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

Recommended dosage for adults (including the elderly): Recommended therapy is one eye drop in the affected eye(s) once daily. 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.

Administration: Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. Use in children and adolescents: Safety and effectiveness in children and adolescents has not been established.

It is contraindicated in patients with: - Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease. - Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock. - Hypersensitivity to the active substances or to any of the excipients

Systemic effects Like other topically applied ophthalmic agents, Latanocom may be absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur. In patients with cardiovascular diseases (e.g. coronary heart disease, sick sinus syndrome, peripheral circulatory disturbances - hypotension, Prinzmetal's Angina, cardiac failure) the 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. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in association with cardiac failures, have been reported following administration of timolol maleate. Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile insulin-dependant diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia. Beta-blockers may also mask the signs of hyperthyroidism. 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 unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions. Concomitant therapy Timolol may interact with other drugs, see 4.5 Interaction with other medicinal products and other forms of interaction. The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when Latanocom is given to patients already receiving an oral beta-blocking agent. The use of two local beta-blockers or two local prostaglandins is not recommended. Ocular effects Latanoprost may gradually change the eye colour by increasing the amount of brown pigment in the iris. Similar to experience with latanoprost eye drops, increased iris pigmentation was seen in 16-20% of all patients treated with Latanocom for up to one year (based on photographs). This effect has predominantly been seen in patients with mixed coloured irides, i.e. green-brown, yellow-brown or blue/grey-brown, and is due to increased melanin content in the stromal melanocytes of the iris. Typically the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. In patients with homogeneously blue, grey, green or brown eyes, the change has only rarely been seen during two years of treatment in clinical trials with latanoprost. The change in iris colour occurs slowly and may not be noticeable for several months to years and it has not been associated with any symptom or pathological changes. No further increase in brown iris pigment has been observed after discontinuation of treatment, but the resultant colour change may be permanent. Neither naevi nor freckles of the iris have been affected by treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed but patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation ensues. Before treatment is instituted patients should be informed of the possibility of a change in eye colour. Unilateral treatment can result in permanent heterochromia. There is no documented experience with latanoprost in inflammatory, neovascular, chronic angle closure or congenital glaucoma, in open angle glaucoma of pseudophakic patients and in pigmentary glaucoma. Latanoprost has no or little effect on the pupil but there is no documented experience in acute attacks of closed angle glaucoma. It is recommended, therefore, that Latanocom should be used with caution in these conditions until more experience is obtained. Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema. Latanocom should be used with caution in these patients. Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures. Use of contact lenses Latanocom contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and is known to discolour soft contact lenses. Close monitoring is required with frequent or prolonged use of Latanocom in dry eye patients, or in conditions where the cornea is compromised. Contact lenses may absorb benzalkonium chloride and these should be removed before applying Latanocom but may be reinserted after 15 minutes.

Specific medicinal product interaction studies have not been performed with Latanocom. 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. The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when Latanocom is given to patients already receiving an oral beta-adrenergic blocking agent, and
the use of two or more topical beta-adrenergic blocking agents is not recommended. Mydriasis has occasionally been reported when timolol was given with epinephrine. There is a potential for additive effects resulting in hypotension and/or marked bradycardia when eye drops with timolol are administered concomitantly with oral calcium channel blockers, guanethidine or beta-blocking agents, antiarrhythmics, digitalis glycosides or parasympathomimetics. The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-
blockers. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia

PREGNANCY Pregnancy Category-C
Latanoprost: There are no adequate data from the use of lantanoprost in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Timolol: There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. Epidemiological studies have not revealed malformative effects but show 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 Latanocom is administered until delivery, the neonate should be carefully monitored during the first days of life. Consequently Xalacom should not be used during pregnancy LACTATION Timolol is excreted into breast milk. Latanoprost and its metabolites may pass into breast milk. Latanocom should therefore not be used in women who are breast-feeding.

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

For latanoprost, the majority of adverse events relate to the ocular system. In data from the extension phase of the Latanocom pivotal trials, 16 - 20% of patients developed increased iris pigmentation, which may be permanent. In an open 5 year latanoprost safety study, 33% of patients developed iris pigmentation (see 4.4). Other ocular adverse events are generally transient and occur on dose administration. For timolol, the most serious adverse events are systemic in nature, including bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic reactions. Treatment related adverse events seen in clinical trials with Latanocom are listed below. Adverse events are categorized by frequency as follows: very common (1/10), common (1/100, <1/10), uncommon (1/1000, <1/100), rare (1/10,0000, <1/1000) and very rare (<1/10,000). Nervous System Disorders: Uncommon: Headache. Eye Disorders: Very common: Increased iris pigmentation. Common: Eye irritation (including stinging, burning and itching), Eye pain. Uncommon: Eye hyperaemia, Conjunctivitis, Vision blurred, Lacrimation increased, Blepharitis, Corneal disorders. Skin and Subcutaneous Tissue Disorders Uncommon: Skin rash, Pruritus. Additional adverse events have been reported specific to the use of the individual components of Xalacom in either in clinical studies, spontaneous reports or in the available literature. For latanoprost, these are: Infections and Infestations: Herpetic Keratitis Nervous System Disorders: Dizziness. Eye Disorders: Eyelash and vellus hair changes (increased length, thickness, pigmentation, and number), Punctate epithelial erosions, periorbital oedema, iritis/uveitis, macular oedema (in aphakic, pseudophakic patients with torn posterior lens capsules or in patients with known risk factors for macular oedema). dry eye, keratitis, corneal oedema and erosions, misdirected eyelashes sometimes resulting in eye irritation, iris cyst, photophobia, periorbital and lid changes resulting in deepening of the eyelid sulcus. Cardiac Disorders: Aggravation of angina in patients with pre-existing disease, Palpitations. Respiratory, Thoracic and Mediastinal Disorders: Asthma, asthma aggravation, dyspnoea, Skin and Subcutaneous Tissue Disorders: Darkening of palpebral skin. Musculoskeletal and Connective Tissue Disorders: Joint pain, muscle pain. General disorders and Administration Site Conditions: Chest pain For timolol, these are: 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 ischaemia, increase in signs and symptoms of myasthenia gravis, dizziness, paresthesia, 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 Ear and Labyrinth Disorders: Tinnitus. 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. Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm (predominately in patients with pre-existing bronchospastic disease), dyspnoea,
cough.
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. 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.
To report any side effect(s): - Saudi Arabia National Pharmacovigilance & Drug Safety Centre (NPC) • Fax: +966-11-205-7662 • Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. • Toll free phone: 8002490000 • E-mail: npc.drug@sfda.gov.sa • Website: www.sfda.gov.sa/npc

Not Available

Pharmacotherapeutic group: Ophthalmological-betablocking agents-timolol , combinations ATC code: S01ED51

Mechanism of action Latanocom consists of two components: latanoprost and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. Latanoprost, a prostaglandin F2alpha analogue, is a selective prostanoid FP receptor agonist that reduces the IOP by increasing the outflow of aqueous humor. The main mechanism of action is increased uveoscleral outflow. Additionally, some increase in outflow facility (decrease in trabecular outflow resistance) has been reported in man. Latanoprost has no significant effect on the production of aqueous humor, the blood-aqueous barrier or the intraocular blood circulation. Chronic treatment with latanoprost in monkey eyes, which had undergone extracapsular lens extraction, did not affect the retinal blood vessels as determined by fluorescein angiography. Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short-term treatment. Timolol is a beta-1 and beta-2 (non-selective) adrenergic receptor blocking agent that has no significant intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Timolol lowers IOP by decreasing the formation of aqueous in the ciliary epithelium. 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. Timolol has not been found to significantly affect the permeability of the blood-aqueous barrier to plasma proteins. In rabbits, timolol was without effect on the regional ocular blood flow after chronic treatment.

Pharmacodynamic effects Clinical effects In dose finding studies, Latanocom produced significantly greater decreases in mean diurnal IOP compared to latanoprost and timolol administered once daily as monotherapy. In two well controlled, double masked six-month clinical studies the IOP reducing effect of Latanocom was compared with latanoprost and timolol monotherapy in patients with an IOP of at least 25 mm Hg or greater. Following a 2-4 week run-in with timolol (mean decrease in IOP from enrollment of 5 mm Hg), additional decreases in mean diurnal IOP of 3.1, 2.0 and 0.6 mm Hg were observed after 6 months of treatment for Xalacom, latanoprost and timolol (twice daily), respectively. The IOP lowering effect of Latanocom was maintained in 6 month open label extensions of these studies. Existing data suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, when considering a recommendation of either morning or evening dosing, sufficient consideration should be given to the lifestyle of the patient and their likely compliance. It should be kept in mind that in case of insufficient efficacy of the fixed combination, results from studies indicate that the use of unfixed administration of Timolol bid and latanoprost once a day might be still efficient. Onset of action of Latanocom is within one hour and maximal effect occurs within six to eight hours. Adequate IOP reducing effect has been shown to be present up to 24 hours post dosage after multiple treatments

Latanoprost Latanoprost is an isopropyl ester prodrug, which per se is inactive, but after hydrolysis by esterases in the cornea to the acid of latanoprost, becomes biologically active. The prodrug is well absorbed through the cornea and all drug that enters the aqueous humor is hydrolyzed during the passage through the cornea. Studies in man indicate that the maximum concentration in the aqueous humor, approximately 15-30 ng/ml, is reached about 2 hours after topical administration of latanoprost alone. After topical application in monkeys latanoprost is distributed primarily in the anterior segment, the conjunctiva and the eyelids. The acid of latanoprost has a plasma clearance of 0.40 l/h/kg and a small volume of distribution, 0.16 l/kg, resulting in a rapid half life in plasma, 17 minutes. After topical ocular administration the systemic bioavailability of the acid of latanoprost is 45%. The acid of latanoprost has a plasma protein binding of 87%. There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The main metabolites, the 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine. Timolol The maximum concentration of timolol in the aqueous humor is reached about 1 hour after topical administration of eye drops. Part of the dose is absorbed systemically and a maximum plasma concentration of 1 ng/ml is reached 10-20 minutes after topical administration of one eye drop to each eye once daily (300 micrograms/day). The half life of timolol in plasma is about 6 hours. Timolol is extensively metabolised in the liver. The metabolites are excreted in the urine together with some unchanged timolol.

Latanocom No pharmacokinetic interactions between latanoprost and timolol were observed although there was an approximate 2-fold increased concentration of the acid of latanoprost in aqueous humor 1-4 hours after administration of Latanocom compared to monotherapy.

Not applicable as the subject product is a generic product

List of Excipients: Each ml of Latanocom Ophthalmic Solution contains the followings: Material Name Benzalkonium Chloride Polysorbate 80 Sodium Chloride Disodium Hydrogen Phosphate Dihydrate Sodium Dihydrogen Phosphate Monohydrate Hydrochloric Acid 1N or Sodium Hydroxide 1N Water for Injection

Excipients used in Latanocom Ophthalmic Solution are found in innovator product and assumed compatible with the drug substance.

24 months ( 2 years unopened )Use within 4 weeks of opening

Store the unopened bottle in a refrigerator (between 2 °C to 8 °C), protected from light. After opening the bottle it is not necessary to store the bottle in a refrigerator but do not store it above 30 °C

Immediate Container: Bormed LE6607-PH LD Polyethylene, white granules, free from visible evidence of contamination. Cap: HDPE (High-Density Polyethylene) Off white caps consisting of: Cylindrical section with vertical grooves and set-on collar with engraving, having spik on inner top of cap. Ring connected with cylindrical part by 8 connecting elements serving as tamper proof. age Outer carton: 280g/m2 grammage paper, dimension 30 mm x 29 mm x 73 mm. Label: 110 x 760 mm, self adhesive Insert/Leaflet: 50-60 g/m2 paper dimension 240 x 120 mm, both sides printed.

No special requirements.