Timolol-Betalek

Reduction of elevated intraocular pressure in conditions such as:

- Ocular hypertension;

- Chronic open-angle glaucoma (including aphakic patients);

- Some cases of secondary glaucoma

Timolol-Betalek Eye Drops 0.5% is contraindicated in patients with:

- Cardiogenic shock;

- Overt cardiac failure;

- Second and third degree AV block not controlled with pace-maker;

- Sinus bradycardia, sick sinus syndrome sino-atrial block;

- Reactive airway disease including bronchial asthma or a history of bronchial asthma;

- Presence or history of severe chronic obstructive pulmonary disease;

- Severe peripheral circulatory disturbances (Raynaud disease);

- Hypersensitivity to the active substance, any of the excipients or other beta-blocking agents.

Like other topically applied ophthalmic drugs, Timolol-Betalek Eye Drops is absorbed systemically.). It is important to notify the parents of potential side effects so they can immediately discontinue the drug therapy. Signs to look for are for example coughing and wheezing. Because of the possibility of apnoea and Cheyne-Stokes breathing, the drug should be used with extreme caution in neonates, infants and younger children. A portable apnoea monitor may also be helpful for neonates on Timolol-Betalek.

There are currently no data available on the effects of Timolol-Betalek Eye Drops 0.5% on the ability to drive or use machinery. It has to be taken into account that dizziness, fatigue, transient ocular irritation, blurred vision and lacrimation may occur occasionally.

Like other topically applied ophthalmic drugs, Timolol-Betalek is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers

Immune system disorders:

Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders:

Hypoglycaemia.

Psychiatric disorders:

Insomnia, depression, nightmares, memory loss.

Nervous system disorders:

Syncope, cerebrovascular accident, cerebral ischemia, increases in signs and symptoms of myasthenia gravis, dizziness, paraesthesia, and headache.

Eye disorders:

Signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), blepharitis, keratitis, blurred vision and choroidal detachment following filtration surgery (see 4.4 Special warnings and special precautions for use), conjunctivitis, decreased corneal sensitivity, dry eyes, corneal erosion ptosis, diplopia.

Cardiac disorders:

Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, cardiac failure.

Vascular disorders:

Hypotension, Raynaud's phenomenon, cold hands and feet, intermittent claudication.

Respiratory, thoracic, and mediastinal disorders:

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), dyspnoea, cough, respiratory failure, nasal congestion.

Gastrointestinal disorders:

Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders:

Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash.

Musculoskeletal and connective tissue disorders:

Myalgia.

Reproductive system and breast disorders:

Sexual dysfunction, decreased libido.

General disorders and administration site conditions:

Asthenia/fatigue.

The following adverse events have been reported but a causal relationship to therapy with Timolol-Betalek eye drops has not been established:-

Metabolism & nutrition disorders: anorexia

Psychiatric disorders: behavioural disorders including confusion, hallucination, anxiety, disorientation, nervousness, somnolence, psychic disturbances.

Eye disorders: aphakic cystoids macular oedema

Cardiac disorders: angina pectoris aggravated

Vascular disorders: hypertension, pulmonary oedema

Gastrointestinal disorders: retroperitoneal fibrosis

Skin and subcutaneous tissue disorders: pemphigoid

Reproductive system and breast disorders: impotence

The following additional adverse events have been reported with oral Timolol-Betalek maleate and may be considered as potential effects of ophthalmic Timolol-Betalek maleate:-

Blood & lymphatic system disorders: purpura non-thrombocytopenic

Metabolism & nutrition disorders: weight loss, hyperglycaemia

Nervous system disorders: vertigo

Psychiatric disorders: concentration impaired

Ear disorders: tinnitus

Vascular disorders: arterial insufficiency, vasodilation

Respiratory, thoracic, and mediastinal disorders: rales, bronchial obstruction,

Hepatobiliary disorders: hepatomegaly

Skin and subcutaneous tissue disorders: skin irritation, pigmentation abnormal, sweating

Musculoskeletal & connective tissue disorders: pain in extremity, arthralgia

Renal and urinary disorders: dysuria

General disorders and administration site conditions: exercise tolerance decreased

In addition, the following additional adverse events have been reported with other beta-adrenergic blocking agents and may be considered as potential effects of ophthalmic Timolol-Betalek maleate:-

Immune system disorders: fever combined with general muscle aches, throat sore, laryngospasm and respiratory distress.

Blood & lymphatic system disorders: agranulocytosis, thrombocytopenic purpura

Psychiatric disorders: catatonia, an acute reversible syndrome (disorientation, memory loss, emotional lability, depressed level of consciousness, performance status decreased).

Gastrointestinal disorders: mesenteric artery thrombosis, colitis ischaemic.

Reproductive system and breast disorders: Peyronie's disease

There have been reports of a syndrome comprising psoriasiform skin rash, conjunctivitis, otitis and sclerosing serositis attributed to the beta-adrenergic receptor blocking agent, practolol. This syndrome has also been reported with Timolol-Betalek maleate.

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 Yellow card scheme at www.mhra.gov.uk/yellowcard

No specific data are available. Overdosage is unlikely to occur as one 5ml bottle of Timolol-Betalek Eye Drops 0.5% contains 25 mgs of Timolol-Betalek maleate compared with the usual adult oral dose of 20-60 mgs per day. However, in the rare event that overdosage occurs the most common signs and symptoms to be expected following overdosage with a beta-adrenergic receptor blocking agent are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. If overdosage occurs, the following measures should be considered:

1 Gastric lavage, if ingested. Studies have shown that Timolol-Betalek cannot be easily removed by hemodialysis.

2 Symptomatic bradycardia: Atropine sulphate, 0.25 to 2mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.

3 Hypotension: A sympathomimetic pressor agent such as dopamine, dobutamine or noradrenaline should be used. In refractory cases, the use of glucagon has been reported to be useful.

4 Bronchopasm: Isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.

5 Acute cardiac failure: conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon which has been reported to be useful.

6 Heart block (second or third degree): Isoprenaline hydrochloride or a pacemaker should be used.

Timolol-Betalek is a non-selective β-adrenergic blocker, which does not possess significant intrinsic sympathomimetic or local anaesthetic (membrane-stabilising) activity. When applied topically in the eye, it reduces both elevated and normal intraocular pressure by inhibiting the production of aqueous humour.

Unlike miotics, Timolol-Betalek reduces intraocular pressure with little or no effect on pupil size or accommodation.

The onset of reduction in intraocular pressure following ocular administration of Timolol-Betalek can be detected within 30 minutes after a single dose The maximum effect usually occurs in one to three hours and significant lowering of intraocular pressure can be maintained for as long as 24 hours following a single dose.

If systemically absorbed, as is possible, Timolol-Betalek maleate is capable of producing beta-blockade elsewhere in the body with consequent systemic effects (increased airway resistance, bradycardia, hypotension etc.)

Paediatric Population:

There is only very limited data available on the use of Timolol-Betalek (0.25%, 0.5% twice daily one drop) in the paediatric population for a treatment period up to 12 weeks. One small, double blinded, randomized, published clinical study conducted on 105 children (n=71 on Timolol-Betalek) aged 12 days - 5 years show to some extent evidence, that Timolol-Betalek in the indication primary congenital and primary juvenile glaucoma is effective in short term treatment.

Topical instillation of 50μl of a 0.5% solution of Timolol-Betalek to the rabbit eye resulted in rapid appearance of Timolol-Betalek in the aqueous humour and to a much lesser degree in the plasma. The concentration in the aqueous humour (mean of 2.47μg/ml) peaked 30 minutes after instillation. The plasma concentration (0.188 μg/ml) also peaked at this time.

Following topical instillation in humans, the Timolol-Betalek concentration in aqueous humour was 8-100 ng/ml within the first hour while the mean plasma concentration was approximately 1 ng/ml within the first few hours (compared with plasma concentrations of 5-50 ng/ml seen with therapeutic doses of oral Timolol-Betalek).

Paediatric Population:

As already confirmed by adult data, 80% of each eye drop passes through the nasolacrimal system where it may be rapidly absorbed into the systemic circulation via the nasal mucosa, conjunctiva, nasolacrimal duct, oropharynx and gut, or the skin from tear overflow. Due to the fact that the blood volume in children is smaller than that in adults a higher circulation concentration has to be taken into account. In addition, neonates have immature metabolic enzyme pathways and it may result in an increase in elimination half-life and potentiating adverse events. Limited data show that plasma Timolol-Betalek levels in children after 0.25% greatly exceed those in adults after 0.5%, especially in infants and are presumed to increase the risk of side effects such as bronchospasm and bradycardia.

Acute Toxicity Studies: Data have been reported in a number of animal species. Oral LD₅₀ in the mouse and rat are 1137 mg/kg and 1028 mg/kg respectively. Subcutaneous LD₅₀ in the mouse and rat are 300 mg/kg and 381 mg/kg respectively.

Chronic Toxicity Studies: No adverse ocular effects were observed with ophthalmic topical administration of Timolol-Betalek in rabbits and dogs in studies lasting one and two years respectively. In studies with oral administration in high doses in dogs and rats, bradycardia and weight increase in the heart, kidneys and liver were observed adverse effects.

Carcinogenicity: In a life-time study in mice, Timolol-Betalek increased the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice when administered orally at doses of 500mg/kg per day, but not at 5 or 50 mg/kg per day. In a 2 year study in rats, oral Timolol-Betalek increased the incidence of adrenal pheochromocytomas in male rats at 300 mg/kg per day but not at 25 or 100 mg/kg per day.

Mutagenicity: Timolol-Betalek was not shown to be mutagenic when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (at doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 0.1 mg per ml).

Reproduction and fertility: Reproduction and fertility studies in rats have not shown that Timolol-Betalek causes any adverse effects on male or female fertility when administered orally at doses of up to 125 times the maximum recommended human oral dose of 30mg. Studies in rats have shown that Timolol-Betalek at doses of up to 50mg/kg/day (50 times the maximum recommended human oral dose) caused delayed foetal ossification; however there were no adverse effects on post-natal development of offspring. Teratogenic studies in mice and rabbits have not shown that Timolol-Betalek at doses of up to 50 mg/kg/day causes foetal malformations. In mice, Timolol-Betalek at doses of 1000 mg/kg/day (1000 times the maximum recommended human oral dose) was maternotoxic and resulted in an increased incidence of foetal resorptions.

In rabbits, Timolol-Betalek at 100 mg/kg/day (100 times the maximum recommended human oral dose) increased incidence of foetal resorptions but not maternotoxicity.

Timolol-Betalek maleate 0.5% eye drops have not been adequately studied in human pregnancy. Although Timolol-Betalek eye drops may be absorbed systemically, daily treatment with Timolol-Betalek Eye Drops 0.5% (1 drop, twice daily in both eyes) will not exceed 0.4mgs Timolol-Betalek compared with the oral therapeutic dose of 20-60 mgs/day. However as a precautionary measure, it is recommended that Timolol-Betalek should not be used in pregnancy, unless the potential benefit to the pregnant woman exceeds the potential risk to the foetus.

Benzalkonium chloride may be deposited in soft contact lenses. These lenses should therefore be removed before instillation of the eye drops and not reinserted earlier than 15 minutes after use.