Continuing Education Activity

Bimatoprost ophthalmic solution is an eye drop medication used to lower intraocular pressure in patients with open-angle glaucoma and ocular hypertension and cosmetically to treat hypotrichosis. It is a prostaglandin F2 alpha analog. This activity covers the indications, mechanisms of action, administration, adverse effects, contraindications and highlights the role of education from an interprofessional team to optimize treatment with bimatoprost ophthalmic solution.

Objectives:

• Describe the different indications for bimatoprost ophthalmic solution.
• Review the different proposed mechanisms of action for ophthalmic bimatoprost solution to lower intraocular pressure and promote eyelash growth.
• Outline the different administration doses and techniques of bimatoprost therapy.
• Summarize the adverse effects and contraindications of bimatoprost therapy.

Indications

Ophthalmic topical bimatoprost is a structural analog of prostaglandin F2α. It has received approval from the United States Food and Drug Administration (FDA) since 2001 as a treatment to lower intraocular pressure (IOP). Evidence indicates that topical bimatoprost is among the most efficacious drugs for reducing IOP in eyes with primary open-angle glaucoma (POAG) and ocular hypertension.[1][2] Growth of the eyelashes is a well-documented side effect of bimatoprost during the treatment of glaucoma.[3] 

In 2008, the FDA approved ophthalmic bimatoprost to treat hypotrichosis, such as for patients post-chemotherapy.[4] Due to the effects of longer, thicker, and darker eyelashes, bimatoprost ophthalmic solution is also often purchased as an ophthalmic applicator product over-the-counter (OTC) for cosmetic purposes.[5] Generic bimatoprost became available in 2015. 

The ophthalmic bimatoprost is available as both topical 0.01% and 0.03% concentrations in the United States. When used to lower IOP, once-daily dosing of bimatoprost may be used alone or concomitantly with another drug such as timolol.[6] In a 12-month comparison study in lowering IOP, bimatoprost 0.01% was demonstrated to be comparable to bimatoprost 0.03%; however, 0.01% had less frequent and severe adverse ocular events and therefore became the primary concentration available in the United States.[7]

Once-daily bimatoprost ophthalmic solution 0.03% applied to the upper eyelashes has been studied extensively as an effective method of enhancing eyelash growth with favorable safety profiles and tolerability.[3][8]

Mechanism of Action

Bimatoprost is a synthetic structural analog of prostaglandin F2α and has been hypothesized to exert its effects as an agonist through prostaglandin FP receptors.[9][10] Because bimatoprost is an amide rather than an ester, it is often labeled as a prostamide.[11]

Reduction of Intraocular Pressure

It has been well demonstrated and validated that bimatoprost and several topical prostaglandin analogs sustainably and effectively reduce IOP and are used as a standard first-line treatment of POAG.[12] This is achieved primarily through enhancing aqueous outflow through the uveoscleral pathway.[13] Specifically, bimatoprost increases the level of matrix metalloproteinases (MMP) in the ciliary muscles and sclera. These MMPs will then induce the decomposition of collagen within the extracellular matrix, resulting in improved uveoscleral outflow.[14] 

It is shown that lowering IOP in patients with ocular hypertension and glaucoma may reduce the risk of disease progression.[7] Several studies have also demonstrated that bimatoprost might have a bimodal mechanism and encourage trabecular outflow in addition to uveoscleral outflow.[13] 

Enhancement of Eyelash Growth

The ability of bimatoprost to promote the growth and thickening of eyelashes was first noted during glaucoma clinical trials to investigate the potential to reduce IOP. Although the previously mentioned prostaglandin receptors have been shown to be involved in the regeneration of the dermal papilla outer root sheath and throughout hair follicles, it remains unknown whether bimatoprost exerts its effects through this pathway.[9][15]

A series of studies demonstrated that with a 2-week course of bimatoprost, a more significant proportion of follicles were in the hair cycle's anagen phase and decreased portion in the telogen phase, suggesting an increased transition from telogen to anagen. Therefore, the study hypothesized that this increased proportion of follicles in the anagen phase allows for the observable enhanced growth of eyelashes with bimatoprost.

Administration

The two methods of administration of Bimatoprost Ophthalmic Solution vary according to the intended effects.

Applying Bimatoprost Ophthalmic Solution for Open-angled Glaucoma

Bimatoprost ophthalmic solution 0.01% or 0.03% may be used as eye drops applied directly to the ocular surface. The usual dose of bimatoprost is one drop every evening, although it may vary depending on the physician's dosing. The patient should wait 5 minutes between the administration of bimatoprost and other ophthalmic drugs. With bimatoprost, 0.03%, reduction of IOP should begin after 4 hours, and the effect will peak at 12 hours but will maintain the reduced IOP through 24 hours.[16] Clinical trials of 1-year duration demonstrate that bimatoprost effectively lowers IOP long-term and is generally well tolerated.[17] 

Applying Bimatoprost Ophthalmic Solution for Hypotrichosis

Bimatoprost ophthalmic solution 0.03% is most commonly used and associated with increased growth and prominence of eyelashes with once-daily administration. The medication is currently available commercially as a bottled solution along with included applicators. Before application, patients should remove contact lenses. It is not recommended to apply any solution directly to the eye. Every evening, a drop of the solution is applied to the single-use-per-eye applicator and then brushed against the base of the upper eyelid margin. The applicator is to be used with only one eye to prevent contaminations. Evidence suggests that the solution should be applied for at least 16 weeks for maximum eyelash prominence.[3] 

Application of new Bimatoprost Implant for Open-angled Glaucoma

Although the topical ophthalmic solution of bimatoprost is highly effective for reducing IOP, there are also serious concerns of disease management due to poor adherence by the patients.[18] Factors associated with decreased adherence to the recommended treatments include difficulty with eye drop administration, frequent dosing, adverse side effects, false perception of the disease, and forgetfulness.[18] 

To circumvent these concerns, a bimatoprost sustained-release implant was developed and approved in the USA in 2020 for patients with ocular hypertension or OAG.[19] The implant is a single, sterile, rod-shaped solid polymer that consists of a 10 or 15-μg dose of bimatoprost.[20] It is preloaded into a single-used applicator then injected into the anterior chamber, allowing the implant to deliver the prostaglandin analog directly to the iris-ciliary body. A recent phase 3 trial demonstrated that after three administrations of the implants at day 1, week 16, and week 32, most patients did not require additional treatment after 12 months and demonstrated noninferiority to topical ophthalmic solutions for OAG.[21][22]

Adverse Effects

Numerous trials have demonstrated the high level of safety and tolerance of bimatoprost when applied to the ocular surface or eyelids.[17][23]

A four-year safety study of bimatoprost eye drop application revealed that other than transient eyelash prominence, the most common adverse events included:

1. Conjunctival hyperemia (46% of patients)
2. Eye pruritus (9% of patients)
3. Dry eye syndrome
4. Burning irritation
5. Pigmentation of eyelid margins
6. Visual disturbances
7. Eye pain
8. Foreign body sensations[23] 

A series of more recent studies have also highlighted prostaglandin-associated periorbitopathy that is commonly seen in all prolonged use of topical prostaglandin analogs, especially with bimatoprost. The periorbitopathy is seen typically with periorbital fat atrophy, mild ptosis, and deepening of upper lid sulcus (seen in 80% of patients using bimatoprost).[24][25] Possibly due to the topic being dominated by industry-sponsored studies, a review noted an underreported incidence of discomfort and prostaglandin-associated periorbitopathy.[26] 

Several case reports have illustrated an association between bimatoprost use and herpetic keratitis.[27][28]

Bimatoprost applied as an eye drop has also been associated with the alteration of iris pigmentation. This is thought to be due to an increased number of melanosomes. In addition, multiple case reports have suggested various prostaglandin analogs such as bimatoprost and latanoprost can be associated with cystoid macular edema (CME) due to their pro-inflammatory effects.[11] Some studies have documented a potential association between using ophthalmic prostaglandin analogs and CME after cataract surgery in glaucoma patients.[29] 

Recent evidence suggests that the safety profile for dermal application of bimatoprost ophthalmic solution 0.03% is more favorable than that seen with topical eye drop application. The following have been reported to occur in fewer than 4% of patients following dermal application:[30]

1. Conjunctival hyperemia (most common at 3.6% of patients)
2. Eye pruritus
3. Skin hyperpigmentation
4. Ocular irritation
5. Dry eye syndrome
6. Eyelid erythema

One significant but rare side effect is the development or re-exacerbation of anterior non-granulomatous uveitis.[31][32] 

The significant difference in the likelihood of adverse effects between the two methods of bimatoprost application may be explained by the sheer difference in dose. A single application of a bimatoprost 0.03% dermally results in only about 5% of the amount applied for treatment for glaucoma.[30]

Contraindications

Bimatoprost is contraindicated in patients with a past medical history of bimatoprost hypersensitivity or hypersensitivity to ingredients within the formulation. These include preservatives such as benzalkonium chloride.

Use of bimatoprost may not be appropriate for some cases of closed-angle glaucoma and inflammatory or neovascular glaucoma. 

Contact lenses should be removed before application of bimatoprost ophthalmic solution. Contact lenses can be reinserted after 15 minutes. 

Intraocular application of bimatoprost ophthalmic solution for glaucoma is contraindicated in neonates, infants, and children due to concern for pigmentation changes after long-term use. 

Safety and efficacy of bimatoprost ophthalmic 0.03% dermal application for hypotrichosis have not been studied in children, neonates, and infants younger than five years old. The application should only be considered if the potential benefits justify the potential calculated risks. 

The use of bimatoprost ophthalmic solution has not been adequately studied in pregnant women.

Monitoring

For treatment of open-angle glaucoma, bimatoprost ophthalmic solution should be initially monitored with regular clinic visits every 2 to 4 weeks until the patient's individualized target IOP is achieved. After the IOP goal is reached, the patient can be reassessed every six months or at the clinician's discretion. Additional parameters to monitor include ocular peri-ocular pigmentation changes. 

When using bimatoprost ophthalmic solution 0.03% dermally for hypotrichosis, monitoring for potential side effects is advised.  When bimatoprost is discontinued, eyelashes may return to their original pre-treatment length and thickness.

Toxicity

Currently, no studies have been performed to evaluate bimatoprost overdose in humans. If an overdose were to occur, manufacturers recommend supportive symptomatic treatment.

Enhancing Healthcare Team Outcomes

Bimatoprost is one of the most effective first-line treatments for both open-angle glaucoma and hypotrichosis of the eyelashes. Several large, double-masked randomized control trials have shown bimatoprost’s superior efficacy in lowering IOP in primary open-angle glaucoma [Level 1], and treatment efficacy of hypotrichosis has been demonstrated.[6][23][33] However, successful treatment of glaucoma is highly dependent on interprofessional efforts to educate, communicate, and monitor for compliance with consistent eye drop use. Patients educated on the importance of the daily bimatoprost intervention were significantly more likely to report lower IOP values, which is critically important to preserve vision [Level 1].[34] Evidence demonstrates that most patients are not bothered by bimatoprost’s most common side effect of hyperemia, especially if a healthcare team member has explained the importance of IOP-lowering medications.

Ultimately, collaboration and communication amongst an interprofessional team of ophthalmologists, ophthalmic technicians, nurses, and the patient will ensure the best care for the patient. A well-educated patient will, in turn, improve patient acceptance and compliance with the prescribed medication, resulting in optimized outcomes.