Combigan

Uses

Brimonidine Tartrate + Timolol Maleate is used for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP.

Combigan is also used to associated treatment for these conditions: Increased Intra Ocular Pressure (IOP), Ocular Hypertension, Facial erythemaIncreased Intra Ocular Pressure (IOP), Migraine, Ocular Hypertension, Open Angle Glaucoma (OAG)

How Combigan works

In the eye, alpha-1 adrenoceptors play a role in vasoconstriction, mydriasis, eyelid retraction, and elevation of intraocular pressure (IOP) whereas alpha-2 adrenoceptors are responsible for IOP reduction via a complex Gi-coupled signaling cascade pathway. Activation of alpha-2 receptors leads to inhibition of adenylyl cyclase and reduction of cyclic AMP levels. As a result, there is a decrease in norpinephrine (NE) release at the synaptic junction, NE-induced stimulation of beta-2 adrenoceptors, and production of aqueous humor by the ciliary epithelium. An elevated IOP is the most significant risk factor for developing glaucomatous optic neuropathy, which is associated with progressive visual field loss and functional disability if left untreated. Regardless of the etiology of the disease, the aim of current therapies for glaucoma is to reduce IOP, as reduction of IOP significantly reduces the risk of progression of vision loss even when IOP is already within the normal range. When administered ophthalmically, brimonidine is rapidly absorbed into the eye, acts as an agonist at ocular alpha-2 adrenoceptors and lowers IOP via a dual mechanism of action. It is proposed that initial dosing of the drug causes a reduction in aqueous humour production and chronic dosing leads to an increase in uveoscleral outflow. Brimonidine does not affect episcleral venous pressure. By reducing IOP, brimonidine aims to reduce the likelihood of glaucomatous visual field loss in ocular hypertension, and slow the progression of visual field defect in established open-angle glaucoma. When applied topically on skin, brimonidine reduces erythema through direct vasocontriction of small arteries and veins. As brimonidine mediates a potent peripheral vasoconstrictive activity by selectively working on the alpha-2 adrenoceptors, the use of brimonidine is thought to be efficacious for the treatment of facial erythema of rosacea, which is thought to arise from vasomotor instability and abnormal vasodilation of the superficial cutaneous vasculature of the face.

Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure.

The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis.

Dosage

Combigan dosage

The recommended dose is one drop of this eye drops in the affected eye(s) twice daily approximately 12 hours apart.

If more than one topical ophthalmic product is to be used, other eye drops should be instilled at least 5 minutes apart.

Safety and effectiveness in children below the age of 2 years have not been established.

Side Effects

The most frequent reactions of this combination are allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, blepharitis, corneal erosion, epiphora, eye dryness, eye pain, eyelid edema, eyelid pruritus, headache, hypertension, superficial punctate keratitis, and visual disturbance.

Toxicity

LD₅₀ and Overdose

Oral LD₅₀ is 50 mg/kg in mice and 100 mg/kg in rats. While there is limited clinial data on brimonidine overdose in adults, some common symptoms from oral overdoses of alpha-2 adrenergic agonists include hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Treatment of an oral overdose includes supportive and symptomatic therapy. Cases of brimonidine overdose have been reported in neonates, infants, and pediatric patients receiving brimonidine tartrate as part of medical treatment of congenital glaucoma or by accidental oral ingestion. In these cases, children experienced symptoms consistent with previously reported oral overdoses of alpha-2 adrenergic agonists in young children.

Nonclinical Toxicology

At oral doses of up to 2.5 and 5 mg/kg/day in pregnant rats and rabbits, brimonidine was not shown to be teratogenic during gestation days 6 through 18. Findings from various in vitro and in vivo studies, including the Ames bacterial assay, CHO cell chromosomal aberration assay, and CD-1 mice studies, did not demonstrate any mutagenic or clastogenic potential of brimonidine. There were no observable adverse effects on male or female fertility when tested at oral doses of up to 1 mg/kg, which is approximately 200 times the systemic exposure following the maximum recommended ophthalmic dose of 0.5% brimonidine.

Use in special populations

Due to limited clinical data on the use of brimonidine pregnant or breastfeeding female patients, the use of brimonidine in these patients is generally not recommended and the use should be only considered after taking into account the benefit-to-risk ratio of continuing the drug therapy in these patients. In nursing mothers, the decision should be made whether to discontinue the drug or discontinue breastfeeding. As the systemic absorption and elimination of brimonidine are not significantly affected by age, the use of brimonidine is considered safe in geriatric patients. In contrast, the use of brimonidine in infants under the age of 2 and pediatric patients under the age of 18 is strongly not recommended due to the reports of serious adverse events following ophthalmic administration of brimonidine in infants between the age of 28 days and 3 months.

The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse.

Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment.

Precaution

Like other topically applied ophthalmic agents, it may be absorbed systemically. Due to the presence of Timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur. Cautions should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular or pulmonary diseases.

Interaction

Specific drug interaction studies on this ophthalmic preparation have not been established

Volume of Distribution

The volume of distribution of brimonidine has not been established. In animal studies, brimonidine was shown to cross the placenta and enter into the fetal circulation to a limited extent. As its lipophilicity is relatively low, brimonidine is not reported to easily cross the blood-brain barrier.

1.3 - 1.7 L/kg

Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung.

Elimination Route

Brimonidine readily penetrates the cornea following ocular administration to reach pharmacologically active concentrations in the aqueous humor and ciliary body, the putative sites of its IOP-lowering activity. Following ocular administration of 0.2% brimonidine solution, the peak plasma concentrations were achieved within 1 to 4 hours.

In a clinical study of adult subjects with facial erythema of rosacea, brimonidine was cutaneously applied on facial skin in a repeated manner. While there was no drug accumulation in plasma, the highest peak plasma concentrations (Cmax) and AUC were 46 ± 62 pg/mL and 417 ± 264 pgxhr/mL, respectively.

The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5% , indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers.

The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration.

Half Life

Following ocular administration of 0.2% brimonidine solution, the systemic half-life was approximately 3 hours.

Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers.

Clearance

The apparent clearance has not been studied. However, the systemic clearance of brimonidine is reported to be rapid. Approximately 87% of the total radioactive dose of brimonidine was shown to be eliminated within 120 hours following oral administration.

One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers.

Elimination Route

Brimonidine and its metabolites are predominantly eliminated via urinary excretion, with 74% of the total dose being found in the urine.

Timolol and its metabolites are mainly found excreted in the urine.

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Lactation: Timolol has been detected in human milk following oral and ophthalmic drug administration. It is not known whether brimonidine passes into human breast milk. However, it has been shown to pass into the milk of nursing animals. Because of the potential for serious adverse reactions from this combination in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Contraindicated in patients with hypersensitivity to any component of this medication, in patients receiving monoamine oxidase (MAO) inhibitor therapy, bronchospasm, bronchial asthma or severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, cardiac failure or cardiogenic shock.

Special Warning

Safety and effectiveness in children below the age of 2 years have not been established.

Acute Overdose

No information is available on overdosage with this drops in humans.

Interaction with other Medicine

Monoamine oxidase inhibitors may result in increased hypotension. Antihypertensives/cardiac glycosides may lower blood pressure. Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia. Use with CNS depressants may result in an additive or potentiating effect. CYP2D6 inhibitors may potentiate systemic beta-blockade.

Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine.

Storage Condition

Store in a cool & dry place, protected from light

Keep out of reach of children

Do not use more than 4 weeks after opening

Innovators Monograph

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