Consumer medicine information

Xalamol 50/5

Latanoprost; Timolol

BRAND INFORMATION

Brand name

Xalamol 50/5

Active ingredient

Latanoprost; Timolol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xalamol 50/5.

What is in this leaflet

This leaflet answers some common questions about XALAMOL 50/5. 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 XALAMOL 50/5 against the benefits they expect it will 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 XALAMOL 50/5 is used for

XALAMOL 50/5 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 buildup 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.

XALAMOL 50/5 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 XALAMOL 50/5 helps control your glaucoma it does not cure it. You must keep using it until your doctor tells you to stop.

Ask your doctor if you have any questions about why XALAMOL 50/5 has been prescribed for you. Your doctor may have prescribed it for another reason.

XALAMOL 50/5 is not recommended for use in children.

The safety and effectiveness of XALAMOL 50/5 in children has not been established.

Before you use XALAMOL 50/5

When you must not use it

Do not use XALAMOL 50/5 if you have an allergy to:

  • any medicine containing latanoprost or timolol maleate
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • add any other specific reactions listed in the PI.

Do not use XALAMOL 50/5 if you have:

  • asthma, or a history of asthma, chronic obstructive lung disease (emphysema) or other breathing problems
  • certain heart conditions, such as a very slow heart rate, an irregular heartbeat, or heart failure

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • heart disease
  • lung disease
  • circulation problems
  • any other types of glaucoma or eye conditions
  • diabetes
  • myasthenia gravis
  • hyperthyroidism

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. There is no adequate experience with XALAMOL 50/5 in pregnant women therefore, it should not be used during pregnancy.

One of the active ingredients in XALAMOL 50/5 has been detected in breast milk. Because of the potential harm to the infant, breastfeeding women should either stop using XALAMOL 50/5 or stop breastfeeding while using it.

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you start using XALAMOL 50/5.

Taking other medicines

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

Some medicines and XALAMOL 50/5 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 (epinephrine), 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 XALAMOL 50/5, you should wait at least 5 minutes between using these eye drops and XALAMOL 50/5
  • 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

These medicines may be affected by XALAMOL 50/5 or may affect how well it works. You may need different amounts of your medicines, or you may need to use different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use XALAMOL 50/5

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

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

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 XALAMOL 50/5 is one drop into the affected eye, or eyes, once daily.

How to use it

If you are wearing soft contact lenses, remove them before putting the drops in your eye. The preservative in XALAMOL 50/5 (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 XALAMOL 50/5.

If using other eye drops in addition to XALAMOL 50/5, 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.

When to use it

Use your medicine at about the same time each day. Using it at the same time each day will have the best effect on your eye pressure. It will also help you remember when to use it.

How long to use it

Continue using your medicine for as long as your doctor tells you.

This medicine helps to 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.

Otherwise, use it as soon as you remember, and then go back to using your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

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 XALAMOL 50/5, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much XALAMOL 50/5. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If XALAMOL 50/5 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 XALAMOL 50/5

Things you must do

To make sure XALAMOL 50/5 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 XALAMOL 50/5. Your doctor will decide whether you should continue using XALAMOL 50/5.

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 XALAMOL 50/5 because of possible contamination of the old one, or may advise you to stop your treatment with XALAMOL 50/5.

If you become pregnant while using this medicine, tell your doctor immediately.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using XALAMOL 50/5.

Tell any other doctors, dentists and pharmacists who treat you that you are use this medicine.

Things you must not do

Do not use XALAMOL 50/5 to treat any other complaints unless your doctor tells you to.

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

Do not stop using your medicine or lower the dosage without checking with your doctor. If you stop using it suddenly, your eye pressure 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 XALAMOL 50/5 affects you. This medicine does not generally 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 XALAMOL 50/5 or that your vision is clear before driving a car or operating machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using XALAMOL 50/5.

This medicine helps most people with glaucoma, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist 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 (loss of appetite)
  • 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

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, 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.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After using XALAMOL 50/5

Storage

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

After opening your medicine, keep the bottle in its box in a in a cool dry place where the temperature stays below 25°C. Do not refrigerate. Keep the box properly closed and protected from light.

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

Do not store XALAMOL 50/5 or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Write the date on the bottle when you open the eye drops and throw out any remaining solution after four (4) weeks.

Open a new bottle every four (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 this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

XALAMOL 50/5 is a clear, colourless liquid solution.

XALAMOL 50/5 comes in a plastic bottle with a dropper and screw cap inside a protective overcap. Remove this overcap before use.

When you first receive your XALAMOL 50/5 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

XALAMOL 50/5 contains 50 micrograms per mL of latanoprost, and 6.83 mg per mL of timolol maleate (equivalent 5 mg per mL of timolol) as the active ingredients.

The eye drops also contain the following inactive ingredients:

  • benzalkonium chloride
  • dibasic sodium phosphate
  • hydrochloric acid
  • monobasic sodium phosphate monohydrate
  • sodium chloride
  • sodium hydroxide
  • water for injections

Sponsor

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in January 2023.

Australian registration numbers:
AUST R 217150

XALAMOL_50/5_cmi\Jan23/00

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Xalamol 50/5

Active ingredient

Latanoprost; Timolol

Schedule

S4

 

1 Name of Medicine

Latanoprost and timolol (maleate).

2 Qualitative and Quantitative Composition

Each mL of Xalamol 50/5 eye drop solution contains 50 microgram of latanoprost and 5 mg of timolol (6.83 mg timolol maleate) as the active ingredients.
Each 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

Xalamol 50/5 is a clear and colourless solution.

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. Xalamol 50/5 should not be used to initiate therapy.

4.2 Dose and Method of Administration

For individual patient use only.

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 Xalamol 50/5 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 Xalamol 50/5 given once daily. Xalamol 50/5 should not be used to initiate therapy.
Xalamol 50/5 should not be given more than once daily because latanoprost is most effective at this dosage. If there is inadequate response to Xalamol 50/5, 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

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 Xalamol 50/5.

4.4 Special Warnings and Precautions for Use

Systemic effects.

Cardiovascular/ respiratory reactions.

Like other topically applied ophthalmic agents, latanoprost/ timolol eye drops 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.

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, 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 (also 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 latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops 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. Latanoprost/ timolol eye drops 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.

Latanoprost/ timolol eye drops 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.

Latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops.
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 latanoprost/ timolol eye drops alone has little or no effect on pupil size, mydriasis has occasionally been reported when timolol is given with adrenaline (epinephrine).
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 latanoprost/ timolol eye drops. 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 latanoprost/ timolol 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, latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops 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 latanoprost and timolol eye drops:

Latanoprost.

Ocular.

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

Timolol.

Eye disorders.

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

Ear and labyrinth disorders.

Tinnitus.

Cardiovascular.

Bradycardia, arrhythmia, atrioventricular block, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, cardiac failure, worsening of angina pectoris.

Vascular disorders.

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

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, skin rash, and 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, depression, behavioural changes and psychiatric disturbances including confusion, hallucinations, anxiety, disorientation, nervousness and memory loss.

Gastrointestinal disorders.

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

Metabolism and nutrition disorders.

Anorexia, masked symptoms of hypoglycaemia in diabetic patients.

Musculoskeletal and connective tissue disorders.

Myalgia, systemic lupus erythematosus.

Urogenital.

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

Post-marketing experience.

The following additional adverse drug reactions have been observed post-marketing with the single component latanoprost and may also be 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 latanoprost/ timolol eye drops.
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 Xalamol 50/5 occurs, treatment should be symptomatic and supportive. Studies have shown that timolol is not readily dialyzable. If Xalamol 50/5 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.

Xalamol 50/5 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 (nonselective) 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.

Latanoprost/ timolol eye drops.

Onset of action of latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops 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 latanoprost/ timolol eye drops 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.

Latanoprost/ timolol eye drops.

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 latanoprost/ timolol eye drops 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 latanoprost/ timolol 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

The excipients in Xalamol 50/5 are: Benzalkonium chloride (as a preservative), dibasic sodium phosphate, hydrochloric acid, monobasic sodium phosphate monohydrate, sodium chloride, sodium hydroxide, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine (see Section 4.4 Special Warnings and Precautions for Use, Use of contact lenses).

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

Before opening.

Store at 2°C to 8°C. Protect from light. Do not freeze.

After opening.

Store below 25°C. Protect from light. Do not freeze. Discard 4 weeks after opening.

6.5 Nature and Contents of Container

Container type: Bottle (LDPE).
Pack size: 1 x 2.5 mL (5 mL bottle).

Australian register of therapeutic goods (ARTG).

AUST R 217150 Xalamol 50/5 latanoprost 50 microgram/mL + timolol (as maleate) 5 mg/mL eye drops bottle.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Chemical name: isopropyl-(Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2- [(3R)-3-hydroxy-5-phenyl-1-pentyl] cyclopentyl]-5-heptenoate.
Molecular formula: C26H40O5.
Molecular weight: 432.58.
Chemical name: (S)-1-(tert-butylamino)- 3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]- 2-propanol maleate (1:1) (salt).
Molecular formula: C13H24N4O3S.C4H4O4.
Molecular weight: 432.50.
Latanoprost is a prostaglandin F2α analogue. 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 Xalamol 50/5 it is purified as a single isomer.
Timolol maleate is a beta-adrenergic receptor blocking agent. It is a white to off-white crystalline powder which is soluble in water, alcohol and practically insoluble in ether.
Xalamol is a sterile, isotonic solution, pH 6.0.

CAS number.

Latanoprost: 130209-82-4.
Timolol maleate: 26921-17-5.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes