TIMONID Eye Drop

BRIMONIDINE TARTRATE AND TIMOLOL MALEATE EYE DROPS IP 0.2% w/v & 0.5% w/v

COMPOSITION

Each ml contains:

Brimonidine Tartrate IP 2 mg

Timolol Maleate IP equ. to Timolol 5 mg

Benzalkonium Chloride Solution BP 0.01 % v/v (as preservative)

Water for Injections BP q.s.

 DESCRIPTION

A clear, colorless to slightly greenish yellow solution.

 PHARMACODYNAMIC

Pharmacotherapeutic group: Ophthalmological – antiglaucoma preparations and miotics – beta-blocking agents – timolol, combinations.

ATC Code: S01ED51

Mechanism of action

Brimonidine Tartrate/Timolol consists of two active substances: brimonidine tartrate and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. Brimonidine Tartrate/Timolol has a rapid onset of action.

Brimonidine tartrate is an alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoreceptor. This selectivity results in no mydriasis and the absence of vasoconstriction in micro vessels associated with human retinal xenografts.

It is thought that brimonidine tartrate lowers IOP by enhancing uveoscleral outflow and reducing aqueous humour formation.

Timolol is a beta1 and beta2 non-selective adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable.

PHARMACOKINETICS

Brimonidine/Timolol

Plasma brimonidine and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to brimonidine/timolol treatment in healthy subjects. There were no statistically significant differences in brimonidine or timolol AUC between brimonidine/timolol and the respective monotherapy treatments. Mean plasma Cmax values for brimonidine and timolol following dosing with brimonidine/timolol were 0.0327 and 0.406 ng/ml respectively.

Brimonidine

After ocular administration of 0.2% eye drops solution in humans, plasma brimonidine concentrations are low. Brimonidine is not extensively metabolised in the human eye and human plasma protein binding is approximately 29%. The mean apparent half-life in the systemic circulation was approximately 3 hours after topical dosing in man.

Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 74% of the dose) was excreted as metabolites in urine within five days; no unchanged drug was detected in urine. In vitro studies, using animal and human liver, indicate that the metabolism is mediated largely by aldehyde oxidase and cytochrome P450. Hence, the systemic elimination seems to be primarily hepatic metabolism.

Brimonidine binds extensively and reversibly to melanin in ocular tissues without any untoward effects. Accumulation does not occur in the absence of melanin.

Brimonidine is not metabolised to a great extent in human eyes.

Timolol

After ocular administration of a 0.5% eye drops solution in humans undergoing cataract surgery, peak timolol concentration was 898 ng/ml in the aqueous humour at one-hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolised in the liver. The half-life of timolol in plasma is about 7 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma protein.

THERAPEUTIC INDICATION

Reduction of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers.

DOSAGE AND ADMINISTRATION

To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.

Posology

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of Brimonidine Tartrate/Timolol 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.

Method of administration

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) or eyelids are closed for two minutes. This should be performed immediately following the instillation of each drop. This may result in a decrease of systemic side effects and an increase in local activity.

Use in renal and hepatic impairment

Brimonidine Tartrate/Timolol has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients.

Paediatric population:

Brimonidine Tartrate/Timolol is contraindicated in neonates and infants (less than 2 years of age).

The safety and effectiveness of brimonidine/timolol in children and adolescents (2 to 17 years of age) have not been established and therefore, its use is not recommended in children or adolescents.

INSTRUCTION FOR USE

Apply TIMONID Eye Drops in the following way:

1. Wash your hands. Tilt your head back and look at the ceiling.
2. Gently pull the lower eyelid down until there is a small pocket.
3. Turn the bottle upside down and gently press the bottle to release drops into eyes that needs treatment.
4. Let go of the lower lid, and close your eye for 30 seconds.
5. To avoid contamination, do not let the tip of dropper touch your eye or anything else.
6. Replace and tighten the cap straight after use.

 OVERDOSE

Rare reports of overdosage with brimonidine/timolol in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained.

Brimonidine

Ophthalmic overdose (Adults):

In those cases, received, the events reported have generally been those already listed as adverse reactions.

Systemic overdose resulting from accidental ingestion (Adults):

There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure.

Paediatric population

Reports of serious adverse effects following inadvertent ingestion of brimonidine by paediatric subjects have been published or reported. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated. All subjects were reported to have made a full recovery, usually within 6-24 hours.

Timolol

Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.

CONTRAINDICATION

• Hypersensitivity to the active substance or to any of the excipients.
• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome sino-atrial block, second or third degree.
• Atrioventricular block not controlled with a pace-maker, overt cardiac failure, cardiogenic shock.
• Use in neonates and infants (less than 2 years of age).
• Patients receiving monoamine oxidase (MAO) inhibitor therapy.
• Patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).

WARNING AND PRECAUTIONS

• It is not for injection.
• Do not use the eye drop with contact lenses.
• Children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg, should be treated with caution and closely monitored due to the high incidence and severity of somnolence. The safety and effectiveness of brimonidine/timolol in children and adolescents (2 to 17 years of age) have not been established.
• Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solution 0.2%, with some reported to be associated with an increase in IOP (Intraocular Pressure).
• Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.
• Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta- blockers.
• Brimonidine/timolol should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
• Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta- blockers may mask the signs and symptoms of acute hypoglycaemia.
• Beta-blockers may also mask the signs of hyperthyroidism.
• Brimonidine/timolol must be used with caution in patients with metabolic acidosis and untreated phaeochromocytoma.
• Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
• Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthetist must be informed if the patient is receiving timolol.

PREGNANCY, LACTATION AND FERTILITY

Pregnancy

There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Brimonidine Tartrate/Timolol should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption.

Brimonidine tartrate

There are no adequate data from the use of brimonidine tartrate in pregnant women. Studies in animals have shown reproductive toxicity at high maternotoxic doses. The potential risk for humans is unknown.

Timolol

Studies in animals have shown reproductive toxicity at doses significantly higher than would be used in clinical practice.

Epidemiological studies have not revealed malformative effects but have shown a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If brimonidine/timolol is administered in pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life.

 Breastfeeding

Brimonidine tartrate

It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat.

Timolol

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption.

Brimonidine Tartrate/Timolol should not be used by women breast-feeding infants.

 DRUG INTERACTION

No interaction studies have been performed.

 ADVERSE EFFECTS

Based on 12-month clinical data, the most commonly reported ADRs were conjunctival hyperaemia (approximately 15% of patients) and burning sensation in the eye (approximately 11% of patients). The majority of these cases was mild and led to discontinuation rates of only 3.4% and 0.5% respectively.

The following adverse drug reactions were reported during clinical trials with brimonidine/timolol and are ranked by system order class and using the following frequency: Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1,000 to <1/100; Rare: ≥1/10,000 to <1/1,000; Very rare: <1/10,000; Not known: cannot be estimated from the available data.

 

System Organ Classification	Frequency	Adverse Effects
Eye disorders	Very Common	Conjunctival hyperaemia, burning sensation
	Common	stinging sensation in the eye, allergic conjunctivitis, corneal erosion, superficial punctate keratitis, eye pruritus, conjunctival folliculosis, visual disturbance, blepharitis, epiphora, eye dryness, eye discharge, eye pain, eye irritation, foreign body sensation
	Uncommon	visual acuity worsened, conjunctival oedema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, and vitreous detachment
Psychiatric disorders	Common	depression
Nervous system disorders	Common	Somnolence, headache
	Uncommon	Dizziness, syncope
Cardiac disorder	Uncommon	Congestive heart failure, palpitations
Vascular disorder	Common	Hypertension
Respiratory, thoracic and mediastinal disorders	Uncommon	Rhinitis, nasal dryness
Gastrointestinal disorder	Common	Oral dryness
	Uncommon	Taste perversion, nausea, diarrhoea
Skin and subcutaneous tissue disorders	Common	Eyelid oedema. Eyelid pruritus, eyelid erythema
	Uncommon	Allergic contact dermatitis
General disorders and administration site conditions	Common	Asthenic conditions

The following additional side effect have been seen with brimonidine:

Inflammation within eye, small pupils, difficulty sleeping, cold-like symptoms, shortness of breath, symptoms involving the stomach and digestion, general allergic reactions, skin reaction including redness, face swelling, itching rash and widening of blood vessels.

PRESENTATION

TIMONID Eye Drops are supplied in 5 ml sterilized opaque plastic container with nozzle and cap.

STORAGE AND OTHER INFORMATION

Store at temperature below 30 °C. Keep this medicine out of the sight and reach of children. Do not touch the dropper tip or dispensing tip to any surface since this may contaminate the solution. Use the solution within one month after opening the container.

 

 

 

 

 

BYS/I/00

TIMONID Eye Drop