Combigan

Approved Indications:

• Reduction of elevated intraocular pressure (IOP) in patients with:
• Open-angle glaucoma
• Ocular hypertension
• Particularly in patients who are inadequately controlled with monotherapy (either brimonidine or timolol alone)

Off-label / Clinically Accepted Use:

• Adjunctive therapy in refractory cases of glaucoma when other agents are insufficient
• Combination therapy in patients with contraindications to prostaglandin analogues

Adults (including elderly):

• Recommended dose: One drop in the affected eye(s) twice daily, approximately 12 hours apart.

Pediatric use:

• Not recommended for use in children under 2 years of age due to the risk of serious systemic adverse reactions, including CNS depression and apnea.
• Use in children aged 2–17 years should be with caution.

Hepatic/Renal Impairment:

• Use with caution; specific dose adjustment not established but close monitoring advised.

Administration Notes:

• Shake the bottle well before use.
• Avoid touching the tip of the container to the eye or any surface.
• Apply pressure on the nasolacrimal duct for 1–2 minutes after instillation to reduce systemic absorption.
• If using other topical eye drops, wait at least 5 minutes between instillations.

This fixed-dose combination contains two agents:

• Brimonidine Tartrate is a selective alpha-2 adrenergic receptor agonist. It lowers IOP by reducing aqueous humor production and increasing uveoscleral outflow.
• Timolol Maleate is a non-selective beta-adrenergic receptor blocker. It reduces IOP primarily by decreasing aqueous humor production through blockade of beta receptors in the ciliary epithelium.

Together, the combination provides an additive effect on IOP reduction via dual mechanisms without significant pharmacologic antagonism.

• Absorption: Both drugs are absorbed through the cornea and conjunctiva. Systemic absorption is limited but may occur.
• Distribution: Timolol and brimonidine can reach systemic circulation and bind variably to plasma proteins.
• Metabolism:
• Brimonidine is extensively metabolized in the liver.
• Timolol undergoes hepatic metabolism via CYP2D6.
• Elimination:
• Brimonidine is excreted mainly in the urine as metabolites.
• Timolol is also excreted renally.
• Half-life:
• Brimonidine: ~2–3 hours
• Timolol: ~4–6 hours (systemic)

• Pregnancy: No FDA pregnancy category assigned. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies showed adverse effects; human data are limited.
• Lactation: Both components may be excreted in breast milk. Due to potential for serious adverse effects in nursing infants (e.g., bradycardia, hypotension, CNS depression), a risk-benefit assessment is essential. Consider either discontinuing breastfeeding or the medication.

• Primary Class: Antiglaucoma Preparation
• Subclass: Combination of Alpha-2 Adrenergic Agonist and Beta-Adrenergic Blocker

• Known hypersensitivity to brimonidine, timolol, or any formulation components
• Bronchial asthma or a history of bronchospastic disease (e.g., COPD)
• Sinus bradycardia, second- or third-degree AV block, or overt cardiac failure
• Neonates and infants (<2 years of age) due to serious CNS side effects
• Concomitant use with monoamine oxidase inhibitors (MAOIs)

• Pediatric use: Serious systemic effects (e.g., apnea, CNS depression) have been reported in young children.
• Cardiovascular risk: May cause bradycardia, hypotension, and heart block; use cautiously in patients with cardiac disease.
• Respiratory disorders: Can worsen symptoms in patients with asthma or obstructive pulmonary disease.
• Depression and CNS effects: Brimonidine can cause drowsiness and fatigue; caution in patients with depression or using CNS depressants.
• Use with MAOIs or tricyclic antidepressants may interfere with brimonidine's metabolism and effect.
• Contact lens wearers: Remove lenses before instillation and wait 15 minutes before reinsertion.
• Systemic absorption: Nasolacrimal occlusion is recommended to reduce systemic exposure.

Common:

• Ocular: Eye redness, burning/stinging, dry eyes, blurred vision, allergic conjunctivitis
• Systemic: Headache, fatigue, dry mouth, drowsiness

Less Common but Serious:

• Cardiovascular: Bradycardia, hypotension
• Respiratory: Dyspnea, bronchospasm
• CNS: Depression, insomnia
• Dermatologic: Skin rash, allergic dermatitis

Pediatric: Apnea, somnolence, hypotonia, hypothermia, feeding difficulties

• CNS depressants (e.g., alcohol, sedatives): Enhanced sedation from brimonidine
• MAO inhibitors (e.g., selegiline): May potentiate brimonidine effects—contraindicated
• Beta-blockers (oral or ophthalmic): Additive cardiovascular or respiratory effects
• Calcium channel blockers, digoxin, and antiarrhythmics: Additive bradycardic effect with timolol
• Clonidine: Risk of withdrawal hypertension if discontinued abruptly while on timolol
• CYP2D6 inhibitors (e.g., quinidine): May increase systemic levels of timolol

• EMA and FDA continue to recommend use in patients insufficiently responsive to monotherapy for IOP reduction.
• Recent guidelines suggest preferring fixed-dose combinations over multiple separate agents to improve adherence and tolerability in glaucoma management.
• Pediatric warnings continue to emphasize avoidance in children under 2 years due to CNS depression risk.

• Storage temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Protect from light.
• Do not freeze.
• Keep bottle tightly closed when not in use.
• Discard 4 weeks after opening to avoid contamination.