Zolopt BR

Uses

It is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist used for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Zolopt BR is also used to associated treatment for these conditions: Increased Intra Ocular Pressure (IOP), Ocular Hypertension, Facial erythemaIncreased Intra Ocular Pressure (IOP), Ocular Hypertension

How Zolopt BR 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.

Brinzolamide is a highly specific inhibitor of CA-II, which is the main CA isoenzyme involved in the secretion of aqueous humor. Inhibition of CA in the ciliary process of the eye slows the formation of bicarbonate, and reduces sodium and fluid transport. This results in a reduction in the rate of aqueous humor secretion and the intraocular pressure. Brinzolamide is absorbed systemically following topical ocular administration. Since it has a high affinity for CA-II, brinzolamide binds extensively to red blood cells, where CA-II is primarily found. As sufficient CA-II activity remains, adverse effects resulting from the systemic inhibition of CA by brinzolamide are not observed. The metabolite N-desethyl brinzolamide is also formed. This metabolite binds to CA and accumulates in red blood cells as well. In the presence of brinzolamide, the metabolite binds mainly to carbonic anhydrase I (CA-I).

Dosage

Zolopt BR dosage

The recommended dose is one drop of this eye drop in the affected eye(s) three times daily. Shake well before use.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

Side Effects

The most frequent reactions of this combination are blurred vision, eye irritation, dysgeusia (bad taste), dry mouth and eye allergy.

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.

Precaution

Due to presence of brinzolamide, a sulfonamide, if signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation. There is an increased potential for developing corneal edema in patients with low endothelial cell counts.

Since brinzolamide and its metabolite are excreted predominantly by the kidney, it is not recommended in patients with severe renal impairment (CrCl < 30 mL/min).

Due to presence of Brimonidine tartrate, caution should be exercised in treating patients with severe cardiovascular disease, vascular insufficiency, CNS disease and hepatic impairment.

Interaction

In patients treated with this drop rare instances to drug interactions have occurred with high-dose salicylate therapy, CNS Depressants, Antihypertensives/ Cardiac Glycosides, Tricyclic Antidepressants, Monoamine Oxidase Inhibitors. Therefore, the potential for such drug interactions should be considered in patients receiving Zolopt BR Tartrate .

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.

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.

Absorbed into systemic circulation following topical ocular application

Half Life

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

111 days

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.

Elimination Route

Brimonidine and its metabolites are predominantly eliminated via urinary excretion, with 74% of the total dose being found 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: It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and 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.

Pediatric Use

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

Contraindication

It is contraindicated in patients who are hypersensitivity to Brinzolamide, Brimonidine Tartrate, or to any ingredient in the formulation and Neonates and Infants (under the age of 2 years).

Special Warning

Use in children: Safety & effectiveness in children below the age of 2 years have not been established.

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

Acute Overdose

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

Interaction with other Medicine

Monoamine oxidase inhibitors may result in increased hypotension. Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. As brimonidine tartrate may reduce blood pressure, caution in using drugs such as antihypertensives / cardiac glycosides is advised. Use with CNS depressants may result in an additive or potentiating effect. The concomitant administration of topical and oral carbonic anhydrase inhibitors is not recommended as there is a potential for an additive effect. The potential for acid-base and electrolyte alterations with high-dose salicylate therapy should be considered.

Storage Condition

Store in a cool & dry place, protected from light

Keep out of reach of children

Shake well before using.

Innovators Monograph

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