false positive results in tests for blood ethylene glycol concentrations [see DRUG INTERACTIONS (7.6)]." }

The following adverse reactions associated with the use mannitol were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use mannitol were identified in clinical studies or postmarketing reports. Because some of these reactions were 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." }

7.1 Nephrotoxic DrugsConcomitant administration of nephrotoxic drugs (e.g., cyclosporine, aminoglycosides) increases the risk of renal failure following administration of mannitol. Avoid use of nephrotoxic drugs with Mannitol Injection, if possible [see WARNINGS AND PRECAUTIONS (5.2)].

{ "type": "p", "children": [], "text": "7.1 Nephrotoxic DrugsConcomitant administration of nephrotoxic drugs (e.g., cyclosporine, aminoglycosides) increases the risk of renal failure following administration of mannitol. Avoid use of nephrotoxic drugs with Mannitol Injection, if possible [see WARNINGS AND PRECAUTIONS (5.2)]." }

7.2 DiureticsConcomitant administration of other diuretics may potentiate the renal toxicity of mannitol. Avoid concomitant administration of other diuretics with Mannitol Injection, if possible [see WARNINGS AND PRECAUTIONS (5.2)].

{ "type": "p", "children": [], "text": "7.2 DiureticsConcomitant administration of other diuretics may potentiate the renal toxicity of mannitol. Avoid concomitant administration of other diuretics with Mannitol Injection, if possible [see WARNINGS AND PRECAUTIONS (5.2)]." }

7.3 Neurotoxic DrugsConcomitant administration of systemic neurotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate the CNS toxicity of mannitol. Avoid use of systemic neurotoxic drugs with Mannitol Injection, if possible [see WARNINGS AND PRECAUTIONS (5.3)].

{ "type": "p", "children": [], "text": "7.3 Neurotoxic DrugsConcomitant administration of systemic neurotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate the CNS toxicity of mannitol. Avoid use of systemic neurotoxic drugs with Mannitol Injection, if possible [see WARNINGS AND PRECAUTIONS (5.3)]." }

7.4 Drugs Affected by Electrolyte ImbalancesThe development of electrolyte imbalances (e.g., hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs that are sensitive to such imbalances (e.g., digoxin, drugs that prolong the QT interval, neuromuscular blocking agents) [see WARNINGS AND PRECAUTIONS (5.4)]. During and following infusion of Mannitol Injection, monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens [see WARNINGS AND PRECAUTIONS (5.5)].

{ "type": "p", "children": [], "text": "7.4 Drugs Affected by Electrolyte ImbalancesThe development of electrolyte imbalances (e.g., hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs that are sensitive to such imbalances (e.g., digoxin, drugs that prolong the QT interval, neuromuscular blocking agents) [see WARNINGS AND PRECAUTIONS (5.4)]. During and following infusion of Mannitol Injection, monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens [see WARNINGS AND PRECAUTIONS (5.5)]." }

7.5 Renally Eliminated DrugsMannitol therapy may increase the elimination, and decrease the effectiveness of treatment with, drugs that undergo significant renal elimination. Concomitant administration of mannitol with lithium may initially increase the elimination of lithium but may also increase the risk of lithium toxicity if patients develop hypovolemia or renal impairment. In patients receiving lithium, consider holding lithium doses during treatment with Mannitol Injection. In patients requiring concomitant administration of lithium and Mannitol Injection, frequently monitor serum lithium concentrations and for signs of lithium toxicity.

{ "type": "p", "children": [], "text": "7.5 Renally Eliminated DrugsMannitol therapy may increase the elimination, and decrease the effectiveness of treatment with, drugs that undergo significant renal elimination. Concomitant administration of mannitol with lithium may initially increase the elimination of lithium but may also increase the risk of lithium toxicity if patients develop hypovolemia or renal impairment. In patients receiving lithium, consider holding lithium doses during treatment with Mannitol Injection. In patients requiring concomitant administration of lithium and Mannitol Injection, frequently monitor serum lithium concentrations and for signs of lithium toxicity." }

7.6 Interference with Laboratory TestsHigh concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations when an assay based on the conversion of phosphate (orthophosphate) to the phosphomolybdate complex is used.

{ "type": "p", "children": [], "text": "7.6 Interference with Laboratory TestsHigh concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations when an assay based on the conversion of phosphate (orthophosphate) to the phosphomolybdate complex is used." }

Mannitol may produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde.

{ "type": "p", "children": [], "text": "Mannitol may produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde." }

8.1 PregnancyRisk Summary

{ "type": "p", "children": [], "text": "8.1 PregnancyRisk Summary" }

The available case report data with mannitol over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Mannitol crosses the placenta and may cause fluid shifts that could potentially result in adverse effects in the fetus (see DATA).No adverse developmental effects from mannitol were reported in published animal studies; however, fluid shifts occurred in fetal ewes in response to maternal infusion of mannitol.

{ "type": "p", "children": [], "text": "The available case report data with mannitol over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Mannitol crosses the placenta and may cause fluid shifts that could potentially result in adverse effects in the fetus (see DATA).No adverse developmental effects from mannitol were reported in published animal studies; however, fluid shifts occurred in fetal ewes in response to maternal infusion of mannitol." }

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

{ "type": "p", "children": [], "text": "The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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

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

Human Data

{ "type": "p", "children": [], "text": "Human Data" }

Published literature reports the presence of mannitol in amniotic fluid when mannitol is administered to pregnant women during the third trimester of pregnancy.

{ "type": "p", "children": [], "text": "Published literature reports the presence of mannitol in amniotic fluid when mannitol is administered to pregnant women during the third trimester of pregnancy." }

8.2 LactationRisk Summary

{ "type": "p", "children": [], "text": "8.2 LactationRisk Summary" }

There are no data on the presence of mannitol in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Mannitol Injection and any potential adverse effects on the breastfed child from Mannitol Injection or from the underlying maternal condition.

{ "type": "p", "children": [], "text": "There are no data on the presence of mannitol in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Mannitol Injection and any potential adverse effects on the breastfed child from Mannitol Injection or from the underlying maternal condition." }

8.4 Pediatric UseMannitol Injection is approved for use in the pediatric population for the reduction of intracranial and intraocular pressure. Studies have not defined the optimal dose of Mannitol Injection in the pediatric population. The safety profile for mannitol use in pediatric patients is similar to adults at dosages described in labeling. However, pediatric patients less than two years of age, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following administration of Mannitol Injection due to decreased glomerular filtration rate and limited ability to concentrate urine [see WARNINGS AND PRECAUTIONS (5.4)].

{ "type": "p", "children": [], "text": "8.4 Pediatric UseMannitol Injection is approved for use in the pediatric population for the reduction of intracranial and intraocular pressure. Studies have not defined the optimal dose of Mannitol Injection in the pediatric population. The safety profile for mannitol use in pediatric patients is similar to adults at dosages described in labeling. However, pediatric patients less than two years of age, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following administration of Mannitol Injection due to decreased glomerular filtration rate and limited ability to concentrate urine [see WARNINGS AND PRECAUTIONS (5.4)]." }

8.5 Geriatric UseMannitol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients with impaired renal function. Evaluate the renal, cardiac and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration of Mannitol Injection [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4, 5.5)].

{ "type": "p", "children": [], "text": "8.5 Geriatric UseMannitol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients with impaired renal function. Evaluate the renal, cardiac and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration of Mannitol Injection [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4, 5.5)]." }

8.6 Renal ImpairmentPatients with pre-existing renal disease, patients with conditions that put them at high risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk of renal failure with administration of mannitol. Evaluate the renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration of Mannitol Injection [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4, 5.5)].

{ "type": "p", "children": [], "text": "8.6 Renal ImpairmentPatients with pre-existing renal disease, patients with conditions that put them at high risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk of renal failure with administration of mannitol. Evaluate the renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration of Mannitol Injection [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4, 5.5)]." }

Signs and symptoms of overdose with Mannitol Injection include renal failure and acute kidney injury, hypo/hypervolemia, hyperosmolarity and electrolyte imbalances, CNS toxicity (e.g., coma, seizures), some of which can be fatal [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4)].

{ "type": "p", "children": [], "text": "Signs and symptoms of overdose with Mannitol Injection include renal failure and acute kidney injury, hypo/hypervolemia, hyperosmolarity and electrolyte imbalances, CNS toxicity (e.g., coma, seizures), some of which can be fatal [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4)]." }

Management of overdosage with Mannitol Injection is symptomatic and supportive. Discontinue the infusion and institute appropriate corrective measures with particular attention to renal, cardiac, and pulmonary systems. Correct fluid and electrolyte imbalances.

{ "type": "p", "children": [], "text": "Management of overdosage with Mannitol Injection is symptomatic and supportive. Discontinue the infusion and institute appropriate corrective measures with particular attention to renal, cardiac, and pulmonary systems. Correct fluid and electrolyte imbalances." }

Mannitol Injection is dialyzable (hemodialysis and peritoneal dialysis), hemodialysis may increase mannitol elimination.

{ "type": "p", "children": [], "text": "Mannitol Injection is dialyzable (hemodialysis and peritoneal dialysis), hemodialysis may increase mannitol elimination." }

Mannitol Injection, USP is a sterile, nonpyrogenic solution of mannitol in water for injection available in a fliptop vial for intravenous administration as an osmotic diuretic.

{ "type": "p", "children": [], "text": "Mannitol Injection, USP is a sterile, nonpyrogenic solution of mannitol in water for injection available in a fliptop vial for intravenous administration as an osmotic diuretic." }

The content and characteristics are as follows:

{ "type": "p", "children": [], "text": "The content and characteristics are as follows:" }

The solution contains no bacteriostat, antimicrobial agent, or added buffer (except for pH adjustment) and is intended only as a single-dose injection.

{ "type": "p", "children": [], "text": "The solution contains no bacteriostat, antimicrobial agent, or added buffer (except for pH adjustment) and is intended only as a single-dose injection." }

Mannitol, USP is chemically designated D-mannitol (C6H14O6), a white crystalline powder or free-flowing granules freely soluble in water. It has the following structural formula:

{ "type": "p", "children": [], "text": "Mannitol, USP is chemically designated D-mannitol (C6H14O6), a white crystalline powder or free-flowing granules freely soluble in water. It has the following structural formula:" }

12.1 Mechanism of ActionMannitol, when administered intravenously, exerts its osmotic diuretic effect as a solute of relatively small molecular size largely confined to the extracellular space. Mannitol hinders tubular reabsorption of water and enhances excretion of sodium and chloride by elevating the osmolarity of the glomerular filtrate.

{ "type": "p", "children": [], "text": "12.1 Mechanism of ActionMannitol, when administered intravenously, exerts its osmotic diuretic effect as a solute of relatively small molecular size largely confined to the extracellular space. Mannitol hinders tubular reabsorption of water and enhances excretion of sodium and chloride by elevating the osmolarity of the glomerular filtrate." }

This increase in extracellular osmolarity affected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and intraocular pressure.

{ "type": "p", "children": [], "text": "This increase in extracellular osmolarity affected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and intraocular pressure." }

12.3 PharmacokineticsDistribution

{ "type": "p", "children": [], "text": "12.3 PharmacokineticsDistribution" }

Mannitol distributes largely to the extracellular space within 20 to 40 minutes after intravenous administration. The volume of distribution of mannitol is approximately 17 L in adults.

{ "type": "p", "children": [], "text": "Mannitol distributes largely to the extracellular space within 20 to 40 minutes after intravenous administration. The volume of distribution of mannitol is approximately 17 L in adults." }

Elimination

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

In subjects with normal renal function, the total clearance is 87 to 109 mL/minute. The elimination half-life of mannitol is 0.5 to 2.5 hours

{ "type": "p", "children": [], "text": "In subjects with normal renal function, the total clearance is 87 to 109 mL/minute. The elimination half-life of mannitol is 0.5 to 2.5 hours" }

Metabolism

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

Only a relatively small amount of the mannitol dose is metabolized after intravenous administration to healthy subjects.

{ "type": "p", "children": [], "text": "Only a relatively small amount of the mannitol dose is metabolized after intravenous administration to healthy subjects." }

Excretion

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

Mannitol is eliminated primarily via the kidneys in unchanged form. Mannitol is filtered by the glomeruli, exhibits less than 10% of tubular reabsorption, and is not secreted by tubular cells. Following intravenous administration, approximately 80% of an administered dose of mannitol is estimated to be excreted in the urine in 3 hours with lesser amounts thereafter.

{ "type": "p", "children": [], "text": "Mannitol is eliminated primarily via the kidneys in unchanged form. Mannitol is filtered by the glomeruli, exhibits less than 10% of tubular reabsorption, and is not secreted by tubular cells. Following intravenous administration, approximately 80% of an administered dose of mannitol is estimated to be excreted in the urine in 3 hours with lesser amounts thereafter." }

Specific Populations

{ "type": "p", "children": [], "text": "Specific Populations" }

Patients with Renal Impairment

{ "type": "p", "children": [], "text": "Patients with Renal Impairment" }

In patients with renal impairment, the elimination half-life of mannitol is prolonged. In a published study, in patients with renal impairment including acute renal failure and end stage renal failure, the elimination half-life of mannitol was estimated at about 36 hours, based on serum osmolarity. In patients with renal impairment on dialysis, the elimination half-life of mannitol was reduced to 6 and 21 hours during hemodialysis and peritoneal dialysis, respectively [see USE IN SPECIFIC POPULATIONS (8.6), OVERDOSAGE (10)].

{ "type": "p", "children": [], "text": "In patients with renal impairment, the elimination half-life of mannitol is prolonged. In a published study, in patients with renal impairment including acute renal failure and end stage renal failure, the elimination half-life of mannitol was estimated at about 36 hours, based on serum osmolarity. In patients with renal impairment on dialysis, the elimination half-life of mannitol was reduced to 6 and 21 hours during hemodialysis and peritoneal dialysis, respectively [see USE IN SPECIFIC POPULATIONS (8.6), OVERDOSAGE (10)]." }

Mannitol Injection 25%, USP is available as 12.5 g/50 mL (0.25 g/mL) of mannitol in a single-dose vial. Supplied as a tray of 25 vials (NDC 0409-4031-01).

{ "type": "p", "children": [], "text": "Mannitol Injection 25%, USP is available as 12.5 g/50 mL (0.25 g/mL) of mannitol in a single-dose vial. Supplied as a tray of 25 vials (NDC 0409-4031-01)." }

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.

{ "type": "p", "children": [], "text": "Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing." }

<div class="scrollingtable"><table width="100%"> <caption> <span> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</span> </caption> <tbody class="Headless"> <tr class="First"> <td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit</td> </tr> <tr class="Last"> <td>NDC 0409-4031-01<br/>Supplied in a tray of 25</td><td>NDC 0404-9905-50<br/>1 single dose vial in a bag<br/>(Vial bears NDC 0409-4031-16)</td><td>25%<br/>12.5 mg/50mL<br/>(0.25 mg/mL)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</span>\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit</td>\n</tr>\n<tr class=\"Last\">\n<td>NDC 0409-4031-01<br/>Supplied in a tray of 25</td><td>NDC 0404-9905-50<br/>1 single dose vial in a bag<br/>(Vial bears NDC 0409-4031-16)</td><td>25%<br/>12.5 mg/50mL<br/>(0.25 mg/mL)</td>\n</tr>\n</tbody>\n</table></div>" }

Inform patients or caregivers of the following risks of Mannitol Injection:

{ "type": "p", "children": [], "text": "Inform patients or caregivers of the following risks of Mannitol Injection:" }

Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.1)]Renal Complications Including Renal Failure [see WARNINGS AND PRECAUTIONS (5.2)].CNS Toxicity [see WARNINGS AND PRECAUTIONS (5.3)]Fluid and Electrolyte Imbalances, Hyperosmolarity [see WARNINGS AND PRECAUTIONS (5.4)]Infusion Site Reactions [see WARNINGS AND PRECAUTIONS (5.6)]

{ "type": "p", "children": [], "text": "Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.1)]Renal Complications Including Renal Failure [see WARNINGS AND PRECAUTIONS (5.2)].CNS Toxicity [see WARNINGS AND PRECAUTIONS (5.3)]Fluid and Electrolyte Imbalances, Hyperosmolarity [see WARNINGS AND PRECAUTIONS (5.4)]Infusion Site Reactions [see WARNINGS AND PRECAUTIONS (5.6)]" }

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc., Lake Forest, IL 60045 USA" }

LAB-1227-2.0

{ "type": "p", "children": [], "text": "LAB-1227-2.0" }