BRIMONIDINE TARTRATE; TIMOLOL MALEATE
Clinical safety rating: safe
Other drugs that lower heart rate or blood pressure can have additive effects Can cause bronchospasm in patients with asthma.
Brimonidine is a selective alpha-2 adrenergic receptor agonist that reduces aqueous humor production and increases uveoscleral outflow. Timolol is a non-selective beta-adrenergic receptor blocker that decreases aqueous humor production by inhibiting beta-2 receptors in the ciliary epithelium.
| Metabolism | Brimonidine is extensively metabolized in the liver primarily by aldehyde oxidase and to a lesser extent by cytochrome P450. Timolol is metabolized in the liver by CYP2D6. |
| Excretion | Brimonidine: primarily renal (74% as unchanged drug); timolol: renal (20% unchanged, remainder as metabolites) and fecal (small amount). |
| Half-life | Brimonidine: ~3 hours (terminal); timolol: ~4–6 hours (terminal). Clinical context: allows twice-daily dosing for brimonidine/timolol combination. |
| Protein binding | Brimonidine: ~29% bound; timolol: ~60% bound (primarily to albumin). |
| Volume of Distribution | Brimonidine: ~1.0 L/kg (wide distribution); timolol: ~1.7 L/kg (extensive tissue distribution). |
| Bioavailability | Ophthalmic: brimonidine ~55% systemic absorption; timolol ~50–80% systemic absorption via nasolacrimal route. |
| Onset of Action | Ophthalmic: brimonidine onset within 2 hours (peak IOP reduction at 2–3 hours); timolol onset within 30–60 minutes. |
| Duration of Action | Brimonidine: 8–12 hours; timolol: up to 24 hours. Combination product dosed twice daily for sustained IOP reduction. |
One drop of the fixed combination (0.2% brimonidine/0.5% timolol) in the affected eye(s) twice daily, approximately 12 hours apart.
| Dosage form | SOLUTION |
| Renal impairment | Contraindicated in severe renal impairment (CrCl <15 mL/min). For moderate impairment (CrCl 15-29 mL/min), use with caution and monitor for systemic effects; no specific dose adjustment established. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh Class C). For moderate impairment (Child-Pugh Class B), use with caution; no specific dose adjustment established. |
| Pediatric use | Contraindicated in neonates and infants (≤2 years). For children >2 years, the same adult dose is recommended (one drop twice daily) but with increased caution due to risk of apnea, bradycardia, and hypotension. |
| Geriatric use | No specific dose adjustment required, but caution is advised due to increased risk of bradycardia, hypotension, and CNS depression. Monitor heart rate and blood pressure regularly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other drugs that lower heart rate or blood pressure can have additive effects Can cause bronchospasm in patients with asthma.
| FDA category | Animal |
| Breastfeeding | Timolol is excreted in breast milk with a milk-to-plasma ratio of 1.1; brimonidine is likely excreted but data limited. Monitor infant for bradycardia, hypotension, and sedation. Use caution; topical administration reduces systemic exposure. |
| Teratogenic Risk | First trimester: No adequate human studies; animal studies show no teratogenicity at clinically relevant doses. Second and third trimesters: Risk of fetal bradycardia and hypotension due to timolol's beta-blockade; brimonidine may cause central nervous system depression in neonates. Avoid in late pregnancy. |
■ FDA Black Box Warning
None
| Common Effects | hypertension |
| Serious Effects |
["Hypersensitivity to brimonidine, timolol, or any component of the formulation","Bronchial asthma or a history of bronchial asthma","Severe chronic obstructive pulmonary disease","Sinus bradycardia, second- or third-degree atrioventricular block, cardiogenic shock, or overt cardiac failure","Neonates and infants (due to risk of central nervous system depression from brimonidine)"]
| Precautions | ["Potential for cardiovascular and respiratory adverse reactions due to timolol (beta-blockade), including bradycardia, heart block, bronchospasm, and exacerbation of heart failure.","May cause severe hypotension, bradycardia, and syncope; use caution in patients with cerebrovascular insufficiency.","May cause central nervous system depression (e.g., fatigue, drowsiness) due to brimonidine; avoid use in patients with impaired mental function.","Contains sulfites; may cause allergic-type reactions including anaphylaxis in susceptible individuals.","Avoid in patients with reactive airway disease, sinus bradycardia, or second- or third-degree atrioventricular block."] |
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| Fetal Monitoring | Monitor fetal heart rate and uterine activity. Assess for signs of fetal bradycardia, especially after maternal beta-blocker use. Neonatal monitoring for bradycardia, hypotension, and respiratory depression after delivery. |
| Fertility Effects | No known direct effects on fertility in humans. In animal studies, no impairment of fertility observed with brimonidine timolol combination at topical doses. |
| Food/Dietary | No clinically significant food interactions. Alcohol consumption may exacerbate orthostatic hypotension and dizziness. |
| Clinical Pearls | Combination therapy reduces intraocular pressure (IOP) by decreasing aqueous humor production (timolol) and increasing uveoscleral outflow (brimonidine). Advise patients to wait 5 minutes between different eye drops to prevent washout. Contraindicated in asthma, COPD, sinus bradycardia, heart block, and severe heart failure. Use caution in patients with depression, Raynaud's, or orthostatic hypotension. Additive effects with oral beta-blockers may cause bradycardia or hypotension. |
| Patient Advice | Instill one drop in the affected eye(s) twice daily, about 12 hours apart. · Wait at least 5 minutes between using this and other eye drops. · Do not touch the dropper tip to your eye or any surface. · Wash hands before and after use. · May cause blurred vision; do not drive or operate machinery until vision clears. · Report slow heart rate, shortness of breath, dizziness, or fainting immediately. · Avoid alcohol as it may increase dizziness or drop in blood pressure. · Monitor for signs of eye infection: pain, redness, discharge. · Do not use while wearing contact lenses; reinsert lenses 15 minutes after instillation. · Store at room temperature, tightly closed. |