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/Timolol single-dose 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/Timolol (multi-dose formulation) 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).

The single-dose container is for single use only; one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use. 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/Timolol single-dose 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/Timolol single-dose in children aged less than 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/Timolol single-dose may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed with Bimatoprost/Timolol (multi-dose formulation). Due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions (ADRs) 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 receiving 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 the 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/Timolol single-dose 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 hypoglycaemia or in 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 beta-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 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

Beta-blocking ophthalmological preparations may block systemic beta-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 eye drops 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 prostaglandin analogue periobitopathy (PAP), during treatment with Bimatoprost/Timolol single-dose. Increased brown iris pigmentation has also been observed during treatment with Bimatoprost/Timolol (multi-dose formulation). Some of these changes may be permanent, and may lead to impaired field of vision and differences in appearance between the eyes when only one eye is treated (see section 4.8).

Macular oedema, including cystoid macular oedema has been reported with Bimatoprost/Timolol (multi-dose formulation). Therefore, Bimatoprost/Timolol single-dose 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/Timolol 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/Timolol solution comes repeatedly in contact with the skin surface. Thus, it is important to apply Bimatoprost/Timolol as instructed and avoid it running onto the cheek or other skin areas.

Other conditions

Bimatoprost/Timolol single-dose has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure, congenital 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/Timolol 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-blocker 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/Timolol single-dose 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 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 Bimatoprost/Timolol single-dose 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-feeding

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, 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/Timolol single-dose should not be used by breast-feeding women.

Fertility

There are no data on the effects of Bimatoprost/Timolol single-dose on human fertility.

4.7. Effects on ability to drive and use machines

Bimatoprost/Timolol single-dose has negligible influence on the ability to drive and use machines. As with any topical 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/Timolol single-dose

Summary of the safety profile

The adverse reactions reported in the clinical study using Bimatoprost/Timolol single-dose were limited to those earlier reported for either Bimatoprost/Timolol (multi-dose formulation) or for the single active substances bimatoprost or timolol. No new adverse reactions specific for Bimatoprost/Timolol single-dose have been observed in clinical studies.

The majority of adverse reactions reported with Bimatoprost/Timolol single-dose were ocular, mild in severity and none were serious. Based on a 12-week study of Bimatoprost/Timolol single-dose administered once daily, the most commonly reported adverse reaction with Bimatoprost/Timolol single-dose was conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatory nature) in approximately 21% of patients and led to discontinuation in 1.4% of patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions that were reported during clinical studies of both Bimatoprost/Timolol single-dose and Bimatoprost/Timolol multi-dose formulations (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

Not known

Dysgeusia2, dizziness

Eye disorders

Very common

conjunctival hyperaemia, prostaglandin analogue periorbitopathy

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 discharge, 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, periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus, eyelid ptosis, enophthalmos, lagophthalmos and eyelid retraction1&2, eyelash discolouration (darkening)1.

Not known

cystoid macular oedema2, eye swelling, vision blurred2, ocular discomfort

Cardiac disorders

Not known

Bradycardia

Vascular disorders

Not known

Hypertension

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

Alopecia, skin discolouration (periocular)

General disorders and administration site conditions

Not known

fatigue

1adverse reactions only observed with Bimatoprost/Timolol single-dose formulation

2adverse reactions only observed with Bimatoprost/Timolol multi-dose formulation

Like other topically applied ophthalmic drugs, 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/Timolol 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, hallucination (frequency not known) 1

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, 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

1adverse reactions observed with Timolol

2adverse reactions observed with Bimatoprost

Description of selected adverse reactions:

Prostaglandin analogue periorbitopathy (PAP)

Prostaglandin analogues including bimatoprost can induce periorbital lipodystrophic changes which can lead to deepening of the eyelid sulcus, ptosis, enophthalmos, eyelid retraction, involution of dermatochalasis and inferior scleral show. Changes are typically mild, can occur as early as one month after initiation of treatment with Bimatoprost/Timolol single-dose may cause impaired field of vision even in the absence of patient recognition. PAP is also associated with periocular skin hyperpigmentation or discoloration and hypertrichosis. All changes have been noted to be partially or fully reversible upon discontinuation or switch to alternative treatments.

Iris hyperpigmentation

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 this medicine, pigmentation of iris may be permanent. 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. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts become more brownish. Neither naevi nor freckles of the iris appear to be affected by the treatment. Periorbital tissue pigmentation has been reported to be reversible in some patients. At 12 months, the incidence of iris hyperpigmentation with bimatoprost 0.1 mg/ml eye drops, solution was 0.5%. After 12 months treatment with bimatoprost / timolol fixed combination, the incidence of iris pigmentation was 0.2%. At 12 months, the incidence with bimatoprost 0.3 mg/ml eye drops, solution was 1.5% (see section 4.8 Table 2) and did not increase following 3 years treatment.

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. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9. Overdose

A topical overdose with Bimatoprost/Timolol single-dose is not likely to occur or to be associated with toxicity.

Bimatoprost

If Bimatoprost/Timolol single-dose is accidentally ingested, the following information may be useful: in 2-week oral mice and rats studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity; this corresponds to a human equivalent dose of 8.1 and 16.2 mg/kg, respectively. These doses are at least 7.5 times higher than the amount of bimatoprost in an accidental dose of the entire contents of a carton of Bimatoprost/Timolol single-dose (90 single-dose containers x 0.4 mL; 36 mL) in a 10 kg child [(36 mL*0.3 mg/mL bimatoprost)/10 kg; 1.08 mg/kg].

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.