Consumer medicine information

Xalacom

Latanoprost; Timolol

BRAND INFORMATION

Brand name

Xalacom

Active ingredient

Latanoprost; Timolol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xalacom.

What is in this leaflet

This leaflet answers some common questions about Xalacom. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Xalacom against the benefits it is expected to have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Xalacom is used for

Xalacom is used to lower raised pressure in the eye and to treat glaucoma. Glaucoma is a condition in which the pressure of fluid in the eye may be high. However, some people with glaucoma may have normal eye pressure.

Glaucoma is usually caused by a build up of the fluid which flows through the eye. This build up occurs because the fluid drains out of your eye more slowly than it is being pumped in. Since new fluid continues to enter the eye, joining the fluid already there, the pressure continues to rise. This raised pressure may damage the back of the eye resulting in gradual loss of sight. Damage can progress so slowly that the person is not aware of this gradual loss of sight. Sometimes even normal eye pressure is associated with damage to the back of the eye.

There are usually no symptoms of glaucoma. If glaucoma is not treated it can lead to serious problems, including total blindness. In fact, untreated glaucoma is one of the most common causes of blindness.

Xalacom is made up of 2 active ingredients, latanoprost and timolol maleate. Latanoprost works by allowing more fluid to flow out from within your eye(s). Timolol maleate lowers the pressure in the eye by reducing the production of fluid.

Latanoprost belongs to a family of medicines called prostaglandin agonists. Timolol maleate belongs to a family of medicines called beta-blockers.

Although Xalacom helps control your glaucoma it does not cure it. So you must keep using it until your doctor tells you to stop.

Ask your doctor if you have any questions about why Xalacom has been prescribed for you. Your doctor may have prescribed it for another reason.

Xalacom is not recommended for use in children. The safety and effectiveness of Xalacom in children have not been established.

Before you use Xalacom

When you must not use it

Do not use Xalacom if:

  • you have an allergy to Xalacom or any of the ingredients listed at the end of this leaflet
    Symptoms of an allergic reaction may include:
    - asthma, wheezing or shortness of breath
    - swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
    - hives, itching or skin rash
    - fainting.
  • you have asthma, or a history of asthma, chronic obstructive lung disease (emphysema) or other breathing problems
  • you have certain heart conditions, such as a very slow heart rate, an irregular heartbeat, or heart failure
  • the bottle/packaging shows signs of tampering
  • the expiry date on the pack has passed.
    If you use this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start using Xalacom, talk to your doctor.

Before you start to use it

Tell your doctor if:

  1. you have had an allergy to any other medicines or any other substances, such as foods, preservatives or dyes
  2. you are pregnant or intend to become pregnant
There is no adequate experience with Xalacom in pregnant women, therefore, it should not be used during pregnancy.
  1. you are breast-feeding or intend to breast-feed
One of the active ingredients in Xalacom has been detected in breast milk. Because of the potential harm to the infant, nursing women should either stop using Xalacom or stop breast-feeding while using it.
  1. you have or have had any medical conditions, especially the following:
  • heart disease
  • lung disease
  • circulation problems
  • any other types of glaucoma or eye conditions
  • diabetes
  • myasthenia gravis
  • hyperthyroidism.

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell him or her before you use Xalacom.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Xalacom may interfere with each other. These include:

  • certain medicines used to treat high blood pressure or heart conditions such as beta-blockers, calcium channel blockers or digoxin
  • certain medicines used to treat irregular heartbeats such as amiodarone and quinidine
  • some medicines used to treat depression, such as phenelzine, fluoxetine or paroxetine
  • some medicines used to treat Parkinson's disease, such as selegiline
  • adrenaline, a hormone used in the treatment of asthma, slow or irregular heartbeat, acute allergic disorders and glaucoma
  • some medicines that may have been prescribed to help you pass urine or restore normal bowel movements
  • narcotics such as morphine used to treat moderate to severe pain
  • eye drops which contain an ingredient called thiomersal. If using such eye drops as well as Xalacom, you should wait at least 5 minutes between using these eye drops and Xalacom
  • medicines used to treat diabetes or high blood sugar
  • some other eye drops that contain a beta-blocker or a prostaglandin. The use of two or more beta-blocker eye drops and/or two or more prostaglandin eye drops at the same time is not recommended.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while using Xalacom.

How to use Xalacom

Use Xalacom only when prescribed by your doctor.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you are being changed from one eye drop to another, follow your doctor's instructions carefully as to when to stop the old drops and when to start the new drops.

How much to use

The usual dose of Xalacom is one drop into the affected eye, or eyes, once daily.

Use Xalacom every day, at about the same time each day, unless your doctor tells you otherwise. Using your eye drops at the same time each day will have the best effect on your eye pressure. It will also help you remember when to use the eye drops.

How to use it

If you are wearing soft contact lenses, remove them before putting the drops in your eye. The preservative in Xalacom (benzalkonium chloride) may be deposited in soft contact lenses. You can put your soft contact lenses back into your eyes 15 minutes after you have used Xalacom.

If using other eye drops in addition to Xalacom, wait at least 5 minutes before putting any other drops in your eye(s).

Be careful not to touch the dropper tip against your eye, eyelid or anything else. Touching the dropper tip against something may contaminate the eye drops and give you an eye infection.

You may find it easier to put drops in your eye while you are sitting or lying down.

  1. Wash your hands well with soap and water.
  2. Twist off the protective overcap from the bottle.
  3. Unscrew the inner cap.
  4. Use your finger to gently pull down the lower eyelid of your affected eye.
  5. Tilt your head back and look up.
  6. Place the tip of the bottle close to but not touching your eye. Squeeze the bottle gently so that only one drop goes into your eye, then release the lower eyelid. Close your eye. Do not blink or rub your eye.
  7. While your eye is closed, place your index finger against the inside corner of your eye and press against your nose for about two minutes. This will help to stop the medicine from draining through the tear duct to the nose and throat, from where it can be absorbed into other parts of your body. Ask your doctor for more specific instructions on this technique.
  8. Screw the inner cap back on the bottle.
  9. Wash your hands again with soap and water to remove any residue.

You may feel a slight burning sensation in the eye shortly after using the eye drops.

If this persists, or is very uncomfortable, contact your doctor or pharmacist.

How long to use it

Continue using Xalacom every day for as long as your doctor prescribes. Xalacom helps control your condition but does not cure it.

If you forget to use it

If you miss a dose, skip the dose you missed and use your next dose when you are meant to. If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not use double the amount to make up for the dose that you missed.

If you use too much (overdose)

If you accidentally put several drops in your eye(s), immediately rinse your eye(s) with warm water.

If you think that you or anyone else may have swallowed Xalacom, immediately telephone your doctor or the Australian Poisons Information Centre (telephone 131 126) for advice, or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

If Xalacom is accidentally swallowed, or if you use too many drops, you may feel light-headed or dizzy, you may faint, have a very slow pulse rate, or have wheezing or difficulty breathing. Other effects include headache, nausea, abdominal pain, fatigue, hot flushes and sweating.

While you are using Xalacom

Things you must do

To make sure Xalacom is working properly, have your eye pressure checked regularly. Have your eyes checked regularly for any other changes, including a change in eye colour. A slow change in eye colour, which may be permanent, has been reported to occur in some patients who use Xalacom. Your doctor will decide whether you should continue using Xalacom.

If you develop an eye infection, receive an eye injury, or have eye surgery tell your doctor. Your doctor may tell you to use a new container of Xalacom because of possible contamination of the old one, or may advise you to stop your treatment with Xalacom.

If you become pregnant while using Xalacom tell your doctor immediately.

If you are about to be started on any new medicine tell your doctor and pharmacist that you are using Xalacom.

Tell all doctors and pharmacists who are treating you that you are using Xalacom.

Things you must not do

Do not give Xalacom to anyone else, even if they have the same condition as you.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not stop using Xalacom without first talking to your doctor. If you stop using your eye drops, your eye pressures may rise again and damage to your eye may occur.

Things to be careful of

Be careful driving or operating machinery until you know how Xalacom affects you. Xalacom generally does not cause any problems with your ability to drive a car or operate machinery. However, it may cause blurred vision in some people. Make sure you know how you react to Xalacom or that your vision is clear before driving a car or operating machinery.

Side effects

Check with your doctor as soon as possible if you have any problems while using Xalacom, even if you do not think the problems are connected with the medicine or are not listed in this leaflet. Like other medicines, Xalacom can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • a slow change in eye colour over a period of time. The iris may become browner in colour and appear darker. This change may be permanent and more noticeable if you are only being treated in one eye
  • blurred vision, double vision or other visual problems
  • allergic reactions including redness, swelling and/or itching of the eye
  • burning, grittiness or stinging of the eyes
  • eye pain
  • redness or watering of the eye/s
  • irritation or feeling of having something in the eye, dry eyes
  • discharge, itching of the eye/s, crusty eyelashes
  • drooping of eyelid/s
  • darkening, thickening, lengthening or an increase in the number of eye lashes and fine hair on the eyelids
  • misdirected eye lashes sometimes causing eye irritation
  • darkening of the skin of the eyelids
  • crusting, redness, thickening, itching or burning of the eyelids
  • sensitivity to light
  • headache
  • tiredness, weakness
  • sleepiness
  • ringing or buzzing in the ears
  • difficulty sleeping, nightmares
  • change in mood such as depression, anxiety or nervousness
  • confusion, disorientation or memory loss
  • hallucinations
  • feeling sick (nausea) or vomiting, upset or painful stomach
  • diarrhoea
  • anorexia
  • dry mouth
  • change to your sense of taste
  • cold hands or feet
  • numbness, tingling and colour change (white, blue then red) in fingers when exposed to the cold (Raynaud's Phenomenon)
  • numbness or tingling in the fingers or toes
  • cough
  • nasal congestion
  • hair loss or thinning
  • less desire for sex
  • impotence or sexual dysfunction
  • muscle/joint pain
  • skin rash.

Tell your doctor immediately if you notice any of the following:

  • fast or irregular heartbeat, also called palpitations
  • dizziness and light-headedness, which may be due to low blood pressure
  • skin rash, itching
  • swelling of hands, feet, ankles or legs.

These may be serious side effects. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop using Xalacom and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • wheezing, difficulty in breathing (asthma or worsening of asthma)
  • shortness of breath
  • very slow pulse, chest pain
  • fainting
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettle rash
  • white deposits or plaque in the cornea causing the transparent front part of your eye to look white or cloudy.

These are very serious side effects. You may need urgent medical attention. These side effects are rare.

Tell your doctor if you notice any other effects. Other side effects not listed above may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using Xalacom

Storage

Keep your eye drops in a safe place away from the sight and reach of children. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Before opening Xalacom, keep the bottle in its box in a refrigerator (2°C - 8°C) protected from light.

After opening Xalacom, keep the bottle in its box in a cool place where the temperature stays below 25°C. You do not need to keep it refrigerated. Keep the box properly closed and protected from light.

Do not store Xalacom or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Do not carry the eye drops in pockets of your clothes. Heat and dampness can destroy some medicines.

Put the top back on the bottle right away after use to avoid contaminating the eye drops.

Disposal

Write the date on the bottle when you open the eye drops and throw out any remaining solution after four weeks.

Open a new bottle every 4 weeks. Eye drops contain a preservative which helps prevent germs growing in the solution for the first four weeks after opening the bottle. After this time there is a greater risk that the drops may become contaminated and cause an eye infection.

If your doctor tells you to stop using the eye drops or they have passed their expiry date, ask your pharmacist what to do with any remaining solution.

Product description

What it looks like

Xalacom eye drops come in a plastic bottle with a dropper and screw cap inside a protective overcap. Remove this overcap before use.

When you first receive your Xalacom bottle, it will appear half full. This corresponds to 2.5 mL of eye drop solution, giving a minimum of 80 drops. This volume is enough to last 4 weeks if used in both eyes.

Ingredients

The active ingredients in Xalacom eye drops are latanoprost and timolol maleate. Each 1 mL of Xalacom contains 50 micrograms of latanoprost and 5 mg of timolol (equivalent to 6.83 mg timolol maleate). Each drop contains about 1.5 micrograms of latanoprost and 150 micrograms of timolol.

Xalacom eye drops also contain:

  • sodium chloride
  • monobasic sodium phosphate monohydrate
  • dibasic sodium phosphate
  • water for injections
  • hydrochloric acid
  • sodium hydroxide
  • benzalkonium chloride (as a preservative).

Identification

Xalacom can be identified by the Australian Register Number AUST R 80311, which is found on the box.

Supplier

Xalacom is supplied in Australia by:

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia
http://www.aspenpharma.com.au

For more information about glaucoma, contact Glaucoma Australia Inc. (telephone 1800 500 880).

This leaflet was revised in March 2021.

Trademarks are owned by or licensed to the Aspen group of companies.

© 2021 Aspen Group of companies or its licensor. All rights reserved.

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Xalacom

Active ingredient

Latanoprost; Timolol

Schedule

S4

 

1 Name of Medicine

Latanoprost and timolol maleate.

2 Qualitative and Quantitative Composition

Xalacom is a combination eye drop containing latanoprost and timolol maleate.
Latanoprost is a prostaglandin F2α analogue.
Xalacom is a sterile, isotonic solution containing 50 microgram/mL of latanoprost and 5 mg/mL of timolol (6.83 mg timolol maleate) in an aqueous buffer solution of pH 6.0.
Each 5 mL bottle contains 2.5 mL eye drop solution corresponding to a minimum of 80 drops of solution. One drop contains approximately 1.5 microgram latanoprost and 150 microgram timolol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Eye drops, solution.
The solution is a clear and colourless liquid, filled in a polyethylene container.

4 Clinical Particulars

4.1 Therapeutic Indications

Reduction of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension who are insufficiently responsive to beta-blockers, prostaglandins or other intraocular pressure lowering medications. Xalacom should not be used to initiate therapy.

4.2 Dose and Method of Administration

Dosage.

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 normal.
The use of Xalacom may be considered in patients who require both timolol and latanoprost, but it is unknown whether patients who are adequately controlled with timolol given twice daily plus latanoprost given once daily will be as well controlled with Xalacom given once daily. Xalacom should not be used to initiate therapy.
Xalacom should not be given more than once daily because latanoprost is most effective at this dosage. If there is inadequate response to Xalacom, consideration should be given to using the individual agents with timolol dose twice daily.

Method of administration.

If more than one topical ophthalmic drug is being used, the eye drop products should be administered at least 5 minutes apart.
Systemic absorption can be minimised by pressure on the tear duct immediately after application of the eye drop.

Use with contact lenses.

The contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Xalacom is contraindicated in patients with:
reactive airway disease including bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease;
sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block, overt cardiac failure, or cardiogenic shock;
known hypersensitivity to latanoprost, timolol maleate or any of the excipients in Xalacom.

4.4 Special Warnings and Precautions for Use

Systemic effects.

Cardiovascular/ respiratory reactions.

Like other topically applied ophthalmic agents, Xalacom may be absorbed systemically. Due to the beta-adrenergic component timolol, the same types of adverse reactions seen with systemic beta-blockers may occur including aggravation of Prinzmetal's angina, aggravation of severe peripheral and central circulatory disorders, bradycardia and hypotension.
Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and death associated with cardiac failure have been reported following administration of timolol. Cardiac failure should be adequately controlled before treatment. Patients with a history of severe cardiac disease should be monitored closely for signs of cardiac failure.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Patients with severe peripheral circulatory disturbance/ disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Timolol maleate 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.
A gradual withdrawal of beta-adrenergic blocking agents prior to major surgery may be considered. Beta-adrenergic blocking agents 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 agents may be reversed by sufficient doses of adrenergic agonists.
Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthetist should be informed when the patient is receiving timolol.

Hypersensitivity 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, 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 drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of 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. There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more local beta-blockers or two or more local prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended.

Hypoglycaemia.

Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents. Beta-blockers may increase the hypoglycaemic effect of agents used to treat diabetes and may mask the signs and symptoms of acute hypoglycaemia.

Hyperthyroidism.

Therapy with beta-blockers may mask certain signs and symptoms of hyperthyroidism and abrupt withdrawal of therapy may precipitate a worsening of symptoms.

Myasthenia gravis.

Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.

Ocular effects.

Iris pigmentation changes.

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 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 homogenously 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.

Eyelid and eyelash changes.

Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost.
Latanoprost may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation and number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Glaucoma.

There is no or limited experience with latanoprost or latanoprost/ timolol 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 experience in acute attacks of closed angle glaucoma. Therefore it is recommended that Xalacom should be used with caution in these conditions until more experience is obtained.

Herpetic keratitis.

Latanoprost should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Macular oedema.

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 and corneal disease.

Choroidal detachment after filtration procedures has been reported with the administration of ocular hypotensive agents.
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

Use of contact lenses.

Xalacom contains benzalkonium chloride which may be absorbed by contact lenses. Several contact lens soaking solutions contain thiomersal which may also form a precipitate with the benzalkonium chloride (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Therefore contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.

Use in the elderly.

No data available.

Paediatric use.

Xalacom is not recommended for use in children. Safety and effectiveness in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No specific interaction studies have been performed with Xalacom.
The potential exists for additive effects resulting in hypotension, and/or marked bradycardia when timolol ophthalmic drops are administered with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone and quinidine), digitalis glycosides, parasympathomimetics, narcotics and monoamine oxidase (MAO) inhibitors.
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.
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 effect of antidiabetic agents (see Section 4.4 Special Warnings and Precautions for Use, Hypoglycaemia).
In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with benzalkonium chloride, the preservative used in Xalacom. If such drugs are used they should be administered with an interval of at least five (5) minutes between applications. Similarly, several contact lens soaking solutions contain thiomersal (see Section 4.4 Special Warnings and Precautions for Use, Use of contact lenses).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies with Xalacom have not been conducted. Latanoprost or timolol maleate alone had no effects on male or female fertility in rats when administered at 250 microgram/kg/day IV or 300 mg/kg/day PO respectively.
(Category C)
Embryofetal development studies with latanoprost have been performed in rats and rabbits. Latanoprost and/or its metabolites cross the placenta of rats. In rabbits, latanoprost caused embryofetal toxicity characterised by increased incidences of late resorption and reduced fetal weight at 5 microgram/kg/day IV and total litter resorption at ≥ 50 microgram/kg/day IV. No embryofetal effects were seen in rabbits at 1 microgram/kg/day IV and in rats at up to 250 microgram/kg/day IV.
Timolol maleate was not teratogenic in mice, rats and rabbits. Embryofetal development studies with timolol maleate in mice and rabbits showed no evidence of embryofetal toxicity at oral doses up to 50 mg/kg/day. At higher doses, increases in resorptions and fetal variations (14 ribs and hypoplastic sternebrae) were noted in mice (1000 mg/kg/day) and increased resorption in rabbits (≥ 90 mg/kg/day). In rats, delayed ossification was seen at ≥ 50 mg/kg/day and a decreased number of caudal vertebral bodies and arches and an increase in hypoplastic sternebrae were noted at 500 mg/kg/day.
There are no adequate and well-controlled studies in pregnant women. Therefore, Xalacom should not be used during pregnancy.
 There are limited experimental animal and no human data available on the pharmacokinetics of latanoprost in lactation. Latanoprost and its metabolites may pass into breast milk.
Timolol maleate has been detected in human milk following oral and ocular administration. Because of the potential for serious adverse reactions from Xalacom in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

In common with other eye preparations, instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

No adverse events specific for Xalacom have been observed in clinical studies. The adverse events have been limited to those earlier reported for latanoprost and timolol.

Adverse events from clinical trials.

Adverse events occurring at a frequency of ≥ 1% in three randomised, double blind comparative trials (004, 005 and 053) are presented in Tables 1 and 2.
The following additional adverse events have been reported with the single component latanoprost.

Eye disorder.

Eye irritation (burning, grittiness, itching, stinging, tearing, redness and foreign body sensation), punctate keratitis, macular oedema, corneal oedema, corneal erosions, eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes), trichiasis, blurred vision, periorbital and lid changes resulting in deepening of the eyelid sulcus, darkening of the palpebral skin of the eyelids, localised skin reaction on the eyelids.

Respiratory, thoracic and mediastinal disorders.

Asthma, asthma aggravation and acute asthma attacks.

Skin and subcutaneous tissue disorders.

Rash.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia.

General disorders and administration site conditions.

Chest pain.

Infections and infestations.

Herpetic keratitis.
The following additional adverse events have been reported with the single component timolol by ocular administration.

Eye disorders.

Visual disturbances including refractive changes, hypoaesthesia eye, signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), vision blurred, dry eyes, corneal erosion, diplopia, ptosis, choroidal detachment (following filtration surgery).

Ear and labyrinth disorders.

Tinnitus.

Cardiac disorders.

Bradycardia, arrhythmia, atrioventricular block, hypotension, heart block, congestive heart failure, palpitation, cardiac arrest, cardiac failure, worsening of angina pectoris.

Vascular disorders.

Claudication, cold hands and feet, hypotension, Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders.

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, pulmonary oedema and nasal congestion.

General disorders and administration site conditions.

Asthenia, fatigue, oedema.

Skin and subcutaneous tissue disorders.

Alopecia, pseudopemphigoid, psoriasiform rash or exacerbation of psoriasis.

Immune system disorders.

Signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, pruritus, localised and generalised rash.

Nervous system disorders.

Cerebral vascular accident, cerebral ischaemia, increase in signs and symptoms of myasthenia gravis, paraesthesia, somnolence, headache, syncope.

Psychiatric disorders.

Nightmares, behavioural changes and psychic disturbances including confusion, hallucinations, anxiety, disorientation, nervousness and memory loss.

Gastrointestinal disorders.

Nausea, diarrhoea, dry mouth, dysgeusia, vomiting, abdominal pain, retroperitoneal fibrosis.

Metabolism and nutrition disorders.

Anorexia, masked symptoms of hypoglycaemia in diabetic patients.

Musculoskeletal and connective tissue disorders.

Myalgia, systemic lupus erythematosus.

Reproductive system and breast disorders.

Decreased libido, Peyronie's disease, sexual dysfunction, impotence.

Post-marketing experience.

The following additional adverse drug reactions have been observed post-marketing with the single component latanoprost and may also relevant for the latanoprost and timolol combination.

Eye disorders.

Iris cyst, pseudopemphigoid of the ocular conjunctiva.

Cardiac disorders.

Unstable angina, angina, palpitations.

Gastrointestinal disorders.

Nausea, vomiting.

Skin and subcutaneous tissue disorders.

Pruritus.
Adverse reactions reported with the use of eye drops containing phosphate buffers.
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 suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

There is no human data available on overdosage with Xalacom.
There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, hypotension, bronchospasm, and cardiac arrest. Apart from ocular irritation and conjunctival or episcleral hyperaemia, the ocular effects of latanoprost administered at high doses are not known.

Treatment.

If overdosage with Xalacom occurs, treatment should be symptomatic and supportive. Studies have shown that timolol is not readily dialyzable. If Xalacom is accidentally ingested the following information may be useful. One bottle contains 125 microgram latanoprost and 12.5 mg timolol. Both timolol and latanoprost are extensively metabolised in the liver. More than 90% of latanoprost is metabolised during the first pass through the liver. Intravenous infusion of up to 3 microgram/kg in healthy volunteers induced no symptoms but a dose of 5.5-10 microgram/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. In patients with bronchial asthma, bronchoconstriction was not induced by latanoprost when applied topically on the eyes in a dose of seven times the clinical dose of latanoprost.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 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 and the combined effect results in additional IOP reduction compared to either compound administered alone.

Latanoprost.

Latanoprost is a selective prostanoid F2α-receptor agonist which reduces IOP by increasing the outflow of aqueous humour. The main mechanism of action is increased uveoscleral outflow. In addition, 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 humour or the blood-aqueous barrier. Latanoprost has no or negligible effects on the intraocular blood circulation when used at the human clinical dose, as studied in monkeys. However, mild to moderate conjunctival or episcleral hyperaemia may occur during topical treatment.
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. Latanoprost in clinical doses has not been found to have any significant pharmacologic effects on the cardiovascular or respiratory systems.

Timolol.

Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by decreasing the formation of aqueous humour in the ciliary epithelium. The precise mechanism of action is not clearly established.

Xalacom.

Onset of action of Xalacom 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.

Clinical trials.

Two 6-month, randomised, double-blind, multicentre clinical studies were conducted to compare the IOP-lowering effect of Xalacom dosed once daily to latanoprost 0.005% dosed once daily and timolol 0.5% dosed twice daily.
The inclusion criteria for patients in both studies consisted of adults with diagnoses of primary open angle glaucoma, pigmentary glaucoma, capsular glaucoma or ocular hypertension. Patients previously on IOP reducing therapy required an IOP at enrolment of ≥ 25 mmHg. Patients not previously on IOP reducing therapy required an IOP of ≥ 30 mmHg on enrolment. In the two studies, 92% and 84% of patients were reported to have been on IOP reducing therapy within 3 months prior to study start. Approximately 70% of these patients were on timolol therapy.
The mean diurnal IOP-lowering effect of Xalacom was greater (1 to 3 mmHg) than that produced by monotherapy with either latanoprost 0.005% or timolol 0.5%. However, there are no data to show the optimal dose of these agents in combination.
Open label extensions of the 2 studies mentioned above were conducted for up to an additional 6 months. The IOP lowering effect of Xalacom was maintained during this period.

5.2 Pharmacokinetic Properties

Latanoprost.

Absorption.

Latanoprost is an isopropyl ester pro drug which is inactive, but after hydrolysis by esterases in the cornea to the acid of latanoprost, becomes biologically active.
The pro drug is well absorbed through the cornea and all the drug that enters the aqueous humour is hydrolysed during the passage through the cornea.

Distribution.

Studies in man indicate that the peak concentration in the aqueous humour, approximately 30 nanogram/mL, is reached about two hours after topical administration of latanoprost alone. After topical application in monkeys latanoprost is distributed primarily in the anterior segment, the conjunctivae and the eye lids. Only minute quantities of the drug reach the posterior segment.
Reduction of the intraocular pressure in man starts about three to four hours after administration of latanoprost alone and maximum effect is reached after 8 to 12 hours. Pressure reduction is maintained for at least 24 hours.
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%.

Metabolism and excretion.

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 1 hour after topical administration of eye drops. Part of the dose is absorbed systemically and a maximum plasma concentration of 1 nanogram/mL is reached 10-20 minutes after topical administration of one eye drop to each eye once daily (300 microgram/day). The half life of timolol in plasma is about 6 hours. Timolol is extensively metabolised in the liver. The metabolites are excreted in urine together with some unchanged timolol.

Xalacom.

No pharmacokinetic interactions between latanoprost and timolol have been observed although the aqueous humour concentrations of the acid of latanoprost tended to be higher 1 to 4 hours after administration of the combination product compared to monotherapy with either agent.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity studies with Xalacom have not been conducted.
Latanoprost was not mutagenic in gene mutation assays in bacteria and mouse lymphoma L5178Y cells and was negative in studies of unscheduled DNA synthesis. Chromosome aberrations were observed with human lymphocytes in vitro but latanoprost did not induce micronucleus formation in vivo.
In vitro and in vivo studies with timolol maleate did not reveal a mutagenic potential.

Carcinogenicity.

Carcinogenicity studies with Xalacom have not been conducted.
Latanoprost was not carcinogenic in either rats or mice when administered by oral gavage at doses up to 170 microgram/kg/day for 24 and 20 months respectively.
No evidence of carcinogenicity was observed with timolol maleate at oral doses up to 100 mg/kg/day in rats and 50 mg/kg/day in mice. However, there was a statistically significant increase in the incidence of adrenal phaeochromocytomas in male rats administered 300 mg/kg/day. In female mice, statistically significant increases in the incidence of benign and malignant pulmonary tumours, benign uterine polyps and mammary carcinomas were found at 500 mg/kg/day. The increased incidence of mammary tumours was considered to be attributed to a species specific elevation in serum prolactin.

Animal toxicity.

No adverse ocular or systemic effects were seen in rabbits treated topically with fixed combinations of latanoprost and timolol maleate for up to 52 weeks or with concomitantly administered latanoprost and timolol ophthalmic solutions for 4 weeks.
In long-term ocular toxicity studies in monkeys, latanoprost has been shown to induce increased iris pigmentation. The pigmentation did not progress upon discontinuation of treatment. The results from pre-clinical studies have demonstrated that the primary mechanism of increased pigmentation is stimulation of melanin production in melanocytes of the iris stroma. There is no evidence of melanocyte proliferation.
Long-term ocular administration of latanoprost at a dose of 6 microgram/eye/day (4 times the daily human dose) to cynomolgus monkeys has also been shown to induce an increase or widening in the palpebral fissure. This effect was reversible upon discontinuation of the drug.
Timolol maleate did not produce any adverse ocular effects in rabbits and dogs, when administered as multiple daily topical doses for up to 52 and 104 weeks, respectively.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate, hydrochloric acid, sodium hydroxide, water for injections, benzalkonium chloride (0.20 mg/mL) (as a preservative agent).

6.2 Incompatibilities

In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with benzalkonium chloride, the preservative used in Xalacom. If such drugs are used they should be administered with an interval of at least five (5) minutes between applications. Similarly several contact lens soaking solutions contain thiomersal.
Xalacom contains benzalkonium chloride which may be absorbed by contact lenses. Several contact lens soaking solutions contain thiomersal which may also form a precipitate with the benzalkonium chloride. Therefore contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store unopened bottle at 2°C to 8°C. Refrigerate. Do not freeze.
Store opened bottle below 25°C. Store in the outer cardboard carton. To be used within 4 weeks after opening.
Protect from light.

6.5 Nature and Contents of Container

Xalacom is supplied in packs of 1 x 2.5 mL and 3 x 2.5 mL*** filled in a polyethylene container.
*** Pack size not available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Latanoprost.

It has a molecular weight of 432.58. It is a colourless to slightly yellow oil which is practically insoluble in water, freely soluble in ethanol, ethyl acetate, isopropanol, methanol, acetone and octanol, and very soluble in acetonitrile.
Sixty four isomers of latanoprost are possible however, for Xalacom it is purified as a single isomer.

Chemical structure.

The chemical name of latanoprost is isopropyl-(Z)-7[(1R,2R,3R,5S) 3,5-dihydroxy-2-[(3R)-3- hydroxy-5-phenyl-1-pentyl]cyclopentyl]-5-heptenoate, according to IUPAC. Its molecular formula is C26H40O5.
The chemical structure is as follows:

CAS number.

130209-82-4.

Timolol maleate.

Timolol maleate is a beta-adrenergic receptor blocking agent. It has a molecular weight of 432.50. It is a white to off-white crystalline powder which is soluble in water, alcohol and practically insoluble in ether.

Chemical structure.

The chemical name of timolol maleate is (S)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Its molecular formula is C13H24N4O3S.C4H4O4.
The chemical structure is as follows:

CAS number.

26921-17-5.

7 Medicine Schedule (Poisons Standard)

S4, Prescription Only Medicine.

Summary Table of Changes