Bimatoprost

Uses and Indications

Bimatoprost ophthalmic solution, available in concentrations of 0.01% and 0.03%, is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Additionally, Bimatoprost is indicated for the treatment of hypotrichosis of the eyelashes, promoting their growth in terms of length, thickness, and darkness.

Limitations of Use

There are no teratogenic or nonteratogenic effects mentioned in the provided data.

Dosage and Administration

Bimatoprost is available in solution/drops and is indicated for use in the treatment of elevated intraocular pressure and for cosmetic enhancement of eyelashes.

For the management of elevated intraocular pressure, the recommended dosage is one drop in the affected eye(s) once daily in the evening.

For cosmetic use, bimatoprost should be applied nightly directly to the skin of the upper eyelid margin at the base of the eyelashes. The application should be performed using the accompanying sterile applicators. Any excess solution that extends beyond the eyelid margin should be blotted away. After each use, the applicator must be disposed of, and a new sterile applicator should be used for the opposite eyelid margin.

Durysta, an implant formulation of bimatoprost, is intended for ophthalmic intracameral administration. This procedure should be conducted under standard aseptic conditions to ensure safety and efficacy.

Healthcare professionals should ensure that patients are instructed on the proper administration techniques to maximize therapeutic outcomes and minimize potential side effects.

Contraindications

Use of Bimatoprost, including its formulations as a solution or drops, is contraindicated in individuals with hypersensitivity to the active substance or any of the excipients.

For Durysta, the implant formulation is contraindicated in patients with ocular or periocular infections, corneal endothelial cell dystrophy, prior corneal transplantation, absent or ruptured posterior lens capsule, and hypersensitivity.

Warnings and Precautions

Pigmentation of the iris, periorbital tissue (eyelid), and eyelashes can occur with the use of bimatoprost. It is important to note that iris pigmentation is likely to be permanent.

Concurrent Use with Other Medications

The concurrent administration of bimatoprost ophthalmic solution and intraocular pressure (IOP)-lowering prostaglandin analogs in ocular hypertensive patients may decrease the IOP-lowering effect. Patients using these products concomitantly should be closely monitored for changes to their IOP.

General Precautions

Users may experience a gradual change to their eyelashes, including increased length, thickness, and number of lashes. This change is usually reversible.

Laboratory Tests

No specific laboratory tests are mentioned for the safe use of bimatoprost.

Emergency Medical Help

No specific instructions for obtaining emergency medical help are provided.

Discontinuation Instructions

No specific instructions for stopping the medication and contacting a doctor are provided.

Side Effects

The most common adverse reaction associated with bimatoprost is conjunctival hyperemia, reported in approximately 31% to 45% of patients. Other frequently observed adverse reactions include:

• Eye Pruritus: Occurring in approximately 3% to 4% of patients.

• Skin Hyperpigmentation: Reported in about 3% to 4% of patients, with potential for permanent pigmentation of the iris, periorbital tissue (eyelid), and eyelashes.

• Eyelash Changes: Patients may experience gradual changes to eyelashes, including increased length, thickness, and number of lashes, which are usually reversible.

Additional adverse reactions noted include:

• Hypersensitivity: Reactions may occur, including local allergic responses.

• Ocular Irritation: Symptoms such as eye pain, foreign body sensation, and dry eye have been reported.

• Visual Disturbances: Including blurred vision and photophobia.

• Periorbital Changes: Such as eyelid edema and skin discoloration.

In clinical trials and postmarketing experiences, other less common adverse reactions have been identified, including:

• Iritis and Uveitis: Inflammation of the iris and uveal tract.

• Corneal Adverse Reactions: Including corneal endothelial cell loss and superficial punctate keratitis.

• Headaches and Asthenia: Generalized fatigue or weakness.

Patients using bimatoprost should be monitored for these adverse reactions, especially when used concurrently with other intraocular pressure-lowering medications, as interactions may affect efficacy.

Drug Interactions

Concurrent administration of bimatoprost ophthalmic solution and other intraocular pressure (IOP)-lowering prostaglandin analogs may result in a decreased IOP-lowering effect. Therefore, it is recommended that patients be monitored for any changes in their IOP when these medications are used together.

Bimatoprost ophthalmic solution, as well as LATISSE, contains benzalkonium chloride, which can be absorbed by soft contact lenses and may lead to discoloration. It is advised that contact lenses be removed prior to the application of these solutions and may be reinserted 15 minutes after application.

No specific drug interactions or laboratory test interactions have been reported for bimatoprost, LATISSE, Lumigan, or Zolymbus.

Pediatric Use

Use of bimatoprost ophthalmic solution 0.03% has been evaluated in a sixteen-week double-masked, randomized, vehicle-controlled study involving pediatric patients who were post-chemotherapy or had alopecia areata, as well as adolescents with hypotrichosis without associated medical conditions. No new safety issues were observed during the study.

Age Ranges

• Adolescents with hypotrichosis (N=40): 15-17 years

• Post-chemotherapy pediatric patients (N=16): 5-17 years

• Alopecia areata pediatric patients (N=15): 5-17 years

Efficacy Outcomes

• In adolescents with hypotrichosis, 19 out of 26 (73%) showed at least a 1-grade increase from baseline in the Global Eyelash Assessment at month 4.

• In post-chemotherapy pediatric patients, 11 out of 13 (85%) demonstrated at least a 1-grade increase from baseline at month 4.

• In alopecia areata pediatric patients, 4 out of 9 (44%) exhibited at least a 1-grade increase from baseline at month 4.

Safety Concerns

Use of bimatoprost in pediatric patients below the age of 16 years is not recommended due to potential safety concerns related to increased pigmentation following long-term chronic use.

Geriatric Use

No overall clinical differences in safety or effectiveness have been observed between elderly patients and other adult patients for Bimatoprost, Latisse, Durysta, Lumigan, and Zolymbus. Therefore, no specific dosage adjustments or additional safety considerations are necessary for geriatric patients. Regular monitoring is recommended to ensure continued efficacy and safety in this population, but no distinct modifications to treatment protocols are indicated based on age alone.

Pregnancy

There are no adequate and well-controlled studies of bimatoprost ophthalmic solution 0.03% administration in pregnant patients. Based on postmarketing experience, there is no increase in the risk of major birth defects or miscarriages associated with bimatoprost.

Embryofetal developmental studies have shown that administration of bimatoprost to pregnant mice and rats during organogenesis resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the human exposure following topical ophthalmic administration. These adverse effects were not observed at lower doses, specifically at 2.6 times (mice) and 47 times (rats) the human exposure.

In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the end of lactation resulted in reduced gestation length, decreased fetal body weight, and increased fetal and pup mortality at oral doses at least 41 times the human systemic exposure. No adverse effects were noted in rat offspring at exposures estimated at 14 times the human exposure.

Due to the limitations of animal reproductive studies in predicting 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 specific studies, abortion was observed in pregnant rats administered bimatoprost orally during organogenesis at a dose of 0.6 mg/kg/day (94 times the human systemic exposure). The No Observed Adverse Effect Level (NOAEL) for abortion was determined to be 0.3 mg/kg/day (47 times the human systemic exposure). No abnormalities were observed in rat fetuses at doses up to 0.6 mg/kg/day.

Similarly, in embryofetal development studies with mice, abortion and early delivery were noted at doses greater than or equal to 0.3 mg/kg/day (33 times the human systemic exposure), with a NOAEL for these effects at 0.1 mg/kg/day (2.6 times the human systemic exposure). No abnormalities were observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure).

In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from gestation day 7 to lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup mortality, as well as 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, with a NOAEL for postnatal development and mating performance of the offspring at 0.1 mg/kg/day (14 times the human systemic exposure).

Lactation

There are no adequate and well-controlled studies regarding the administration of bimatoprost ophthalmic solution 0.03% in nursing mothers. The potential for excretion of bimatoprost in breast milk has not been established, and it is unclear whether topical ocular treatment could lead to sufficient systemic absorption to produce detectable quantities in human milk.

Animal studies indicate that bimatoprost is present in the breast milk of lactating rats when administered at intravenous doses significantly higher than the recommended human ophthalmic dose. Specifically, at a dose of 1 mg/kg, bimatoprost was found in breast milk at levels 324 times the recommended human dose on a mg/m² basis. However, no data are available from animal studies at clinically relevant doses.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for bimatoprost ophthalmic solution 0.03% and any potential adverse effects on the breastfed child. Caution is advised when administering this medication to lactating mothers, as the effects on breastfed infants and milk production remain unknown. Bimatoprost should only be used during lactation if the potential benefits justify the risks to the infant.

Renal Impairment

Patients with renal impairment may require careful consideration when using Bimatoprost and its formulations, including Lumigan and Latisse.

For Lumigan, dosage adjustments may be necessary for patients with renal impairment. It is recommended that renal function be monitored regularly, particularly for those with a creatinine clearance of less than 30 mL/min, who should receive a reduced dose. Additionally, renal function tests should be performed prior to initiation of treatment and periodically throughout the course of therapy to ensure patient safety.

No specific information regarding renal impairment, dosage adjustments, or monitoring is provided for Bimatoprost in its other formulations, including Latisse and Durysta. Therefore, healthcare providers should exercise caution and consider individual patient circumstances when prescribing these medications to patients with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment have no specific dosage adjustments, monitoring requirements, or precautions outlined for the use of Bimatoprost, Latisse, Durysta, Lumigan, or Zolymbus. The available data does not provide any information regarding the safety or efficacy of these medications in this patient population. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing these treatments to patients with liver problems.

Overdosage

In the event of an overdose with bimatoprost ophthalmic solution, 0.03%, no specific information is available regarding overdosage in humans. Treatment should be symptomatic. In animal studies involving oral administration (by gavage) in mice and rats, doses up to 100 mg/kg/day did not produce any observable toxicity. This dose, when expressed as mg/m², is at least 70 times higher than the accidental dose of one bottle of bimatoprost ophthalmic solution, 0.03%, for a child weighing 10 kg.

For bimatoprost ophthalmic solution, 0.01%, similar findings are noted, with no reported toxicity at doses up to 100 mg/kg/day in animal studies. This dose is at least 210 times higher than the accidental dose for a 10 kg child.

Monitoring and supportive care are recommended in cases of overdose, although specific symptoms related to bimatoprost overdose have not been documented.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Bimatoprost was evaluated for its carcinogenic potential in both mice and rats. In a study where it was administered by oral gavage for 104 weeks, no carcinogenic effects were observed at doses of up to 2 mg/kg/day in mice and 1 mg/kg/day in rats. These doses correspond to approximately 192 and 291 times the human systemic exposure following topical administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on blood AUC levels.

In terms of mutagenicity, bimatoprost was not found to be mutagenic or clastogenic in several assays, including the Ames test, the mouse lymphoma test, and the in vivo mouse micronucleus tests.

Regarding fertility, bimatoprost did not impair reproductive capabilities in male or female rats at doses up to 0.6 mg/kg/day, which is at least 103 times the human systemic exposure based on blood AUC levels following topical ophthalmic administration of bimatoprost 0.03%.

No information was provided regarding teratogenic effects or non-teratogenic effects in the available data.

Storage and Handling

Bimatoprost ophthalmic solution is supplied in sterile configurations, specifically in opaque white low-density polyethylene round screw neck bottles or white opaque polypropylene bottles, both equipped with tips and turquoise opaque caps. Each package includes sterile, disposable applicators.

The product should be stored at a temperature range of 2°C to 25°C (36°F to 77°F). It is essential to keep the solution in its original container to maintain its integrity. After opening, bimatoprost ophthalmic solution, 0.03%, can be used until the expiration date stamped on the bottle.

For the implant formulation, DURYSTA, it is stored refrigerated at 2°C to 8°C (36°F to 46°F) and is packaged in a sealed foil pouch containing desiccant, ensuring optimal preservation of the product.

Zolymbus gel should be stored at 20°C to 30°C (68°F to 86°F), protected from light, and kept in the original pouch. Once the pouch is opened, the single-dose containers may remain in the opened foil pouch for up to 14 days at the same temperature. Patients are advised to note the date of opening on the pouch and discard any unused containers after 14 days.