Description

Brimonidine Tartrate

Brimonidine Tartrate is the tartrate salt form of brimonidine, a selective alpha-2 adrenergic receptor agonist.

Chemical Name: 70359-46-5; Brimonidine tartarate

Molecular formula: C15H16BrN5O6

Molecular weight: 442.226 g/mol

Timolo Maleate

Timolol is a nonselective beta-adrenergic receptor blocker.

Chemical Name: Timolol maleate (S)- Timolol maleate 26921-17-5

Molecular formula: C17H28N407S

Molecular weight: 432.492 g/mol

Indications:

Brimosoft-T is indicated 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 on monotherapy.

Dosage and administration:

The recommended dose of Brimosoft-T is one drop in the affected eye(s) twice daily, approximately 12 hours apart. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.

Contraindications:

Reactive Airway Disease Including Asthma, COPD

Brimonidine 0.2% and Timolol 0.5% Eye drops is contraindicated in patients with reactive airway disease including bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease.

Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock

Brimonidine 0.2% and Timolol 0.5% Eye drops is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure.

Neonates and Infants (Under the Age of 2 Years)

Brimonidine 0.2% and Timolol 0.5% Eye drops is contraindicated in neonates and infants (under the age of 2 years).

Hypersensitivity Reactions

Brimonidine 0.2% and Timolol 0.5% Eye drops is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past.

Warnings and Precautions

Potential for Severe Respiratory or Cardiac Reactions

Severe respiratory reactions and cardiac reactions including death dur to bronchospasm in patients with asthma, and rarely death in association with cardiac failure have been reported following systemic or ophthalmic administration of timolol maleate. Ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension.

Cardiac Failure

Beta-adrenergic receptor blockade by Timolol may precipitate severe Heart failure. At the first sign or symptom of cardiac failure, Brimonidine 0.2% and Timolol 0.5% Eye drops should be discontinued.

Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease should, in general, not receive beta-blocking agents, including Brimonidine 0.2% and Timolol 0.5% Eye drops.

Potential of Vascular Insufficiency

Brimonidine 0.2% and Timolol 0.5% Eye drops may potentiate syndromes associated with vascular insufficiency. Brimonidine 0.2% and Timolol 0.5% Eye drops should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.

Increased Reactivity to Allergens

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens.

Potentiation of Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. 

Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Masking of Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs. (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might. precipitate a thyroid storm. 

Ocular Hypersensitivity

Ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solutions 0.2%, with some reported to be associated with an increase in intraocular pressure.

Contamination of Topical Ophthalmic Products after Use

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. Impairment of Beta-adrenergically Mediated Reflexes during Surgery

The necessity or desirabilty of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. If necessary during surgery, the effects of beta-adrenergic blocking agents may

be reversed by sufficient doses of adrenergic agonists

Use in Special populations

Pregnancy:

There are no adequate and well-controlled studies in pregnant women using Brimonidine 0.2% and Timolol 0.5% Eye drops. It only should be given if benefit to mother outweigh the risk to the fetus.

Nursing Mothers

Because of the potential for serious adverse reactions from Brimonidine 0.2% and Timolol 0.5% Eye drops 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.

Pediatric Use (< 18 years of age)

Brimonidine 0.2% and Timolol 0.5% Eye drops is contraindicated in children under the age of 2 years. The safety and effectiveness of Brimonidine 0.2% and Timolol 0.5% Eye drops have been established in the age groups 2-16 years of age.

Geriatric Use (> 65 years of age)

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

Hepatic impairment

Brimonidine 0.2% and Timolol 0.5% Eye drops has not been studied in patients with hepatic impairment.

Renal Impairment

Brimonidine 0.2% and Timolol 0.5% Eye drops has not been studied in patients with renal impairment.

Adverse Reactions

In clinical trials of 12 months duration with Brimonidine 0.2% and Timolol 0.5% Eye drops, the most frequent reactions associated with its use occurring in approximately 5% to 15% of the patients included: allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging.

The following adverse reactions were reported in 1% to 5% of patients: asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial punctate keratitis, and visual disturbance.

Drug-Drug Interactions

Antihypertensives/Cardiac Glycosides

Because Brimonidine 0.2% and Timolol 0.5% Eye drops may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with Brimonidine 0.2% and Timolol 0.5% Eye drops is advised.

Beta-adrenergic Blocking Agents

Patients who are receiving a beta-adrenergic blocking agent either orally or intravenously and Brimonidine 0.2% and Timolol 0.5% Eye drops should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

Calcium Antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents, such as Timolol Maleate and oral or intravenous calcium antagonists because of possible left ventricular failure and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

Catecholamine-depleting Drugs

Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia.

CNS Depressants

Although specific drug interaction studies have not been conducted with Brimonidine 0.2% and Timolol 0.5% Eye drops, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered.

Digitalis and Calcium Antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

CYP2D6 Inhibitors

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D8 inhibitors (e.g., quinidine, SSRis) and timolol.

Tricyclic Antidepressants

Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side effect such as hypotension. Caution, however, is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

Clinical Pharmacology

Mechanism of Action

Brimonidine 0.2% and Timolol 0.5% Eye drops is comprised of two components: brimonidine tartrate and timolol. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma.

Brimonidine is a relatively selective alpha-2 adrenergic receptor agonist while timolol is non selective beta-adrenergic receptor inhibitor. Both brimonidine and timolol have a rapid onset of action, with peak ocular hypotensive effect seen at two hours post dosing for brimonidine and one to two hours for timolol.

Timolol maleate is a beta1 and beta2 adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

Pharmacokinetics

Absoption

Following ophthalmic administration plasma concentrations of bimonidine peaked at 1 to 4 hours after ocular dosing. Peak plasma concentrations of timolol occurred approximately 1 to 3 hours post-dose. (AUC) for brimonidine 0.2% and Timolol 0.5% Eye drops observed was 128±61 pghr/ml following 7 days bid application.

Distribution

The protein binding of timolol is approximately 60%. The protein binding of brimonidine has not been studied.

Metabolism

In humans, brimonidine is extensively metabolized by the liver. Timolol is partially metabolized by the liver.

Excretions

Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated with 120 hours, with 74% found in the urine. Unchanged timolol and its metabolites are excreted by the kidney.

Half-Life: Half life for brimonidine was observed approximately 3 hours while that of timolol is about 7 hours after ocular administration.

Storage:

Store protected from light & moisture at a temperature not exceeding 25°C.

Do not freeze.

Keep out of reach of children.

Presentation

Brimosoft-T eye drops is available in 5ml pack.