BRIMONIDINE TARTRATE AND TIMOLOL MALEATE_- brimonidine tartrate and timolol maleate_solution/ drops

Brimonidine tartrate and timolol maleate ophthalmic solution is comprised of two components: brimonidine tartrate and timolol. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage. Brimonidine tartrate and timolol maleate ophthalmic solution is a relatively selective alpha-2 adrenergic receptor agonist with a 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. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow. Timolol maleate is a beta 1 2 Absorption In a crossover study of Brimonidine tartrate and timolol maleate ophthalmic solution, brimonidine tartrate 0. 2%, and timolol 0. 5% administered twice daily for 7 days in healthy volunteers, the mean brimonidine area-under-the-plasma-concentration-time curve (AUC) for Brimonidine tartrate and timolol maleate ophthalmic solution was 128 +/- 61 pghr/mL versus 141 +/- 106 pghr/mL for the respective monotherapy treatments; mean C max max In a parallel study in patients dosed twice daily with Brimonidine tartrate and timolol maleate ophthalmic solution, twice daily with timolol 0. 5%, or three times daily with brimonidine tartrate 0. 2%, one-hour post dose plasma concentrations of timolol and brimonidine were approximately 30-40% lower with Brimonidine tartrate and timolol maleate ophthalmic solution than their respective monotherapy values. The lower plasma brimonidine concentrations with Brimonidine tartrate and timolol maleate ophthalmic solution appears to be due to twice-daily dosing for Brimonidine tartrate and timolol maleate ophthalmic solution versus three-times dosing with brimonidine tartrate 0. Distribution Metabolism Excretion S pecial Populations.

Brimonidine tartrate and timolol maleate ophthalmic solution 0. 5% is an alpha-adrenergic receptor agonist with a beta-adrenergic receptor inhibitor 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; the IOP-lowering of Brimonidine tartrate and timolol maleate ophthalmic solution dosed twice a day was slightly less than that seen with the concomitant administration of 0. 5% timolol maleate ophthalmic solution dosed twice a day and 0. 2% brimonidine tartrate ophthalmic solution dosed three times per day. Brimonidine tartrate and timolol maleate ophthalmic solution is an alpha-adrenergic receptor agonist with a beta-adrenergic receptor inhibitor 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; the IOP-lowering of Brimonidine tartrate and timolol maleate ophthalmic solution dosed twice a day was slightly less than that seen with the concomitant administration of timolol maleate ophthalmic solution, 0. 5% dosed twice a day and brimonidine tartrate ophthalmic solution, 0. 2% dosed three times per day.

The recommended dose is one drop of Brimonidine tartrate and timolol maleate ophthalmic solution 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. One drop in the affected eye(s), twice daily approximately 12 hours apart.

Most common adverse reactions occurring in approximately 5 to 15% of patients included allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging. 1 To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Brimonidine tartrate and timolol maleate ophthalmic solution Brimonidine Tartrate (0. 2%) Timolol (Ocular Administration) Body as a whole Cardiovascular Digestive Immunologic Nervous System/Psychiatric Skin Hypersensitivity Respiratory [see Contraindications (4. 1)] Endocrine [see Warnings and Precautions (5. 7)] Special Senses Urogenital The following reactions have been identified during post-marketing use of brimonidine tartrate ophthalmic solutions, timolol ophthalmic solutions, or both in combination, in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, timolol ophthalmic solutions, or a combination of these factors, include: eyelid erythema extending to the cheek or forehead, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, rash, and vasodilation), and tachycardia. In infants, apnea, bradycardia, coma, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported [see Contraindications (4. 3) and Use in Specific Populations (8. 4)] Oral Timolol/Oral Beta-blockers Allergic Body as a whole Cardiovascular Digestive Hematologic Endocrine Skin Musculoskeletal Nervous System/Psychiatric Respiratory Urogenital.

Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease. 3 Sinus bradycardia, atrioventricular block, overt cardiac failure, cardiogenic shock. 2 Neonates and infants (under the age of 2 years). 3 Hypersensitivity to any component of this product. 4 Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in patients with reactive airway disease including bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease [see Warnings and Precautions (5. 3)] Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure [see Warnings and Precautions (5. 2)] Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in neonates and infants (under the age of 2 years). Local hypersensitivity reactions have occurred following the use of different components of Brimonidine tartrate and timolol maleate ophthalmic solution. Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past.

Not for use in children below the age of 2 years. Use with caution in children >= 2 years of age. 4 Teratogenicity studies have been performed in animals. Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2. 5 mg/kg/day) and rabbits (5 mg/kg/day) achieved AUC exposure values 580 and 37-fold higher, respectively, than similar values estimated in humans treated with Brimonidine tartrate and timolol maleate ophthalmic solution, 1 drop in both eyes twice daily. Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day [4,200 times the maximum recommended human ocular dose of 0. 012 mg/kg/day on a mg/kg basis (MRHOD)] demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (83,000 times the MRHOD) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses 8,300 times the MRHOD without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women; however, in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Because animal reproduction studies are not always predictive of human response, Brimonidine tartrate and timolol maleate ophthalmic solution should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Timolol has been detected in human milk following oral and ophthalmic drug administration. It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from Brimonidine tartrate and timolol maleate ophthalmic solution 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. Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in children under the age of 2 years [see Contraindications (4. 3)] No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

Antihypertensives/cardiac glycosides may lower blood pressure. 1 Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. 2 Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. 3 Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia. 4 Use with CNS depressants may result in an additive or potentiating effect. 5 Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. 6 CYP2D6 inhibitors may potentiate systemic beta-blockade. 7 Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. 8 Monoamine oxidase inhibitors may result in increased hypotension. 9 Because Brimonidine tartrate and timolol maleate ophthalmic solution may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with Brimonidine tartrate and timolol maleate ophthalmic solution is advised. Patients who are receiving a beta-adrenergic blocking agent either orally or intravenously and Brimonidine tartrate and timolol maleate ophthalmic solution 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. Caution should be used in the co-administration of beta-adrenergic blocking agents, such as Brimonidine tartrate and timolol maleate ophthalmic solution, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided. 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, which may result in vertigo, syncope, or postural hypotension. Although specific drug interaction studies have not been conducted with Brimonidine tartrate and timolol maleate ophthalmic solution, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. Potentiated systemic beta-blockade (e. , decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e. , quinidine, SSRIs) and timolol. Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with Brimonidine tartrate and timolol maleate ophthalmic solution in humans can lead to resulting interference with the IOP-lowering effect. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. 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.

OVERDOSAGE
There have been reports of inadvertent overdosage with timolol ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. With the exception of hypotension, very limited information exists on accidental ingestion of brimonidine in adults. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine ophthalmic solutions as part of medical treatment of congenital glaucoma or by accidental oral ingestion [see Use in Specific Populations (8.4)]
NONCLINICAL TOXICOLOGY
With brimonidine tartrate, no compound-related carcinogenic effects were observed in either mice or rats following a 21-month and 24-month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats achieved 150 and 210 times, respectively, the plasma C max In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day [approximately 25,000 times the maximum recommended human ocular dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)]. Similar differences were not observed in rats administered oral doses equivalent to approximately 8,300 times the daily dose of Brimonidine tartrate and timolol maleate ophthalmic solution in humans. In a lifetime oral study of timolol maleate in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, (approximately 42,000 times the MRHOD), but not at 5 or 50 mg/kg/day (approximately 420 to 4,200 times higher, respectively, than the MRHOD). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin. Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro in vivo in vivo Timolol maleate was devoid of mutagenic potential when tested in vivo in vitro Reproduction and fertility studies in rats with timolol maleate and in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at doses up to approximately 100 times the systemic exposure following the maximum recommended human ophthalmic dose of Brimonidine tartrate and timolol maleate ophthalmic solution.
CLINICAL STUDIES
Clinical studies were conducted to compare the IOP-lowering effect over the course of the day of Brimonidine tartrate and timolol maleate ophthalmic solution administered twice a day (BID) to individually-administered brimonidine tartrate ophthalmic solution, 0.2% administered three times per day (TID) and timolol maleate ophthalmic solution, 0.5% BID in patients with glaucoma or ocular hypertension. Brimonidine tartrate and timolol maleate ophthalmic solution BID provided an additional 1 to 3 mm Hg decrease in IOP over brimonidine treatment TID and an additional 1 to 2 mm Hg decrease over timolol treatment BID during the first 7 hours post dosing. However, the IOP-lowering of Brimonidine tartrate and timolol maleate ophthalmic solution BID was less (approximately 1-2 mm Hg) than that seen with the concomitant administration of 0.5% timolol BID and 0.2% brimonidine tartrate TID. Brimonidine tartrate and timolol maleate ophthalmic solution administered BID had a favorable safety profile versus concurrently administered brimonidine TID and timolol BID in the self-reported level of severity of sleepiness for patients over age 40.

Alembic Pharmaceuticals Inc.

BRIMONIDINE TARTRATE AND TIMOLOL MALEATE_- brimonidine tartrate and timolol maleate_solution/ drops Product manual source documgent