Comarestol 50 µg/ 5 mg/ml Ophthalmic Solution

Reduction of intraocular pressure (IOP) in patients with open angle glaucoma and ocular hypertension who are not controlled on, or are intolerant to, monotherapy with compounds other than latanoprost and timolol.

Posology
The tamper evident overcap should be removed before use.
Use in adults (including the elderly)
One drop in the affected eye(s) once daily. The dosage of Comarestol should not exceed once daily since it has been shown that more frequent administration decreases the intra-ocular pressure lowering effect. If one dose is missed, treatment should continue with the next dose as planned.
Paediatric population:
Safety and effectiveness in children have not been established.
Method of administration
For ocular use only. If more than one topical ophthalmic medicine is being used, they should be administered at least 5 minutes apart.

Known hypersensitivity to latanoprost, timolol maleate, benzalkonium, or to any of the excipients of Comarestol listed in 6.1. Reactive airway disease including bronchial asthma or a history of bronchial asthma, chronic obstructive pulmonary disease. Sinus bradycardia, second or third degree atrioventricular block, cardiac failure, cardiogenic shock. Pregnancy and lactation (see section 4.6).

Systemic effects
Comarestol is absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking medicines may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. 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.
Cardiac disorders
In 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 the 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. Aggravation of Prinzmetalu2019s angina, hypotension, bradycardia, cardiac reactions, and rarely, death in association with cardiac failures have been reported following administration of timolol.
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, as aggravation of peripheral and central circulatory disorders may occur after topical application of timolol maleate as in Comarestol.
Respiratory disorders
Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. Comarestol 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.
Hypoglycaemia/diabetes
Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may increase the hypoglycaemic effect of medicines used to treat diabetes and may mask the signs and symptoms of acute hypoglycaemia. Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of therapy may precipitate a worsening of this condition.
Corneal diseases
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking medicines
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 medicine. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking medicines 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 doses 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. A gradual withdrawal of beta-adrenergic blocking medicines prior to major surgery should be considered. Beta-adrenergic blocking medicines impair the ability of the heart to respond to beta-adrenergically mediated reflex stimuli, which may augment the risk of general anaesthesia in surgical procedures. Protracted severe hypotension during anaesthesia and difficulty restarting and maintaining the heartbeat have been reported. During surgery, the effects of beta-adrenergic blocking medicines may be reversed by sufficient doses of adrenergic agonists.

No specific medicine interaction studies have been performed with Comarestol. There have been reports of paradoxical elevations in intraocular pressure following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended. 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, beta-adrenergic blocking medicines, anti-dysrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine. 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. The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when Comarestol is given to patients already receiving an oral beta-adrenergic blocking medicine, and the use of two or more topical beta-adrenergic blocking medicines is not recommended. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers. Beta-blockers may increase the hypoglycaemic effect of anti-diabetic medicines. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4). The concomitant use of Comarestol with hypoglycaemic medicines, phenothiazines and various anti-dysrhythmic medicines may have interactions with life-threatening consequences.

Pregnancy
Comarestol is contraindicated in pregnancy (see section 4.3).
Breastfeeding
Comarestol should not be used in breastfeeding women, or breastfeeding should be stopped as timolol is excreted into breast milk and latanoprost and its metabolites may pass into breast milk (see section 4.3).
Fertility
Neither Latanoprost nor timolol have been found to have any effect on male or female fertility in animal studies.

Instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

Summary of the safety profile
The adverse events of Comarestol are similar to those reported earlier for latanoprost and timolol (see section 4.4). Based on evidence from consecutive photographs, increased iris pigmentation was seen in 16 u2013 20 % of all patients who received latanoprost-timolol eye drops for up to one year. The most frequent findings of increased iris pigmentation were in patients with green-brown, yellow-brown and blue/grey/brown irides. In patients with homogenously blue, grey, green or brown eyes, the change was only rarely seen. Darkening, thickening and lengthening of the eye lashes has been reported. The most frequently reported undesirable effects in clinical trials were irritation of the eye, including stinging, burning and itching, eye hyperaemia, corneal disorders, conjunctivitis, blepharitis, eye pain, headache and skin rash.
Table 1: Adverse reactions associated with Latanoprost-Timolol preparations
System Organ Classification Frequency Undesirable effects
Infections and infestations Frequent Infection, sinusitis, upper respiratory tract infection
Metabolism and nutrition disorders Frequent Diabetes mellitus, hypercholesterolaemia
Psychiatric disorders Frequent Depression
Nervous system disorders Frequent Headache
Eye disorders Frequent Eye irritation (including stinging, burning, itching, foreign body sensation), eye pain, increased iris pigmentation, abnormal vision, cataract, conjunctival disorder, keratitis, photophobia, visual field defect, errors of refraction Less frequent Corneal disorders, conjunctivitis, blepharitis, eye hyperaemia, increased lacrimation
Vascular disorders Frequent Hypertension
Skin and subcutaneous tissue disorders Frequent Hypertrichosis, rash, skin disorder Less frequent Pruritus
Musculoskeletal and connective tissue disorders Frequent Arthritis
Table 2: Adverse reactions associated with Latanoprost
System Organ Classification Frequency Undesirable effects
Infections and infestations Frequency unknown Herpetic keratitis
Nervous system disorders Frequency unknown Dizziness
Eye disorders Frequent Eye irritation (burning, grittiness, itching, stinging and foreign body sensation), eyelid oedema, punctate keratitis Frequency unknown Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes); misdirected eyelashes sometimes resulting in eye irritation, periorbital oedema; iritis; uveitis; macular oedema including cystoid macular oedema dry eye; keratitis; corneal oedema; corneal erosion; trichiasis; iris cyst; photophobia; periorbital and lid changes resulting in deepening of the eyelid sulcus; eyelid oedema; localised skin reaction on the eyelids;
Table 3: Timolol Maleate (ocular administration)
System Organ Classification Frequency Undesirable effects
Immune system disorders Frequency unknown Systemic allergic reactions including anaphylactic reaction, angioedema, urticaria, localised and generalised rash, pruritus
Metabolism and nutrition disorders Frequency unknown Anorexia, masked symptoms of hypoglycaemia in diabetic patients
Psychiatric disorders Frequency unknown Behavioural changes and psychic disturbances including confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss, decreased libido, insomnia, nightmares, depression
Nervous system disorders Frequency unknown Cerebrovascular accident, cerebral ischaemia, dizziness, increases in signs and symptoms of myasthenia gravis, paraesthesia, headache, syncope
Eye disorders Frequency unknown Choroidal detachment following filtration surgery (see section 4.4), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, signs and symptoms of ocular irritation (e.g., burning, stinging, itching, tearing and redness), dry eyes, ptosis, blepharitis, blurred vision
Ear and labyrinth disorders Frequency unknown Tinnitus
Cardiac disorders Frequency unknown Cardiac arrest, atrioventricular block, congestive heart failure, chest pain, dysrhythmia, bradycardia, oedema, palpitations, worsening of angina pectoris
Vascular disorders Frequency unknown Cold hands and feet, hypotension, Raynaud's phenomenon, claudication
Respiratory, thoracic and mediastinal disorders Frequency unknown Bronchospasm (predominately in patients with pre-existing bronchospastic disease), cough, dyspnoea, nasal congestion, pulmonary oedema, respiratory failure
Gastrointestinal disorders Frequency unknown Abdominal pain, vomiting, diarrhoea, dry mouth, dysgeusia, dyspepsia, nausea, retroperitoneal fibrosis
Skin and subcutaneous tissue disorders Frequency unknown Skin rash, psoriasiform rash, exacerbation of psoriasis, alopecia
Musculoskeletal and connective tissue disorders Frequency unknown Myalgia, Systemic lupus erythematosus
Reproductive system and breast disorders Frequency unknown Sexual dysfunction, decreased libido, Peyronieu2019s disease
General disorders and administration site conditions Frequency unknown Asthenia, fatigue, chest pain, oedema
Cases of corneal calcification have been reported less frequent in association with the use of phosphate containing eyedrops in some patients with significantly damaged corneas.

No data are available in humans with regard to overdose with Comarestol. Symptoms
Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac arrest. Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic side effects are known if latanoprost is overdosed. In patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost such as contained in Comarestol when applied topically in the eyes in a dose seven times the clinical dose of latanoprost. There have been reports of inadvertent overdosage with latanoprost-timolol eye drops resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking medicines such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest.
Treatment
If symptoms of overdose occur the treatment should be symptomatic and supportive. If accidentally ingested orally the following information may be useful: Studies have shown that timolol does not dialyse readily. Latanoprost is extensively metabolised during the first pass through the liver. Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5,5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. These events were mild to moderate in severity and resolved without treatment, within 4 hours after terminating the infusion.