Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma

  1. NAME OF THE MEDICINAL PRODUCT

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma

  1. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains:
Bimatoprost…………………………..0.3mg
Timolol (as 6.8mg of timolol maleate)…5mg

Excipient with known effect

Each ml of solution contains 0.05 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

  1. PHARMACEUTICAL FORM

Eye drops, solution.

Colourless to slightly yellow solution.

  1. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

Recommended dosage in adults (including older people)

The recommended dose is one drop of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma in the affected eye(s) once daily, administered either in the morning or in the evening. It should be administered at the same time each day.

Existing literature data for  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing (see section 5.1).

If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.

Renal and hepatic impairment

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma has not been studied in patients with hepatic or renal impairment. Therefore caution should be used in treating such patients.

Paediatric population

The safety and efficacy of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma in children aged 0 to 18 years has not been established. No data are available.

Method of administration

If more than one topical ophthalmic medicinal product is to be used, each one should be instilled at least 5 minutes apart.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.

4.3 Contraindications

▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

▪ 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 pace-maker. Overt cardiac failure, cardiogenic shock.

4.4 Special warnings and precautions for use

Like other topically applied ophthalmic medicinal products, the active substances (timolol/ bimatoprost) in  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. Due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-blockers may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Cardiac disorders

Patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal’s angina and cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.

Vascular disorders

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 disorders

Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma 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.

Endocrine disorders

Beta-adrenergic blocking medicinal products should be administered with caution in patients subject to spontaneous hypoglycemia or to patients with labile diabetes as beta-blockers may mask the signs and symptoms of acute hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

Ophthalmic β-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

Other beta-blocking agents

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended (see section 4.5).

Anaphylactic reactions

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

Surgical anaesthesia

β-blocking ophthalmological preparations may block systemic β-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

Hepatic

In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost had no adverse reactions on liver function over 24 months. There are no known adverse reactions of ocular timolol on liver function.

Ocular

Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid or periocular skin and increased brown iris pigmentation since these have been observed during treatment with bimatoprost and  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma. Increased iris pigmentation is likely to be permanent, and may lead to differences in appearance between the eyes if only one eye is treated. After discontinuation of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma, pigmentation of iris may be permanent. After 12 months treatment with Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma, the incidence of iris pigmentation was 0.2%. After 12 months treatment with bimatoprost eye drops alone, the incidence was 1.5% and did not increase following 3 years treatment. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased iridial pigmentation are not known. Iris colour changes seen with ophthalmic administration of bimatoprost may not be noticeable for several months to years. Neither nevi nor freckles of the iris appear to be affected by treatment. Periorbital tissue pigmentation has been reported to be reversible in some patients.

Macular oedema, including cystoid macular oedema, has been reported with  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma. Therefore,  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy).

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma should be used with caution in patients with active intraocular inflammation (e.g. uveitis) because the inflammation may be exacerbated.

Skin

There is a potential for hair growth to occur in areas where  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma solution comes repeatedly in contact with the skin surface. Thus, it is important to apply  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma as instructed and avoid it running onto the cheek or other skin areas.

Excipients

The preservative in  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma, benzalkonium chloride, may cause eye irritation. Contact lenses must be removed prior to application, with at least a 15-minute wait before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Contact with soft contact lenses must be avoided.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Therefore monitoring is required with frequent or prolonged use of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma in dry eye patients or where the cornea is compromised.

Other conditions

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.

In studies of bimatoprost 0.3 mg/ml in patients with glaucoma or ocular hypertension, it has been shown that more frequent exposure of the eye to more than 1 dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma with other prostaglandin analogues should be monitored for changes to their intraocular pressure.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed with the bimatoprost / timolol fixed combination.

There is a potential for additive effects resulting in hypotension, and/or marked bradycardia when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, guanethidine, beta-adrenergic blocking agents, parasympathomimetics, anti-arrhythmics (including amiodarone) and digitalis glycosides.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of the bimatoprost / timolol fixed combination in pregnant women.  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.

Bimatoprost

No adequate clinical data in exposed pregnancies are available. Animal studies have shown reproductive toxicity at high maternotoxic doses (see section 5.3).

Timolol

Epidemiological studies have not revealed malformative effects but 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  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma is administered until delivery, the neonate should be carefully monitored during the first days of life. Animal studies with timolol have shown reproductive toxicity at doses significantly higher than would be used in clinical practice (see section 5.3).

Breast-feedingTimolol

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, see section 4.2.

Bimatoprost

It is not known if bimatoprost is excreted in human breast milk but it is excreted in the milk of the lactating rat.  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma should not be used by breast-feeding women.

Fertility

There are no data on the effects of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma on human fertility.

4.7 Effects on ability to drive and use machines

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma has negligible influence on the ability to drive and use machines. As with any ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machines.

4.8 Undesirable effects

 Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma

Summary of the safety profile

The adverse reactions reported in clinical studies using  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma were limited to those earlier reported for either of the single active substances bimatoprost and timolol. No new adverse reactions specific for  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma have been observed in clinical studies.

The majority of adverse reactions reported in clinical studies using  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma were ocular, mild in severity and none were serious. Based on 12-month clinical data, the most commonly reported adverse reaction was conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatory nature) in approximately 26% of patients and led to discontinuation in 1.5% of patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions that have been reported during clinical studies with all  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma formulations (multi-dose and single-dose) (within each frequency grouping, adverse reactions are presented in order of decreasing seriousness) or in the post-marketing period.

The frequency of possible adverse reactions listed below is defined using the following convention:

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 Frequency cannot be estimated from available data

Table 1

System Organ Class Frequency Adverse reaction
Immune system disorders Not known hypersensitivity reactions including signs or symptoms of allergic dermatitis, angioedema, eye allergy
Psychiatric disorders Not known Insomnia2, nightmare2
Nervous system disorders Common headache, dizziness2
Not known Dysgeusia2
Eye disorders Very common conjunctival hyperaemia.
Common punctuate keratitis, corneal erosion2, burning sensation2, conjunctival irritation1, eye pruritus, stinging sensation in the eye2, foreign body sensation, dry eye, erythema of eyelid, eye pain, photophobia, eye discharge2, visual disturbance2, eyelid pruritus, visual acuity worsened2, blepharitis2, eyelid oedema, eye irritation, lacrimation increased, growth of eyelashes.
Uncommon iritis2, conjunctival oedema2, eyelid pain2, abnormal sensation in the eye1, asthenopia, trichiasis2, iris hyperpigmentation2, deepening of eyelid sulcus, eyelid retraction2, eyelash discolouration (darkening)1.
Not known cystoid macular oedema2, eye swelling, vision blurred2
Cardiac disorders Not known Bradycardia
Respiratory, thoracic and mediastinal disorders Common Rhinitis2
Uncommon dyspnoea
Not known bronchospasm (predominantly in patients with pre-existing bronchospastic disease) 2, asthma
Skin and subcutaneous tissue disorders Common blepharal pigmentation2, hirsutism2, skin hyperpigmentation (periocular).
Not known Alopecia2
General disorders and administration site conditions Not known fatigue

1adverse reactions only observed with Ganfort single-dose formulation

2adverse reactions only observed with Ganfort multi-dose formulation

Like other topically applied ophthalmic drugs,  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma (bimatoprost/timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Additional adverse reactions that have been seen with either of the active substances (bimatoprost or timolol), and may potentially occur also with  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma are listed below in Table 2:

Table 2

System Organ Class Adverse reaction
Immune system disorders systemic allergic reactions including anaphylaxis1
Metabolism and nutrition disorders hypoglycaemia1
Psychiatric disorders depression1, memory loss1, hallucination1
Nervous system disorders syncope1, cerebrovascular accident1, increase in signs and symptoms of myasthenia gravis1, paraesthesia1, cerebral ischaemia1
Eye disorders decreased corneal sensitivity1, diplopia1, ptosis1, choroidal detachment following filtration surgery (see section 4.4)1, keratitis1, blepharospasm2, retinal haemorrhage2, uveitis2,
Cardiac disorder atrioventricular block1, cardiac arrest1, arrhythmia1, cardiac failure1, congestive heart failure1, chest pain1, palpitations1, oedema1
Vascular disorders hypotension1, hypertension2, Raynaud’s phenomenon1, cold hands and feet1
Respiratory, thoracic and mediastinal disorders Asthma exacerbation2, COPD exacerbation2, cough1
Gastrointestinal disorders nausea1,2, diarrhoea1, dyspepsia1, dry mouth1, abdominal pain1, vomiting1
Skin and subcutaneous tissue disorders psoriasiform rash1 or exacerbation of psoriasis1, skin rash1
Musculoskeletal and connective tissue disorders myalgia1
Reproductive system and breast disorders sexual dysfunction1, decreased libido1
General disorders and administration site conditions asthenia1,2
Investigations liver function tests (LFT) abnormal2

1 adverse reactions observed with Timolol

2 adverse reactions observed with Bimatoprost

Adverse reactions reported in phosphate containing eye drops

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

4.9 Overdose

A topical overdose with Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma is not likely to occur or to be associated with toxicity.

Bimatoprost

If Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma is accidentally ingested, the following information may be useful: in two-week oral rat and mouse studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 70-times higher than the accidental dose of one bottle of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma in a 10 kg child.

Timolol

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

If overdose occurs treatment should be symptomatic and supportive.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmological, – beta-blocking agents

Mechanism of action

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma consists of two active substances: bimatoprost and timolol. 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.  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma has a rapid onset of action.

Bimatoprost is a potent ocular hypotensive active substance . It is a synthetic prostamide, structurally related to prostaglandin F (PGF) that does not act through any known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified. The mechanism of action by which bimatoprost reduces intraocular pressure in man is by increasing aqueous humour outflow through the trabecular meshwork and enhancing uveoscleral outflow.

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.

Clinical effects

The IOP-lowering effect of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma is non-inferior to that achieved by adjunctive therapy of bimatoprost (once daily) and timolol (twice daily).

Existing literature data for  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing.

Paediatric population

The safety and efficacy of  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma in children aged 0 to 18 years has not been established.

5.2 Pharmacokinetic properties

 Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma medicinal product

Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma treatment in healthy subjects. Systemic absorption of the individual components was minimal and not affected by co-administration in a single formulation.

In two 12-month studies where systemic absorption was measured, no accumulation was observed with either of the individual components.

Bimatoprost

Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limit of detection (0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and AUC 0-24hrs values were similar on days 7 and 14 at approximately 0.08 ng/ml and 0.09 ng•hr/ml respectively, indicating that a steady drug concentration was reached during the first week of ocular dosing.

Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in humans at steady-state was 0.67 1/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 88%.

Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.

Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose administered to healthy volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. The elimination half-life, determined after intravenous administration, was approximately 45 minutes; the total blood clearance was 1.5 1/hr/kg.

Characteristics in older people

After twice daily dosing, the mean AUC 0-24hrs value of 0.0634 ng•hr/ml bimatoprost in the elderly (subjects 65 years or older) were significantly higher than 0.0218 ng•hr/ml in young healthy adults. However, this finding is not clinically relevant as systemic exposure for both elderly and young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood over time and the safety profile was similar in elderly and young patients.

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 4 to 6 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma.

5.3 Preclinical safety data

 Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma medicinal product

Repeated dose ocular toxicity studies on  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma showed no special hazard for humans. The ocular and systemic safety profile of the individual components is well established.

Bimatoprost

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential. Studies in rodents produced species-specific abortion at systemic exposure levels 33- to 97-times that achieved in humans after ocular administration.

Monkeys administered ocular bimatoprost concentrations of ≥0.03% daily for 1 year had an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. The increased iris pigmentation appears to be caused by increased stimulation of melanin production in melanocytes and not by an increase in melanocyte number. No functional or microscopic changes related to the periocular effects have been observed, and the mechanism of action for the periocular changes is unknown.

Timolol

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

  1. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzalkonium chloride, Sodium chloride, Sodium phosphate dibasic heptahydrate, Citric acid monohydrate, Hydrochloric acid or sodium hydroxide (to adjust pH), Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Chemical and physical in-use stability has been demonstrated for 28 days at 25°C.

From a microbiological point of view, the in-use storage times and conditions are the responsibility of the user and would normally not be longer than 28 days at 25°C.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

White opaque low-density polyethylene bottles with polystyrene screw cap. Each bottle has a fill volume of 3 ml.

The following pack sizes are available: cartons containing 1 or 3 bottles of 3 ml. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

  1. MANUFACTURED IN INDIA BY:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

BIMATOPROST AND TIMOLOL MALEATE OPHTHALMIC SOLUTION
0.03% & 0.5% W/V
TAJ PHARMA

PACKAGE LEAFLET: INFORMATION FOR THE USER

Bimatoprost/timolol

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, please ask your doctor, pharmacist, or nurse.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

WHAT IS IN THIS LEAFLET:

  1. What Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma is and what it is used for
  2. What you need to know before you use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma
  3. How to use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma
  4. Possible side effects
  5. How to store Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma
  6. Contents of the pack and other information
    1. WHAT BIMATOPROST AND TIMOLOL MALEATE OPHTHALMIC SOLUTION 0.03% & 0.5% W/V TAJ PHARMA IS AND WHAT IT IS USED FOR

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma contains two different active substances (bimatoprost and timolol) that both reduce pressure in the eye. Bimatoprost belongs to a group of medicines called prostamides, a prostaglandin analogue. Timolol belongs to a group of medicines called beta-blockers.

Your eye contains a clear, watery liquid that feeds the inside of the eye. Liquid is constantly being drained out of the eye and new liquid is made to replace this. If the liquid cannot drain out quickly enough, the pressure inside the eye builds up and could eventually damage your sight (an illness called glaucoma).  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma works by reducing the production of liquid and also increasing the amount of liquid that is drained. This reduces the pressure inside the eye.

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma eye drops are used to treat high pressure in the eye in adults, including the elderly. This high pressure can lead to glaucoma. Your doctor will prescribe you  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma when other eye drops containing beta-blockers or prostaglandin analogues have not worked sufficiently on their own.

  1. WHAT YOU NEED TO KNOW BEFORE YOU USE BIMATOPROST AND TIMOLOL MALEATE OPHTHALMIC SOLUTION 0.03% & 0.5% W/V TAJ PHARMA

Do not use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma eye drops, solution

  • if you are allergic to bimatoprost, timolol, beta-blockers or any of the other ingredients of Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma (listed in section 6)
  • if you have now or have had in past respiratory problems such as asthma, severe chronic obstructive bronchitis (severe lung disease which may cause wheeziness, difficulty in breathing and/ or long-standing cough)
  • if you have heart problems such as low heart rate, heart block, or heart failure

Warnings and precautions

Before you use this medicine, tell your doctor if you have now or have had in the past

  • coronary heart disease (symptoms can include chest pain or tightness, breathlessness or choking), heart failure, low blood pressure,
  • disturbances of heart rate such as slow heart beat
  • breathing problems, asthma or chronic obstructive pulmonary disease
  • poor blood circulation disease (such as Raynaud’s disease or Raynaud’s syndrome)
  • overactivity of the thyroid gland as timolol may mask signs and symptoms of thyroid disease
  • diabetes as timolol may mask signs and symptoms of low blood sugar
  • severe allergic reactions
  • liver or kidney problems
  • eye surface problems
  • separation of one of the layers within the eyeball after surgery to reduce the pressure in the eye
  • known risk factors for macular oedema (swelling of the retina within the eye leading to worsening vision), for example, cataract surgery

Tell your doctor before surgical anaesthesia that you are using Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma as timolol may change effects of some medicines used during anaesthesia.

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma may cause your eyelashes to darken and grow, and cause the skin around the eyelid to darken too. The colour of your iris may also go darker over time. These changes may be permanent. The change may be more noticeable if you are only treating one eye.  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma may cause hair growth when in contact with the skin surface.

Children and adolescents

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma should not be used in children and teenagers under 18.

Other medicines and Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma can affect or be affected by other medicines you are using, including other eye drops for the treatment of glaucoma. Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Tell your doctor if you are using or intend to use medicines to lower blood pressure, heart medicine, medicines to treat diabetes, quinidine (used to treat heart conditions and some types of malaria) or medicines to treat depression known as fluoxetine and paroxetine.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Do not use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma if you are pregnant unless your doctor still recommends it.

Do not use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma if you are breast-feeding. Timolol may get into your breast milk.

Ask your doctor for advice before taking any medicine during breast-feeding.

Driving and using machines

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma may cause blurred vision in some patients. Do not drive or use machines until the symptoms have cleared.

 Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma contains Benzalkonium chloride

Ganfort contains a preservative called benzalkonium chloride. Benzalkonium chloride may cause eye irritation and is also known to discolour soft contact lenses. Do not use the drops while your contact lenses are in your eyes. Wait at least 15 minutes after using the eye drops before putting your lenses back in your eyes.

  1. HOW TO USE BIMATOPROST AND TIMOLOL MALEATE OPHTHALMIC SOLUTION 0.03% & 0.5% W/V TAJ PHARMA

Always use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The usual dose is one drop once a day, either in the morning or in the evening in each eye that needs treatment. Use at the same time each day.

Instructions for use

You must not use the bottle if the tamper-proof seal on the bottle neck is broken before you first use it.

  1. Wash your hands. Tilt your head back and look at the ceiling.
    2. Gently pull down the lower eyelid until there is a small pocket.
    3. Turn the bottle upside down and squeeze it to release one drop into each eye that needs treatment.
    4. Let go of the lower lid, and close your eye.
    5. Whilst keeping the eye closed, press your finger against the corner of the closed eye (the site where the eye meets the nose) and hold for 2 minutes. This helps to stop Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma getting into the rest of the body.

If a drop misses your eye, try again.

To avoid contamination, do not let the tip of the bottle touch your eye or anything else. Put the cap back on and close the bottle straight after you have used it.

If you use  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma with another eye medicine, leave at least 5 minutes between putting in  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma and the other medicine. Use any eye ointment or eye gel last.

If you use more Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma than you should

If you use more Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma than you should, it is unlikely to cause you any serious harm. Put your next dose in at the usual time. If you are worried, talk to your doctor or pharmacist.

If you forget to use  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma

If you forget to use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma, use a single drop as soon as you remember, and then go back to your regular routine. Do not use a double dose to make up for a forgotten dose.

If you stop using  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma should be used every day to work properly.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

  1. POSSIBLE SIDE EFFECTS

Like all medicines,  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma can cause side effects, although not everybody gets them. You can usually carry on taking the drops, unless the effects are serious. If you’re worried, talk to a doctor or pharmacist. Do not stop using Ganfort without speaking to your doctor.

The following side effects may be seen with  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma (multi-dose and/or single-dose):

Very common side effects

These may affect more than 1 user in 10

Affecting the eye

Redness.

Common side effects

These may affect 1 to 9 users in 100

Affecting the eye

burning, itching, stinging, irritation of the conjunctiva (see-through layer of the eye), sensitivity to light, eye pain, sticky eyes, dry eyes, a feeling of something in the eye, small breaks in the surface of the eye with or without inflammation, difficulty in seeing clearly, redness and itching of the eyelids, hair growing around the eye, darkening of the eyelids, darker skin colour around the eyes, longer eyelashes, eye irritation, watery eyes, swollen eyelids, reduced vision.

Affecting other parts of the body

runny nose, dizziness, headache.

Uncommon side effects

These may affect 1 to 9 users in 1,000

Affecting the eye

abnormal sensation in the eye, iris inflammation, swollen conjunctiva (see-through layer of the eye), painful eyelids, tired eyes, in-growing eyelashes, darkening of iris colour, eyes appear sunken, eyelid has moved away from the surface of the eye, darkening of eyelashes.

Affecting other parts of the body

shortness of breath.

Side effects where the frequency is not known

Affecting the eye

cystoid macular oedema (swelling of the retina within the eye leading to worsening vision), eye swelling, blurred vision.

Affecting other parts of the body

difficulty breathing / wheezing, symptoms of allergic reaction (swelling, redness of the eye and rash of the skin), changes in your taste sensation, slowing of heart rate, difficulty sleeping, nightmare, asthma, hair loss, tiredness.

Additional side effects have been seen in patients using eye drops containing timolol or bimatoprost and so may possibly be seen with  Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma. Like other medicines applied into eyes, timolol is absorbed into the blood. This may cause similar side effects as seen with ”intravenous” and /or “oral” beta-blocking agents. The chance of having side effects after using eye drops is lower than when medicines are for example, taken by mouth or injected. Listed side effects include reactions seen within bimatoprost and timolol when used for treating eye conditions:

  • Severe allergic reactions with swelling and difficulty breathing which could be life-threatening
  • Low blood sugar
  • Depression; memory loss; hallucination
  • Fainting; stroke; decreased blood flow to the brain; worsening of myasthenia gravis (increased muscle weakness); tingling sensation
  • Decreased sensation of your eye surface; double vision; drooping eyelid; separation of one of the layers within the eyeball after surgery to reduce the pressure in the eye; inflammation of the surface of the eye, bleeding in the back of the eye (retinal bleeding), inflammation within the eye, increased blinking
  • Heart failure; irregularity or stopping of the heartbeat; slow or fast heartbeat; too much fluid, mainly water, accumulating in the body; chest pain
  • Low blood pressure, high blood pressure, swelling or coldness of your hands, feet and extremities, caused by constriction of your blood vessels
  • Cough, worsening of asthma, worsening of the lung disease called chronic obstructive pulmonary disease (COPD)
  • Diarrhoea; stomach pain; feeling and being sick; indigestion; dry mouth
  • Red scaly patches on skin; skin rash
  • Muscle pain
  • Reduced sexual urge; sexual dysfunction
  • Weakness
  • An increase in blood test results that show how your liver is working

Other side effects reported with eye drops containing phosphates

In very rare cases, some patients with severe damage to the clear layer at the front of the eye (the cornea) have developed cloudy patches on the cornea due to calcium build-up during treatment.

Reporting side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via:

  1. HOW TO STORE BIMATOPROST AND TIMOLOL MALEATE OPHTHALMIC SOLUTION 0.03% & 0.5% W/V TAJ PHARMA

Keep Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma out of the sight and reach of children.

Do not use Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma after the expiry date which is stated on the bottle label and the carton after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Once opened, solutions may become contaminated, which can cause eye infections. Therefore, you must throw away the bottle 4 weeks after you first opened it, even if some solution is left. To help you remember, write down the date that you opened it in the space on the carton.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

  1. CONTENTS OF THE PACK AND OTHER INFORMATION

What Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma contains

Each ml of solution contains:
Bimatoprost…………………………..0.3mg
Timolol (as 6.8mg of timolol maleate)…5mg

The other ingredients are benzalkonium chloride (a preservative), sodium chloride, sodium phosphate dibasic heptahydrate, citric acid monohydrate and purified water. Small amounts of hydrochloric acid or sodium hydroxide may be added to bring the solution to the correct pH (acidity) level.

What Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma looks like and contents of the pack

Bimatoprost and Timolol Maleate Ophthalmic Solution 0.03% & 0.5% w/v Taj Pharma is a colourless to slightly yellow, clear eye drop solution in a plastic bottle. Each pack contains either 1 or 3 plastic bottles each with a screw-cap. Each bottle is about half full and contains 3 millilitres of solution. This is enough for 4 weeks’ usage. Not all pack sizes may be marketed.

  1. MANUFACTURED IN INDIA BY:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com