BIMATOPROST- bimatoprost_solution/ drops

CLINICAL PHARMACOLOGY
Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. It selectively mimics the effects of naturally occurring substances, prostamides. Bimatoprost is believed to lower intraocular pressure (IOP) in humans by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. After one drop of bimatoprost ophthalmic solution, 0. 03% was administered once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0. 025 ng/mL) in most subjects within 1. 5 hours after dosing. Mean C max 0-24hr Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma. Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites. Following an intravenous dose of radiolabeled bimatoprost (3. 12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12. 2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.
Absorption
After one drop of bimatoprost ophthalmic solution, 0.03% was administered once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean C max 0-24hr
Distribution
Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma.
Metabolism
Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.
Elimination
Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.

Bimatoprost ophthalmic solution, 0. 03% is a prostaglandin analog indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. ( 1 Bimatoprost ophthalmic solution, 0. 03% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension.

One drop in the affected eye(s) once daily in the evening. ( 2 The recommended dosage is one drop in the affected eye(s) once daily in the evening. Bimatoprost ophthalmic solution, 0. 03% should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum effect reached within approximately 8 to 12 hours. 03% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

Most common adverse reaction is conjunctival hyperemia (45%). 1 To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical trials, the most frequent events associated with the use of bimatoprost ophthalmic solution, 0. 03% occurring in approximately 15% to 45% of patients, in descending order of incidence, included conjunctival hyperemia, growth of eyelashes, and ocular pruritus. Approximately 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse events occurring in approximately 3 to 10% of patients, in descending order of incidence, included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and eyelash darkening. The following ocular adverse events reported in approximately 1 to 3% of patients, in descending order of incidence, included: eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, and conjunctival edema. In less than 1% of patients, intraocular inflammation was reported as iritis. Systemic adverse events reported in approximately 10% of patients were infections (primarily colds and upper respiratory tract infections). The following systemic adverse events reported in approximately 1 to 5% of patients, in descending order of incidence, included headaches, abnormal liver function tests, asthenia and hirsutism. The following reactions have been identified during postmarketing use of bimatoprost ophthalmic solution, 0. 03% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost ophthalmic solution, or a combination of these factors, include: abnormal hair growth, dizziness, eyelid edema, hypertension, nausea, and periorbital and lid changes associated with a deepening of the eyelid sulcus.

USE IN SPECIFIC POPULATIONS
Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. 4 Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels. At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced. There are no adequate and well-controlled studies of bimatoprost ophthalmic solution, 0. 03% administration in pregnant women. Because animal reproductive studies are not always predictive of human response. Bimatoprost ophthalmic solution, 0. 03% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether bimatoprost ophthalmic solution, 0. 03% is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when bimatoprost ophthalmic solution, 0. 03% is administered to a nursing woman. No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients. In patients with a history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, bimatoprost 0. 03% had no adverse effect on liver function over 48 months.
Pregnancy Category C
Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels. At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced. There are no adequate and well-controlled studies of bimatoprost ophthalmic solution, 0.03% administration in pregnant women. Because animal reproductive studies are not always predictive of human response. Bimatoprost ophthalmic solution, 0.03% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Warnings and Precautions, Intraocular Inflammation ( 5.3

OVERDOSAGE
No information is available on overdosage in humans. If overdose with bimatoprost ophthalmic solution, 0.03% occurs, treatment should be symptomatic. In oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m 2
NONCLINICAL TOXICOLOGY
Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks. Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (at least 103 times the recommended human exposure based on blood AUC levels).
CLINICAL STUDIES
In clinical studies of patients with open angle glaucoma or ocular hypertension with a mean baseline IOP of 26 mmHg, the IOP-lowering effect of bimatoprost ophthalmic solution, 0.03% once daily (in the evening) was 7 to 8 mmHg.

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