Bimatoprost-Brimonidine-Dorzol (brimonidine tartrate/dorzolamide HCl/bimatoprost)

Dosage and concentration of dorzolamide hydrochloride are expressed in terms of dorzolamide.

For the treatment of open-angle glaucoma or ocular hypertension in adults and pediatric patients, the usual dosage of dorzolamide is 1 drop of a 2% ophthalmic solution in the affected eye(s) 3 times daily.

If the target intraocular pressure (IOP) is not achieved, alternative or additional ocular hypotensive agents may be required. (See Uses: Ocular Hypertension and Glaucoma.) When dorzolamide is used in fixed combination with timolol for the treatment of open-angle glaucoma or ocular hypertension in adults and pediatric patients 2 years of age or older, the usual dosage is 1 drop of an ophthalmic solution containing dorzolamide 2% and timolol 0.5% in the affected eye(s) twice daily. Because of the potential for additive systemic effects, combined use of topical dorzolamide and an oral carbonic anhydrase inhibitor (e.g., acetazolamide, dichlorphenamide, methazolamide) is not recommended by the manufacturer.

Topical dorzolamide has not been evaluated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute). Because dorzolamide and N-desethyldorzolamide are eliminated principally via renal excretion, the manufacturer states that topical ocular use of the drug in patients with severe renal impairment is not recommended.

Topical dorzolamide has not been evaluated in patients with hepatic impairment, and the manufacturer states that the drug should be used with caution in such patients.

Brimonidine tartrate is applied topically to the eye as an ophthalmic solution. Brimonidine tartrate also is commercially available in fixed combination with brinzolamide (as an ophthalmic suspension) and in fixed combination with timolol (as an ophthalmic solution) for topical application to the eye.

Although topical brimonidine has been administered twice daily as an ocular hypotensive agent in certain clinical studies, reductions in intraocular pressure (IOP) induced by the drug appear to diminish 8 hours following administration. Therefore, the manufacturers recommend administering brimonidine tartrate 0.1, 0.15, or 0.2% ophthalmic solution 3 times daily at intervals of approximately 8 hours. The fixed-combination ophthalmic suspension containing brinzolamide and brimonidine tartrate also is administered 3 times daily. However, when used in fixed combination with timolol, brimonidine is administered twice daily at intervals of approximately 12 hours. For self-medication for temporary relief of ocular redness, brimonidine tartrate 0.025% may be administered up to 4 times daily.

The fixed-combination ophthalmic suspension containing brinzolamide and brimonidine tartrate should be shaken well prior to use.

Care should be taken to avoid contamination of the dispensing container. (See Bacterial Keratitis under Cautions: Warnings/Precautions.)

Some brimonidine ophthalmic preparations contain benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of each dose of these preparations, but may be reinserted 15 minutes after the dose. The manufacturer of brimonidine tartrate 0.025% ophthalmic solution states that contact lenses may be reinserted 10 minutes after the dose.

If the patient is receiving more than one topical ophthalmic preparation, the preparations should be administered at least 5 minutes apart.

Dorzolamide hydrochloride is applied topically to the eye as an ophthalmic solution. Dorzolamide hydrochloride also is commercially available in fixed combination with timolol maleate for topical application to the eye as an ophthalmic solution.

Care should be taken to avoid contamination of the solution container. (See Cautions: Precautions and Contraindications.)

Dorzolamide ophthalmic solution and some formulations of dorzolamide and timolol ophthalmic solution contain benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to topical application of each dose of these preparations, but may be reinserted 15 minutes after the dose.

Preservative-free dorzolamide and timolol ophthalmic solution in single-use containers should be administered topically to one or both eyes immediately after the container is opened; since sterility cannot be maintained after the individual unit is opened, any remaining contents should be discarded immediately after administration.

If the patient is receiving more than one ophthalmic preparation, the preparations should be administered at least 5 minutes apart.

No dosing information is available for this tab.

No dosing information is available for this tab.

No formal drug interaction studies using bimatoprost have been performed. The manufacturer states that pharmacokinetic interactions are unlikely.

No formal drug interaction studies have been performed.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Dorzolamide/Carbonic Anhydrase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dorzolamide and other carbonic anhydrase inhibitors cause a decrease in aqueous humor secretion by slowing the formation of bicarbonate ions with a subsequent reduction of sodium and fluid transport which results in a reduction of intraocular pressure.(1)

CLINICAL EFFECTS: If dorzolamide is given with other carbonic anhydrase inhibitors it may cause electrolyte disturbances, because dorzolamide can be absorbed systemically.(1)

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.

PATIENT MANAGEMENT: The manufacturer of dorzolamide states that concurrent use with oral carbonic anhydrase inhibitors is not recommended.(1)

DISCUSSION: Although no human data is available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following administration of dorzolamide and oral carbonic anhydrase inhibitors.(1)

Iop-Lowering Prostaglandin Analogs/Bimatoprost Topical

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: When used ophthalmically to lower intraocular pressure, prostaglandin analogs may be at the top of the dose-response curve. Use of an additional prostaglandin may result in decreased effectiveness.(1)

CLINICAL EFFECTS: Concurrent use of topical bimatoprost may result in decreased effectiveness of ophthalmic prostaglandin analogs and an increase in intraocular pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients using ophthalmic prostaglandin analogs to lower intraocular pressure should be monitored for changes in their intraocular pressure.(1) Use of topical bimatoprost may need to be discontinued in patients who stop responding to their ophthalmic prostaglandin analogue.

DISCUSSION: Studies have shown that the ophthalmic administration of bimatoprost twice daily is less effective at lowering intraocular pressure than ophthalmic bimatoprost administered once daily. Concurrent use of topical bimatoprost may decrease the effectiveness of ophthalmic prostaglandin analogs.(1)

Bimatoprost is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Brimonidine is contraindicated in neonates and infants younger than 2 years of age. (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Brimonidine also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

• Aphakia
• Cystoid macular edema
• Iritis
• Uveitis

• Buerger's disease
• Cerebrovascular disorder
• Depression
• No disease contraindications
• Orthostatic hypotension
• Raynaud's phenomenon

Conjunctival hyperemia, growth of eyelashes, and ocular pruritus occurred in approximately 15-45% of patients who received bimatoprost 0.03% ophthalmic solution for reduction of IOP in clinical trials. Approximately 3% of patients discontinued therapy because of conjunctival hyperemia. Ocular dryness, visual disturbance, ocular burning, foreign body sensation, ocular pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and eyelash darkening have been reported in approximately 3-10% of patients who received bimatoprost 0.03% ophthalmic solution in clinical trials. Adverse ocular effects reported in approximately 1-3% of patients include ocular discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, and conjunctival edema. Adverse systemic events reported in approximately 1-10% of patients include infection (primarily colds and upper respiratory tract infections), headache, abnormal liver function test results, asthenia, and hirsutism.

Conjunctival hyperemia was reported in 31% of patients who received bimatoprost 0.01% ophthalmic solution for reduction of IOP in clinical trials. Approximately 1.6% of patients discontinued therapy because of conjunctival hyperemia. Conjunctival edema, conjunctival hemorrhage, eye irritation, ocular pain, ocular pruritus, eyelid erythema, eyelid pruritus, growth of eyelashes, hypertrichosis, instillation site irritation, punctate keratitis, skin hyperpigmentation, blurred vision, and decreased visual acuity were reported in 1-4% of patients who received bimatoprost 0.01% ophthalmic solution.

The most common adverse reactions reported during clinical trials in patients receiving bimatoprost 0.03% ophthalmic solution applied to the skin of the upper eyelid margins to increase eyelash growth include ocular pruritus, conjunctival hyperemia, and skin hyperpigmentation, each reported in approximately 3-4% of patients. Ocular irritation, dry eye symptoms, periorbital erythema, foreign body sensation, abnormal hair growth, and iris hyperpigmentation also were reported.

Adverse effects reported in approximately 10-30% of patients receiving brimonidine tartrate 0.1-0.2% ophthalmic solution include oral dryness, ocular or conjunctival hyperemia, burning and stinging, allergic conjunctivitis, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. In addition, corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, GI symptoms, hypertension, asthenia, conjunctival blanching, abnormal vision, visual disturbances, and muscular pain have been reported in approximately 3-9% of patients receiving brimonidine tartrate 0.1-0.2% ophthalmic solution.

Adverse effects reported in approximately 1-4% of patients receiving brimonidine tartrate 0.025% ophthalmic solution include decreased visual acuity, conjunctival or ocular hyperemia, dry eye, instillation site pain, and headache.

More Frequent

• Conjunctival hyperemia
• Follicular conjunctivitis
• Headache disorder
• Ocular itching
• Ocular itching
• Ocular redness

Less Frequent

• Blepharitis
• Blurred vision
• Cataracts
• Chemosis
• Chest pain
• Conjunctival hemorrhage
• Conjunctivitis
• Corneal erosion
• Depression
• Diabetes mellitus
• Dizziness
• Eyelid edema
• Eyelid erythema
• Gastrointestinal irritation
• Hypertension
• Infection
• Mucopurulent conjunctivitis
• Myalgia
• Nasal congestion
• Nausea
• Ocular discomfort
• Ocular pain
• Ocular pain
• Punctate keratitis
• Rhinitis
• Sneezing
• Syncope
• Visual changes
• Visual changes
• Vitreous detachment
• Vomiting

Rare or Very Rare

• Abnormal hepatic function tests
• Agranulocytosis
• Allergic conjunctivitis
• Angioedema
• Aplastic anemia
• Bacterial keratitis
• Bradycardia
• Bronchospastic pulmonary disease
• Chemosis
• Choroidal detachment
• Contact dermatitis
• Cystoid macular edema
• Dyspnea
• Epistaxis
• General weakness
• Hepatic necrosis
• Hypersensitivity drug reaction
• Hypertension
• Iridocyclitis
• Iris hyperpigmentation
• Iritis
• Myopia
• Ocular inflammation
• Ocular pain
• Paresthesia
• Skin rash
• Sore throat
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Urolithiasis

More Frequent

• Allergic conjunctivitis
• Conjunctival hyperemia
• Drowsy
• Dry eye
• Dysgeusia
• Eye tearing
• Fatigue
• Hirsutism
• Hyperpigmentation of eyelid
• Hypertrichosis of eyelid eyelashes
• Ocular irritation
• Ocular irritation
• Ocular irritation
• Ocular itching
• Punctate keratitis
• Xerostomia

Less Frequent

• Acute abdominal pain
• Arthralgia
• Arthritis
• Blepharitis
• Blepharoconjunctivitis
• Blurred vision
• Blurred vision
• Bronchitis
• Cataracts
• Conjunctival blanching
• Conjunctivitis
• Corneal staining
• Cough
• Dry eye
• Dry eye
• Dysgeusia
• Dyspepsia
• Dyspnea
• Eye tearing
• Eyelid crusting
• Eyelid erythema
• Foreign body sensation of eye
• Foreign body sensation of eye
• General weakness
• Headache disorder
• Hypercholesterolemia
• Hypotension
• Infection
• Insomnia
• Keratitis
• Muscle weakness
• Ocular discharge
• Ocular hypertension
• Ocular redness
• Osteoporosis
• Palpitations
• Pharyngitis
• Photophobia
• Photophobia
• Sinusitis
• Skin rash
• Symptoms of anxiety
• Visual field defect
• Vitreous floater

Rare or Very Rare

• Allergic dermatitis
• Asthenopia
• Blepharoptosis
• Deepening of upper eyelid sulcus
• Dizziness
• Dizziness
• Dry nose
• Dry skin
• Enophthalmos
• Eye tearing
• Eyelid crusting
• Eyelid edema
• General weakness
• Headache disorder
• Hordeolum
• Hypotrichosis of eyelid lashes
• Iritis
• Madarosis of eyelid
• Nausea
• Nausea
• Ocular discharge
• Periorbital edema
• Photophobia
• Trichiasis
• Trichorrhexis of eyelashes
• Xerostomia

No enhanced messaging available.

Use of bimatoprost for the treatment of open-angle glaucoma or ocular hypertension in pediatric patients younger than 16 years of age is not recommended because of potential safety concerns related to increased pigmentation following long-term use. (See Pigmentation under Cautions: Warnings/Precautions.)

In a randomized, double-blind, vehicle-controlled study in 71 pediatric patients 5-17 years of age with hypotrichosis, topical application of bimatoprost 0.03% to the upper eyelid margins once daily for 16 weeks was associated with improvement in overall eyelash prominence, as measured by an increase of at least one grade on the 4-point Global Eyelash Assessment (GEA) scale from baseline to week 16, in 73% of adolescents with hypotrichosis not associated with a contributory medical condition and 85 or 44% of pediatric patients with hypotrichosis caused by chemotherapy or associated with alopecia areata, respectively; response rates for vehicle recipients with these respective conditions were 7, 100, and 33%. No new safety concerns were identified in this study.

Safety and efficacy of topical brimonidine tartrate for the treatment of open-angle glaucoma or ocular hypertension in pediatric patients younger than 2 years of age have not been established. Because potentially serious adverse effects, including apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence, have been reported in infants treated with topical brimonidine tartrate, use of the drug is contraindicated in infants younger than 2 years of age. In a well-controlled clinical study in children 2-7 years of age with glaucoma who received brimonidine tartrate 0.2% ophthalmic solution 3 times daily, the most commonly observed adverse effects were somnolence and decreased mental alertness; approximately 16% of these children discontinued therapy because of somnolence. The incidence of somnolence generally appeared to be age and weight related, occurring in 50-83% of children 2-6 years of age and 25% of those 7 years of age who weighed more than 20 kg.

The individual components of brinzolamide and brimonidine tartrate fixed-combination ophthalmic suspension have been studied in pediatric patients 4 weeks to 5 years of age (brinzolamide) and 2-7 years of age (brimonidine).

Safety and efficacy of brimonidine tartrate and timolol fixed-combination ophthalmic solution in pediatric patients 2-16 years of age have been established based on evidence from adequate and well-controlled studies of the fixed combination in adults and additional data from a study evaluating the individually administered drugs (brimonidine tartrate 0.2% administered 3 times daily as an adjunct to timolol therapy) in children 2-7 years of age with glaucoma.

Safety and efficacy of brimonidine tartrate 0.025% ophthalmic solution for self-medication for relief of ocular redness due to minor irritation have not been established in children younger than 5 years of age. Safety and efficacy in pediatric patients 5 years of age or older are supported by evidence from controlled clinical trials in adults and additional data from a safety study that included both adults and pediatric patients 5 years of age or older.

In developmental studies in animals, bimatoprost exposure was compared with the human exposure following once-daily, bilateral, topical administration of bimatoprost 0.3% to the eyes (cornea or conjunctival sac). Abortion or early delivery was observed in mice and rats at exposure levels of at least 33 and 94 times human exposure but not at exposure levels of 2.6 and 47 times human exposure, respectively. Reduced gestation period, reduced fetal body weight, and increased fetal and pup mortality were observed in rats at exposures levels of at least 41 times human exposure. No adverse effects were observed in rat offspring at exposures estimated at 14 times human exposure.

There are no adequate and well-controlled studies using bimatoprost in pregnant women. Postmarketing experience has revealed no increase in the risk of major birth defects or spontaneous abortions. Bimatoprost should be used during pregnancy only if the potential benefits justify the possible risk to the fetus.

In studies in animals, brimonidine crossed the placenta and entered the fetal circulation to a limited extent; no evidence of teratogenicity was observed. There are no adequate and well-controlled studies of brimonidine to date in pregnant women. Brimonidine should be used during pregnancy only if potential benefits to the woman justify the potential risk to the fetus.

Reproduction studies in rabbits using oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 37 times higher than the lower limit of detection in human plasma following ocular administration revealed malformations of the vertebral bodies. These malformations occurred at dosages that caused metabolic acidosis and decreased body weight gain in dams and decreased fetal weight. Reproductive studies in rabbits using oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 15 times higher than the lower limit of detection in human plasma following ocular administration did not reveal evidence of teratogenic effects or embryotoxicity.

There are no adequate and controlled studies to date using dorzolamide in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

It is not known whether bimatoprost is distributed into human milk following topical application to the eye. Bimatoprost is distributed into milk in rats following IV administration at a dose equivalent to 324 times the recommended human ocular dose of bimatoprost 0.03%; animal data are lacking at clinically relevant doses. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for bimatoprost and any potential adverse effects of the drug on the breast-fed infant.

Brimonidine is distributed into milk in animals. It is not known whether brimonidine is distributed into human milk following topical application to the eye. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

In lactating rats given oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 52 times higher than the lower limit of detection in human plasma following ocular administration, decreases of 5-7% in body weight gain in offspring and developmental delay (i.e., incisor eruption, vaginal canalization, eye opening) secondary to lower fetal body weight have been reported.

It is not known whether dorzolamide is distributed into human milk. Because of the potential for serious adverse reactions to dorzolamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

No overall differences in safety and efficacy have been observed between geriatric patients and younger adults.

No substantial differences in safety and efficacy have been observed between geriatric patients and younger adults.