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Brinzolamide and Brimonidine

Pronunciation

(brin ZOH la mide & bri MOE ni deen)

Index Terms

  • Brimonidine and Brinzolamide
  • Brinzolamide and Brimonidine Tartrate
  • Brinzolamide/Brimonid Tartrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, ophthalmic:

Simbrinza: Brinzolamide 1% and brimonidine tartrate 0.2% (8 mL) [contains benzalkonium chloride]

Brand Names: U.S.

  • Simbrinza

Pharmacologic Category

  • Alpha2 Agonist, Ophthalmic
  • Carbonic Anhydrase Inhibitor (Ophthalmic)
  • Ophthalmic Agent, Antiglaucoma

Pharmacology

Brinzolamide inhibits carbonic anhydrase, leading to decreased aqueous humor secretion. This results in a reduction of intraocular pressure (IOP).

Brimonidine has selective agonism for alpha2-receptors and causes reduction of aqueous humor formation and increased uveoscleral outflow

Absorption

Brinzolamide: Topical: Into systemic circulation

Distribution

Brinzolamide: Accumulates extensively in red blood cells, binding to carbonic anhydrase (brinzolamide and metabolite)

Metabolism

Brimonidine: Extensively, hepatic

Brinzolamide: To N-desethyl brinzolamide

Excretion

Brimonidine: Urine (74%)

Brinzolamide: Urine (predominantly as unchanged drug)

Time to Peak

Brimonidine: Within 0.5 to 4 hours

Half-Life Elimination

Brimonidine: 2 to 3 hours

Brinzolamide: 111 days

Protein Binding

Brinzolamide: ~60%

Use: Labeled Indications

Reduction of intraocular pressure: Treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma

Contraindications

Hypersensitivity to brinzolamide, brimonidine, or any component of the formulation; children <2 years of age

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to sulfonamides; concurrent monoamine oxidase (MAO) inhibitor therapy or antidepressant therapy that affects noradrenergic transmission (eg, tricyclic antidepressants, mianserin); severe renal impairment; hyperchloremic acidosis

Dosing: Adult

Reduction of intraocular pressure: Ophthalmic:

US labeling: Instill 1 drop in affected eye(s) 3 times daily

Canadian labeling: Instill 1 drop in affected eye(s) 2 times daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Children ≥2 years and Adolescents: Ophthalmic: Refer to adult dosing. Note: The Canadian labeling does not recommend use in patients <18 years.

Dosing: Renal Impairment

US labeling:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling.

CrCl <30 mL/minute: Use is not recommended (has not been studied; brinzolamide and metabolite are excreted predominately by the kidney).

Canadian labeling:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

CrCl <30 mL/minute: Use is contraindicated.

Dosing: Hepatic Impairment

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Canadian labeling: Use is not recommended.

Administration

Shake bottle well prior to administration. If using additional topical ophthalmic preparations, separate administration by at least 5 minutes. Remove contact lenses prior to administration and wait 15 minutes after administration before reinserting. Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may occur from using contaminated solutions.

Storage

Store at 2°C to 25°C (36°F to 77°F). After opening the bottle, the Canadian labeling recommends discarding the 10 mL bottle within 125 days and the 5 mL bottle within 32 days.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alpha-/Beta-Agonists (Indirect-Acting): Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis. Avoid combination

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Brinzolamide. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Iobenguane I 123: Alpha2-Agonists may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Brimonidine (Ophthalmic). MAO Inhibitors may increase the serum concentration of Brimonidine (Ophthalmic). Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic). Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tricyclic Antidepressants: May diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic). Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Percentages as reported with combination product. Also see individual agents.

1% to 10%:

Gastrointestinal: Dysgeusia (3% to 5%), xerostomia (3% to 5%)

Hypersensitivity: Local ocular hypersensitivity reaction (3% to 5%)

Ophthalmic: Blurred vision (3% to 5%), eye irritation (3% to 5%)

Warnings/Precautions

Concerns related to adverse events:

• Acid-base disturbances: Brinzolamide is absorbed systemically following topical administration; acid-base disturbances reported with oral carbonic anhydrase inhibitors may occur following topical application.

• Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions has caused bacterial keratitis.

• CNS effects: May cause CNS depression and/or blurred vision, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Sulfonamide (“sulfa”) allergy: The FDA-approved and Health Canada-approved product labelings for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Acute angle-closure (narrow-angle) glaucoma: Use has not been studied in patients with acute angle-closure glaucoma (Canadian labeling recommends avoiding use in these patients).

• Cardiovascular disease: Use with caution in patients with coronary insufficiency or severe or unstable cardiovascular disease.

• Cerebrovascular insufficiency: Use with caution in patients with cerebral insufficiency; may precipitate or aggravate symptoms.

• Corneal endothelium: Use with caution in patients with low endothelial cell counts; may be at increased risk of corneal edema.

• Depression: Use with caution in patients with depression; may precipitate or aggravate symptoms.

• Hepatic impairment: Use with caution in patients with hepatic impairment; has not been evaluated in this population. Due to lack of data, the Canadian labeling recommends avoiding use in hepatic impairment.

• Orthostatic hypotension: Use with caution in patients with orthostatic hypotension; may precipitate or aggravate symptoms.

• Renal impairment: Use is not recommended (US labeling) or contraindicated (Canadian labeling) in patients with severe renal impairment; use has not been evaluated in this population. Use caution in mild or moderate renal impairment due to possible risk of acid/base disturbances.

• Thromboangiitis obliterans: Use with caution in patients with thromboangiitis obliterans; may precipitate or aggravate symptoms.

• Vascular insufficiency: Use with caution in patients with vascular insufficiency, including Raynaud disease; may precipitate or aggravate symptoms.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Ophthalmic solution: May contain benzalkonium chloride which may be absorbed by contact lenses; remove lens prior to administration and wait 15 minutes before reinserting. Allow at least 5 minutes between applications with other eye drops. To avoid contamination, do not touch tip of container to any surface. Benzalkonium chloride may also cause punctate keratopathy or toxic ulcerative keratopathy. If use is frequent or prolonged, monitor closely.

Monitoring Parameters

Ophthalmic exams and IOP periodically

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination product; refer to individual monographs. The Canadian labeling recommends avoiding use of this combination product in women who are pregnant or of childbearing potential and not using contraception.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience blurred vision, change in taste, headache, dry mouth, burning, stinging, foreign body sensation in eye, or fatigue. Have patient report immediately to prescriber signs of a severe sulfonamide reaction (rash; red, swollen, blistered, or peeling skin; red or irritated eyes; mouth, throat, nose, or eye sores; fever, chills, or pharyngitis; cough that is new or worse; loss of strength and energy; any bruising or bleeding; or signs of liver problems like dark urine, fatigue, lack of appetite, nausea or abdominal pain, light-colored stools, vomiting, or jaundice), vision changes, or eye pain, or severe eye irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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