Britivin

Britivin Uses, Dosage, Side Effects, Food Interaction and all others data.

Brimodin contains the active ingredient brimonidine. It is a relatively selective alpha-2 adrenergic receptor agonist and approximately 1000 times more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoceptor.

Topical administration of brimonidine decreases intraocular pressure (IOP) in humans. When used as directed, brimonidine ophthalmic solution reduces elevated IOP with minimal effect on cardiovascular parameters.

Brimonidine has a rapid onset of action, with the peak ocular hypotensive effect occurring at approximately 2 hours post-dosing. The duration of effect is 12 hours or greater.

Fluorophotometric studies in animals and humans suggest that brimonidine has a dual mechanism of action. Brimonidine lowers IOP by reducing aqueous humor production and increasing uveoscleral outflow.

Brimonidine is a highly selective alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenergic receptor than the alpha1-adrenergic receptor. This characteristic gives the drug some therapeutic advantages, since it reduces the risk of systemic side effects, such as systemic hypotension, bradycardia, and sedation. In addition, there is a reduction in the risk for developing alpha-1 mediated ocular unwanted effects, such as conjunctival blanching, mydriasis, and eyelid retraction. However, despite high alpha-2 receptor specificity, brimonidine may still produce alpha-1 adrenoceptor-mediated ocular effects, such as conjunctival vasoconstriction. Brimonidine has a peak ocular hypotensive effect occurring at two hours post-dosing. In a randomized, double-blind clinical study, ocular administration of 0.2% brimonidine in healthy volunteers resulted in a 23% reduction of mean intraocular pressure from baseline at 3 hours following administration. In comparative studies consisting of patients with open-angle glaucoma or ocular hypertension, the ocular hypotensive effect of brimonidine was maintained during treatment periods of up to 1 year.

Brimonidine mediates vasoconstrictive effects and it was shown to exhibit anti-inflammatory properties in ex vivo human skin model and in vivo inflammation models. In a clinial trials consisting of adults with moderate to severe facial erythema of rosacea, brimonidine was shown to improve the extent of redness at 3 hours after application, compared to placebo. It was shown to be a potent vasoconstrictor of human subcutaneous vessels with a diameter of less than 200 µm. In in vivo mouse inflammation models, brimonidine displayed anti-inflammatory properties by inhibiting edema. In a randomized, double-blind study, brimonidine reduced erythema for the 12 hours of the study in a dose-dependent manner.

When adminsitered systemically, brimonidine was shown to cause cardiovascular effects by decreasing blood pressure, decreasing heart and respiratory rate, and prolonging the PR interval in the electrocardiogram. This is due to the targeting of adrenoceptors by the drug. Although the clinical significance has not been established, there is evidence that brimonidine exhibits neuroprotective activity in experimental models of cerebral ischemia and optic nerve injury. In vitro studies show that brimonidine mediated protective effects on neuronal cells from kainate acid insult and on cultured retinal ganglion cells from glutamate-induced cytotoxicity, which is a possible mediator of secondary neuronal degeneration in human glaucoma. Neuroprotective actions of brimonidine were also demonstrated in rat models of acute retinal ischemia and chronic IOP elevation. It has been proposed that brimonidine may exert neuroprotective effects on the retina and optic nerve by enhancing intrinsic retinal ganglion cell survival mechanisms and/or induction of neuronal survival factors, such as bFGF. However, further investigations are needed to conclude on these possible therapeutic benefits of the drug.

Timolol is a non-selective β-adrenergic receptor blocker. It does not have significant intrinsic sympathomimetic activity, direct myocardial depressant activity or local anaesth activity. Exact mechanism of ocular hypotensive effect is unclear, but it is thought to be related to reduction of aqueous humour formation. β-blockade also causes lowering of BP.

Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses.

Britivin
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Britivin
Generic	Timolol + Brimonidine
Weight	0.5%
Type	Eye Drops
Therapeutic Class
Manufacturer	Zivira Labs Pvt Ltd
Available Country	India
Last Updated:	September 19, 2023 at 7:00 am

Uses

It is effective for lowering intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension.

Timolol Maleate Ophthalmic Solution is used for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Britivin 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 Britivin 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

Britivin dosage

The recommended dose is 1 drop of ophthalmic solution in the affected eye(s) twice daily (doses taken approximately 12 hours apart).

If more than one topical ophthalmic medicine is to be used, other eye drops should not be used within 5 to 10 minutes of using this eye drops.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Eye drops Solution: Initially, instill 1 drop of 0.25% solution bid into the affected eye(s), may increase to 1 drop of 0.5% solution bid if there is inadequate response; decrease to 1 drop once daily if controlled. Do not exceed 1 drop bid of 0.5% solution.

Gel-forming eye drops:0.25% or 0.5% Gel-forming eye drops: Instill 1 drop into the affected eye(s) once daily.

Side Effects

Headache; itching of eye; redness of eye or inner lining of eyelid; swelling of eyelid; tearing of eye.

Burning and stinging sensation of the eyes, bradycardia, hypotension, arrhythmia and AV or SA nodal block, CHF, pulmonary oedema, Raynaud's phenomenon, headache, dizziness, fatigue, asthenia, abdominal discomfort, nausea, constipation, hypoglycaemia.

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

General

Brimonidine ophthalmic solution 0.2% should be used with caution in patients with known hypersensitivity to other alpha-adrenoceptor agonists.

Although brimonidine had minimal effect on blood pressure and heart rate of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease.

Brimonidine has not been studied in patients with hepatic or renal impairment; caution should be exercised in treating such patients.

Brimonidine should be used with caution in patients with depression, cerebral or coronary insufficiency.

Patients with inadequate cardiac function, DM, myasthenia gravis, cerebrovascular insufficiency, history of atopy. Avoid abrupt withdrawal as it may exacerbate angina symptoms or precipitate MI in patients with coronary artery disease, or precipitate thyroid crisis in patients with thyrotoxicosis. Patients undergoing major surgery. May mask signs of hyperthyroidism and hypoglycaemia. Ophth soln should not be used as monotherapy for angle-closure glaucoma. Renal and hepatic impairment. Pregnancy and lactation.

Interaction

Although specific drug interaction studies have not been conducted with brimonidine, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered.

Although Timolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timolol Maleate and epinephrine has been reported occasionally. Drug interactions of Timolol Maleate have been noticed with concomitant administration of beta-adrenergic blocking agents (both oral and topical), calcium antagonists, catecholamine-depleting drugs, digitalis, quinidin, clonidine, injectable epinephrine.

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:

Brimonidine has not been studied in pregnant women. Studies in animals have shown that brimonidine crosses the placenta, but very high doses have not been shown to cause harmful effects in the fetus.

Lactation:

It is not known whether brimonidine passes into human breast milk. However, it has been shown to pass into the milk of nursing animals.

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

Lactation: Timolol has been detected in breast milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from Timolol 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

This eye drops are contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication.Brimonidine Tartrate is also contraindicated in patients receiving monoaminase oxidase inhibitor therapy.

Timolol is contraindicated in patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock, hypersensitivity to any component of this product.

Acute Overdose

No data is available on overdosage of brimonidine ophthalmic solution in humans.

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.