LUMERA

Bimatoprost ophthalmic solution 0.03% is a synthetic prostamide analog with ocular hypotensive activity.

Its chemical name is ( Z )-7-[(1 R,2 R,3 R,5 S )-3,5­-Dihydroxy-2-[(1 E,3 S )-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5.

• N -ethylheptenamide, and its molecular weight is 415.58.

Its molecular formula is

C 25 H 37 NO 4.

Its chemical structure is

Bimatoprost is a white to off-white color powder, which is freely soluble in methanol and slightly soluble in water.

Bimatoprost ophthalmic solution 0.03% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg. Bimatoprost ophthalmic solution 0.03% contains Active: bimatoprost 0.3 mg/mL; Inactives: benzalkonium chloride 0.05 mg/mL, citric acid monohydrate, disodium hydrogen phosphate heptahydrate, sodium chloride and water for injection.

Sodium hydroxide and/or hydrochloric acid may be added to adjust pH.

The pH during its shelf life ranges from 6.8 to 7.8.

Reduction of intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension who are not adequately responding to topical beta blockers or prostaglandin analogues.

As with other ophthalmic medicinal products for local use, the active substances (timolol/ bimatoprost) contained in BIMATOPROST / TIMOLOL BIOGARAN may pass into the general circulation.

No increase in systemic absorption of each active ingredient n.

• has been observed.

Because of the presence of a beta-adrenergic component, timolol, cardiovascular, pulmonary and other adverse reactions, similar to those reported with beta-blockers by general route, are likely to occur.

Systemic adverse reactions after topical ophthalmic administration are lower than after systemic administration.

To reduce systemic absorption, Cardiac disorders Patients with cardiovascular disease (e.g., coronatric disease, angor of Prinzmetal disorder, angor of the obestrobatic disorder or heart failure, and under treatment of beta-blockers should be considered.

Patients with a potential for cardiovascular disease should be monitored for any signs of a disease, if the patient has a serious disease, be the obestrobic disorder, be the obestrobetic disorder, be the obestrobular disorder, be the obestrobular disorder, and the obestrobic.

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.

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. 12.3 Pharmacokinetics 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 and

AUC 0-24hr values were similar on days and 14 at approximately 0.08 ng/mL and 0.09 ng•hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing.

There was no significant systemic drug accumulation over time.

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.

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 1.5 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.

The pharmacotherapeutic class: the ophthalbabate-prostimulation is the low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low-level, low.

The following are the adverse reactions reported in clinical studies using the combination Bimatoprost/Timolol: the adverse reactions observed in the two active substances, bimatoprost and timolol taken separately.

No other adverse reactions specific to the combination Bimatoprost/Timolol n.

• were observed in clinical studies.

Most of the adverse reactions observed in clinical studies using the combination Bimatoprost/Timolol were ocular and moderate intensity, and no n-was described as serious.

Based on clinical data obtained over 12 months, the most commonly reported adverse reactions are conjunctival hyperhemia (usually minimal to moderate and considered as non-inflammatory), which is produced in about 26% of patients with an estimated number of symptoms B.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.D.

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 general toxicity studies, doses up to 100 mg/kg/day did not produce any toxicity.

This dose expressed as mg/m is at least 70 times higher than the accidental dose of one bottle of bimatoprost ophthalmic solution 0.03% for a 10 kg child.

Bimatoprost ophthalmic solution 0.03% is contraindicated in patients with hypersensitivity to bimatoprost or to any of the ingredients.

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 to 12 hours.

Bimatoprost ophthalmic solution 0.03% 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 minutes apart.

One drop in the affected eye(s) once daily in the evening.

Bimatoprost ophthalmic solution 0.03% is a clear, colorless sterile solution.

Practically free from visible particles packed in opaque white LDPE container with LDPE nozzle and turquoise color HDPE cap. 0.03% 2.5 mL fill in 5 mL bottle NDC 65862-802-44 5 mL fill in 10 mL bottle NDC 65862-802-05 7.5 mL fill in 10 mL bottle NDC 65862-802-10 Storage: Store at 2°C to 25°C (36°F to 77°F).

After opening, bimatoprost ophthalmic solution, 0.03% can be used until the expiration date stamped on the bottle.

There are no adequate and well-controlled studies of bimatoprost ophthalmic solution 0.03% administration in pregnant women.

There is no increase in the risk of major birth defects or miscarriages based on bimatoprost postmarketing experience.

In embryofetal developmental studies, administration of bimatoprost in pregnant mice and rats during organogensis, resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the human exposure at the recommended clinical dose (based on blood area under the curve [AUC] levels).

These adverse effects were not observed at 2.6 times (mice) and 47 times (rats) the human exposure at the recommended clinical dose.

In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the end of lactation resulted in reduced gestation length and fetal body weight, and increased fetal and pup mortality at oral doses at least 41 times the human systemic exposure at the recommended clinical dose (based on blood AUC levels).

No adverse effects were observed in rat offspring at exposures estimated at 14 times the human exposure at the recommended clinical dose (based on blood AUC levels).

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.

In an embryofetal development rat study, abortion was observed in pregnant rats administered bimatoprost orally during organogenesis at 0.6 mg/kg/day (94 times the human systemic exposure at the recommended human ophthalmic dose [RHOD], based on AUC).

Level (NOAEL) for abortion was 0.3 mg/kg/day (estimated at 47 times the human systemic exposure at the RHOD, based on AUC).

No abnormalities were observed in rat fetuses at doses up to 0.6 mg/kg/day. In an embryofetal development mouse study, abortion and early delivery were observed in pregnant mice administered bimatoprost orally during organogenesis at doses greater than or equal to 0.3 mg/kg/day (33 times the human systemic exposure at the RHOD, based on AUC).

NOAEL for abortion and early delivery was 0.1 mg/kg/day (2.6 times the human systemic exposure at the RHOD, based on AUC).

No abnormalities were observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure at the RHOD, based on AUC).

In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from gestation day to lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup mortality, and reduced pup body weight at doses greater than or equal to 0.3 mg/kg/day. These effects were observed at exposures at least 41 times the human systemic exposure at the RHOD, based on AUC.

NOAEL for postnatal development and mating performance of the offspring was 0.1 mg/kg/day (estimated at 14 times the human systemic exposure at the RHOD, based on AUC).

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.

No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.