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XALACOM™ eye drops

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

XALACOM™ eye drops

COMPOSITION:
Each millilitre contains latanoprost 50 micrograms and timolol maleate equivalent to 5 mg timolol. Preservative: Benzalkonium chloride 0,02 % m/v.
One drop contains approximately 1,5 micrograms latanoprost and 150 micrograms timolol.

PHARMACOLOGICAL CLASSIFICATION:
A 15.4 Ophthalmic preparations: Other

PHARMACOLOGICAL ACTION:
Pharmacodynamic properties:
Mechanism of action:
Xalacom™ consists of two components: latanoprost and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of action.
Latanoprost, a prostaglandin F2alpha analogue, is a prostanoid selective prostaglandin F2 (FP) receptor agonist that reduces the IOP by increasing the outflow of aqueous humour.
The main mechanism of action is increased uveoscleral outflow. Additionally some increase in outflow activity (decrease in trabecular outflow resistance) has been reported in man.
Latanoprost has no significant effect on the production of aqueous humour, the blood-aqueous barrier or the intraocular blood circulation. 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. Timolol lowers IOP by decreasing aqueous humour formation in the ciliary epithelium. The precise mechanism of action has not been clearly established.
Pharmacodynamic effects:
Clinical effects:
Onset of action of Xalacom™ is within one hour, and maximal effect occurs within six to eight hours. IOP reducing effect has been shown to be present up to 24 hours post dosage after multiple treatments.
Pharmacokinetic properties:
Latanoprost:
Latanoprost is an isopropyl ester prodrug that 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 humour is hydrolysed during the passage through the cornea. Studies in man indicate that the maximum concentration in the aqueous humour, approximately 30 ng/mL, is reached about 2 hours after topical administration of latanoprost alone.
The acid of latanoprost has a plasma clearance of 0,4 L/h/kg and a small volume of distribution, 0,16 L/kg, resulting in a rapid half-life in plasma, of 17 minutes.
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 humour is reached about one 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 4 hours. Timolol is extensively metabolised in the liver. The metabolites are excreted in the urine together with some unchanged timolol.
Xalacom™
No pharmacokinetic interactions between latanoprost and timolol were observed, although there is a tendency for increased concentrations of the acid of latanoprost in aqueous humour 1 to 4 hours after administration of Xalacom™ compared to monotherapy.

INDICATIONS:
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.

CONTRA-INDICATIONS:
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.
Hypersensitivity to any component of this product.
The safety in pregnancy has not been established.
Xalacom should not be used in breast-feeding women, or breast-feeding should be stopped as timolol is excreted into breast milk and latanoprost and its metabolites may pass into breast milk.

WARNINGS:
Systemic effects
Cardiovascular/respiratory reactions:
Xalacom™ may be absorbed systemically.
Due to the beta-adrenergic component timolol, aggravation of Prinzmetal’s angina, aggravation of severe peripheral and central circulatory disorders, bradycardia and hypotension may occur.
Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure, have been reported following administration with timolol. Cardiac failure should be adequately controlled before treatment.
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 responsive to repeated challenge with such allergens, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.
Concomitant therapy:
Timolol may interact with other medicines. See “Side-effects, special precautions and interactions”.
The effect on intraocular pressure or the known effects of systemic beta-blockade may be exaggerated when Xalacom™ 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.
Additional effects of combination products, which contain a beta-blocker:
Xalacom™ should be administered with caution in patients subjected to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents. Xalacom™ may mask the signs and symptoms of acute hypoglycaemia.
Therapy with Xalacom™ may mask certain symptoms of hyperthyroidism and abrupt withdrawal of therapy may precipitate a worsening of symptoms.
Therapy with Xalacom™ may aggravate symptoms of myasthenia gravis.
Ocular effects:
Latanoprost may gradually change the eye colour by increasing the amount of brown pigment in the iris. This effect has predominantly been seen in patients with mixed colour irides, i.e. green-brown, yellow-brown or blue/grey/brown, and is due to the increased melanin content in the stromal melanocytes in the iris. Typically the brown pigmentation around the pupil spreads concentrically towards the periphery in the affected eyes, but the entire iris or parts of it may become more brownish.
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 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 or limited 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 little or no effect on the pupil, but there is no experience in acute attacks of closed angle glaucoma. Therefore it is recommended that Xalacom™ should not be used 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. Xalacom™ should be used with caution in these patients.
Choroidal detachment after filtration procedures has been reported with the administration of ocular hypotensive agents.
Use of contact lenses
Xalacom™ contains benzalkonium chloride which may be absorbed by contact lenses. The contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.
Children:
Safety and effectiveness in children has not been established. Xalacom™ is therefore not recommended for use in children.
Effects on the ability to drive and use machines:
In common with other eye preparations, instillation of eye drops may cause transient blurring of vision.
Benzalkonium chloride:
As the possibility of adverse effects on the corneal permeability and the danger of disruption of the corneal epithelium with prolonged or repeated usage of benzalkonium chloride-preserved ophthalmological preparations cannot be excluded, regular ophthalmological examination is required.
Caution should be exercised in the use of benzalkonium chloride-preserved topical medication over an extended period in patients with extensive ocular surface disease.

DOSAGE AND DIRECTIONS FOR USE:
The tamper evident overcap should be removed before use.
Recommended dosage for adults (including the elderly):
Recommended therapy is one drop in the affected eye(s) once daily.
If one dose is missed, treatment should continue with the next dose as planned.
Administration:
If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.

SIDE-EFFECTS, SPECIAL PRECAUTIONS AND INTERACTIONS:
The adverse events of Xalacom™ are similar to those reported earlier for latanoprost and timolol.
Based on evidence from consecutive photographs, increased iris pigmentation was seen in 16-20% of all patients who received Xalacom™ 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.
Additional adverse events that have been seen with one of the components and may occur with Xalacom^®:
Latanoprost:
Ocular: foreign body sensation, punctate epithelial erosions, macular oedema/cystoid macular oedema, iritis/uveitis, corneal oedema and erosions
Respiratory: asthma, asthma exacerbation and dyspnoea
Skin: darkening of the eyelid skin

Timolol:
Special senses: signs and symptoms of ocular irritation, keratitis, decreased corneal sensitivity, and dry eyes, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis, choroidal detachment (following filtration surgery), tinnitus
Cardiovascular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud’s phenomenon, cold hands and feet.
Respiratory: bronchospasm (predominantly in patients with pre-existing brochospastic disease), respiratory failure, dyspnoea, cough.
Body as a whole: asthenia, fatigue, chest pain.
Skin: alopecia, psoriasiform rash or exacerbation of psoriasis.
Hypersensitivity: symptoms of allergic reactions including angioedema, urticaria, localised and generalised rash.
Nervous system/psychiatric: dizziness, depression, insomnia, nightmares, memory loss, increase in signs and symptoms of myasthenia gravis, paraesthesia.
Urogenital: decreased libido, Peyronie’s disease.
Immunologic: systemic lupus erythematosus

Interaction with other medicinal products and forms of interaction:
Specific medicine interaction studies have not been performed with Xalacom^®.
The potential exists for additive effects resulting in hypotension and/or marked bradycardia when eye drops containing timolol are administered with calcium-channel blockers, catecholamine-depleting drugs or beta-blocking agents, antiarrhythmics (including amiodarone and quinidine), digitalis glycosides, parasympathomimetics, narcotics and monoamine oxidase (MAO) inhibitors.
Although Xalacom™ alone has little or no effect on pupil size, mydriasis has occasionally been reported when timolol is given with adrenaline.
Beta-blockers may increase the hypoglycaemic affect of anti-diabetic agents.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No data are available in humans in regard to overdosage with Xalacom^®.
Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic side effects are known if latanoprost is overdosed. Symptoms of systemic timolol overdosage are bradycardia, hypotension, bronchospasm and cardiac arrest.
If such symptoms occur, the treatment should be symptomatic and supportive. Studies have shown that timolol does not dialyse readily. If latanoprost is accidentally ingested, the following may be useful: 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.

IDENTIFICATION:
A clear and colourless solution, free of visible particles

PRESENTATION:
The drops are available in a 5 mL multidose, clear, colourless, low-density polyethylene bottle, with a clear, linear, low-density polyethylene dropper tip (applicator), protected with a yellow inner high-density polyethylene screw cap, and a clear, colourless tamper-evidentovercap of low-density polyethylene.
Each bottle contains 2,5 mL eye drop solution.

STORAGE INSTRUCTIONS:
Store in a refrigerator (2°C - 8°C) in the original carton. Once the bottle is opened the contents must be used within 30 days and may be stored at room temperature up to 25°C. After opening, the bottle must be stored in the carton to protect it from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
36/15.4/0043

APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George St
MIDRAND
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
20 NOVEMBER 2002

New addition to this site: February 2005
Source: Pharmaceutical Industry
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