Consumer medicine information

LATANOPROST TIMOLOL SANDOZ Eye Drops

Latanoprost; Timolol

BRAND INFORMATION

Brand name

Latanoprost/Timolol Sandoz

Active ingredient

Latanoprost; Timolol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using LATANOPROST TIMOLOL SANDOZ Eye Drops.

What is in this leaflet

This leaflet answers some common questions about Latanoprost/Timolol Sandoz Eye drops. 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 taking Latanoprost/Timolol Sandoz Eye drops 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 Latanoprost/Timolol Sandoz Eye drops is used for

This medicine is used to treat 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.

It contains two active ingredients, latanoprost and timolol maleate. Latanoprost belongs to a group of medicines called prostaglandin agonists. Latanoprost works by allowing more fluid to flow out from within your eye(s).

Timolol maleate belongs to a family of medicines called beta blockers. Timolol maleate lowers the pressure in the eye by reducing the production of fluid.

Latanoprost/ Timolol Sandoz Eye Drops will help your glaucoma but will 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 this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Latanoprost/Timolol Sandoz Eye drops is not recommended for use in children. Safety and effectiveness in children has not been established.

Before you use Latanoprost/Timolol Sandoz Eye drops

When you must not use it

Do not use this medicine if you have an allergy to:

  • Latanoprost or timolol maleate, the active ingredients, or to any of the other ingredients listed at the end of this leaflet under Product Description
  • any other similar medicines.

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
  • fainting.

Do not use this medicine if you have or have had any of the following medical conditions:

  • 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.

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
  • any other types of glaucoma or eye conditions
  • diabetes
  • myasthenia gravis - a muscle disease in which the muscles become weak and tire easily
  • hyperthyroidism - an underactive thyroid gland, causing a decrease in metabolism
  • circulation problems.

Tell your doctor if you are pregnant or plan to become pregnant. There is no adequate experience with Latanoprost/ Timolol Eye drops in pregnant women, therefore it should not be used during pregnancy. Your doctor can discuss with you the risks and benefits involved

Tell your doctor if you are breast-feeding or intend to breast feed. One of the active ingredients in Latanoprost/ Timolol Eye drops has been detected in breast milk. Because of the potential harm to the infant, nursing women should either stop using it or stop breast-feeding 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 him/her before you start using Latanoprost/Timolol Sandoz Eye drops.

Taking other medicines

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

Some medicines and Latanoprost/Timolol Sandoz Eye drops 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, clonidine or digoxin
  • certain medicines used to treat irregular heartbeats such as amiodarone and quinidine
  • some medicines used to treat depression, such as monoamine oxidase inhibitors (MAOIs), 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 Latanoprost/Timolol Sandoz Eye drops, you should wait at least 5 minutes between using these eye drops and Latanoprost/Timolol Sandoz Eye drops.
  • 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 Latanoprost/Timolol Sandoz Eye drops 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 Latanoprost/Timolol Sandoz Eye drops

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, 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 Latanoprost/Timolol Sandoz Eye drops is one drop into the affected eye, or eyes, once daily.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to use.

Follow the instructions they give you. If you use the wrong dose, Latanoprost/Timolol Sandoz Eye drops may not work as well and your problem may not improve.

How to use it

If you are wearing soft contact lenses, remove them before putting the drops in your eye. The preservative in Latanoprost/Timolol Sandoz Eye drops (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 Latanoprost/Timolol Sandoz Eye drops.

If using other eye drops in addition to Latanoprost/Timolol Sandoz Eye drops, 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, and 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 Latanoprost/Timolol Sandoz Eye drops

Use your medicine 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 long to use Latanoprost/Timolol Sandoz Eye drops

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

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not use a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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) in warm water.

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to the Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much Latanoprost/Timolol Sandoz Eye drops. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

The accidental swallowing of Latanoprost/Timolol Sandoz Eye drops or the use of too many drops may cause lightheadness or dizziness, you may faint, have a very slow pulse rate or may induce wheezing or difficult breathing. You also feel headache, nausea, abdominal pain, fatigue, hot flushes and sweating.

While you are using Latanoprost/Timolol Sandoz Eye drops

Things you must do

To make sure Latanoprost/Timolol Sandoz Eye drops 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 Latanoprost/Timolol Sandoz Eye drops. Your doctor will decide whether you should continue using Latanoprost/Timolol Sandoz Eye drops.

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 Latanoprost/Timolol Sandoz Eye drops because of possible contamination of the old one, or may advise you to stop your treatment with Latanoprost/Timolol Sandoz Eye drops.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Latanoprost/Timolol Sandoz Eye drops.

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

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

Things you must not do

Do not use Latanoprost/Timolol Sandoz Eye drops 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 without checking with 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 Latanoprost/Timolol Sandoz Eye drops affects you. Latanoprost/Timolol Sandoz Eye drops 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 Latanoprost/Timolol Sandoz Eye drops 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 Latanoprost/Timolol Sandoz Eye drops.

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 more brown 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 or 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, crusty eyelashes or watering of the eye/s
  • 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
  • hallucinations, confusion, disorientation or memory loss
  • 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.

These are mild side effects of the medicine and are short-lived.

Tell your doctor as soon as possible 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 urgent 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 nettlerash
  • 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 else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After using Latanoprost/Timolol Sandoz Eye drops

Storage

Keep your medicine in the original container.

Before opening Latanoprost/Timolol Sandoz Eye drops, keep your medicine in its box in a refrigerator (2°C - 8°C) protected from light.

After opening Latanoprost/Timolol Sandoz Eye drops, keep your medicine in its box in a cool place where the temperature stays below 25°C but do not refrigerate. Keep the box properly closed and protected from light.

Do not store Latanoprost/Timolol Sandoz Eye drops 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.

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

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 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 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

Latanoprost/Timolol Sandoz Eye drops come in a plastic bottle with a dropper and screw cap inside a protective overcap. Remove the overcap before use.

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

Ingredients

Active ingredients:

  • Each 1mL of Latanoprost/Timolol Sandoz Eye drops contains 50 micrograms of latanoprost and 5 mg of timolol (equivalent to 6.83mg timolol maleate)
  • Each drop contains about 1.5 micrograms of latanoprost and 150 micrograms of timolol.

Inactive ingredients:

  • sodium chloride
  • dibasic anhydrous sodium phosphate
  • monobasic dihydrate sodium phosphate
  • water for injections
  • benzalkonium chloride (as a preservative).

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 634 500

Novartis New Zealand Ltd
PO Box 99102
Newmarket, Auckland 0754
New Zealand
Tel: 0800 354 335

This leaflet was revised in February 2016.

Australian Registration Number

Latanoprost 50mcg/mL - Timolol (as maleate) 5mg/mL Eye Drops:
AUST R 204403

Published by MIMS January 2017

BRAND INFORMATION

Brand name

Latanoprost/Timolol Sandoz

Active ingredient

Latanoprost; Timolol

Schedule

S4

 

Name of the medicine

Latanoprost and timolol maleate.

Excipients.

Benzalkonium chloride (0.2 mg/mL) as a preservative, anhydrous dibasic sodium phosphate, monobasic sodium phosphate dihydrate, sodium chloride and water for injections.

Description

Latanoprost.

Chemical name: isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2- [(3R)3-hydroxy-5-phenylpentyl]- cyclopentyl]-5-heptenoate. Empirical formula: C26H40O5. MW: 432.59. CAS: 130209-82-4. Latanoprost is a prostaglandin F2α analogue. Sixty four isomers of latanoprost are possible however it is purified as a single isomer. Latanoprost is a colourless to pale yellowish viscous oil. Latanoprost is practically insoluble in water, freely soluble in ethanol, ethyl acetate, isopropanol, methanol, acetone, octanol and is very soluble in acetonitrile.

Timolol maleate.

Chemical name: (S)-1-(tert-butylamino)- 3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]- 2-propanol maleate (1:1) (salt). Empirical formula: C13H24N4O3S. C4H4O4. MW: 432.49. CAS: 26921-17-5. Timolol maleate is a beta-adrenergic receptor blocking agent. Timolol maleate is a white or almost white, crystalline powder. It is freely soluble in water and ethanol, sparingly soluble in chloroform, very slightly soluble in cyclohexane and insoluble in isooctane and ether.
Latanoprost/Timolol Sandoz 50/5 eye drops is a sterile solution containing 50 microgram/mL of latanoprost and 5 mg/mL of timolol (6.83 mg timolol maleate) in an aqueous buffer solution pH 6.0.

Pharmacology

Pharmacodynamics.

Latanoprost and timolol eye drops 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 and timolol eye drops.

Onset of action of latanoprost and 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 postdosage after multiple treatments.

Pharmacokinetics.

Latanoprost. Latanoprost is an isopropyl ester prodrug which is inactive, but after hydrolysis by esterases in the cornea to the acid of latanoprost, becomes biologically active.

Absorption.

The prodrug is well absorbed through the cornea and all 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.

Metabolism.

The acid of latanoprost has a plasma clearance of 0.40 L/h.kg and a small volume of distribution, 0.16 L/kg, resulting in a rapid half-life in plasma, 17 minutes. After topical ocular administration, the systemic bioavailability of the acid of latanoprost is 45%. The acid of latanoprost has a plasma protein binding of 87%. There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver.

Excretion.

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 and 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.

Clinical Trials

Two 6 month, randomised, double blind, multicentre clinical studies were conducted to compare the IOP lowering effect of latanoprost and 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 and 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 and timolol eye drops was maintained during this period.

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. Latanoprost/ timolol eye drops should not be used to initiate therapy.

Contraindications

Latanoprost/Timolol Sandoz 50/5 eye drops is contraindicated in the following.
Reactive airway disease including bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sinoatrial block, second or third degree atrioventricular block, overt cardiac failure, or cardiogenic shock.
Known hypersensitivity to latanoprost, timolol maleate or to any component in Latanoprost/Timolol Sandoz 50/5 eye drops.

Precautions

Systemic effects.

Like other topically applied ophthalmic agents, latanoprost and timolol eye drops are absorbed systemically. Incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see Dosage and Administration.

Cardiovascular/ respiratory reactions.

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. In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.
Respiratory 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 anaesthesiologist 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 (see also Interactions with Other Medicines).
The effect on intraocular pressure or the known effects of systemic beta-blockade may be exaggerated when latanoprost and timolol eye drops is given to patients already receiving an oral beta-blocking agent. The response of these patients should be closely observed. 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.

Additional effects of beta-blockade.

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

Ocular effects.

Latanoprost may gradually change the eye colour by increasing the amount of brown pigment in the iris. This effect has predominantly been seen in patients with mixed 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 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.
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 and timolol eye drops should be used with caution in these conditions until more experience is obtained.
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, 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 and timolol eye drops should be used with caution in these patients.
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 and 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 Interactions with Other Medicines). Therefore contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.

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 preclinical 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 cynomologus 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.

Effects on fertility.

Fertility studies with latanoprost and timolol eye drops 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 intravenous (IV) or 300 mg/kg/day orally (PO) respectively.

Use in pregnancy.

(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 and timolol eye drops should not be used during pregnancy.

Use in lactation.

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 and 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.

Paediatric use.

Latanoprost and timolol eye drops is not recommended for use in children. Safety and effectiveness in children have not been established.

Genotoxicity.

Mutagenicity studies with latanoprost and 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 and timolol eye drops 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.

Effects on ability to drive and use of 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.

Interactions

No specific interaction studies have been performed with latanoprost and timolol eye drops.
There have been reports of paradoxical elevations in intraocular pressure following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended.
The 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.
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.
Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.
The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when latanoprost/ timolol is given to patients already receiving an oral beta-adrenergic blocking agent, and the use of two or more topical beta-adrenergic blocking agents is not recommended.
Although latanoprost and timolol eye drops 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. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see Precautions, Additional effects of beta-blockade).
In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with benzalkonium chloride, the preservative used in Latanoprost/Timolol Sandoz 50/5 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 Precautions, Use of contact lenses).

Adverse Effects

No adverse events specific for latanoprost and timolol drops have been observed in clinical studies. The adverse events have been limited to those earlier reported for latanoprost and timolol. For latanoprost, the majority of adverse events relate to the ocular system. For timolol, the most serious adverse events are systemic in nature, including bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic reactions.
Like other topically applied ophthalmic medicinal products, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic adverse drug effects after topical ophthalmic administration is lower than for systemic administration. Listed adverse effects include reactions seen within the class of ophthalmic beta-blockers.

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.

Foreign body sensation, punctate epithelial erosions, periorbital oedema, macular oedema (in aphakic, pseudophakic patients with torn posterior lens capsules or in patients with known risk factors for macular oedema), dry eye, corneal oedema and erosions, eyelash and vellus hair changes (increased length, thickness, pigmentation and number), misdirected eyelashes sometimes resulting in eye irritation and blurred vision, iris cyst, photophobia, periorbital and lid changes resulting in deepening of the eyelid sulcus.

Respiratory, thoracic and mediastinal disorders.

Asthma, asthma aggravation and acute asthma attacks.

Skin and subcutaneous tissue disorders.

Darkening of the palpebral skin of the eyelids and localised skin reaction on the eyelids.

Musculoskeletal and connective tissue disorders.

Muscle/ joint pain.

Cardiac disorders.

Aggravation of angina in patients with pre-existing disease, palpitations.

General disorders and administration site conditions.

Nonspecific chest pain.

Infections and infestations.

Herpetic keratitis.

Timolol.

Special senses.

Decreased corneal sensitivity and dry eyes, 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) and tinnitus.

Cardiovascular.

Bradycardia, arrhythmia, atrioventricular block, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, cardiac failure, oedema, claudication, Raynaud's phenomenon, cold hands and feet and worsening of angina pectoris.

Respiratory, thoracic and mediastinal disorders.

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

Body as a whole.

Asthenia and fatigue.

Skin and subcutaneous tissue disorders.

Alopecia, pseudopemphigoid, skin rash and psoriasiform rash or exacerbation of psoriasis.

Hypersensitivity.

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

Nervous system/ psychiatric.

Nightmares, memory loss, increase in signs and symptoms of myasthenia gravis, paraesthesia, somnolence, headache, depression, behavioural changes and psychiatric disturbances including confusion, hallucinations, anxiety, disorientation and nervousness.

Digestive.

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.

Urogenital.

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

Immunologic.

Systemic lupus erythematosus.

Postmarketing experience.

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.

Dosage and Administration

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 Latanoprost/Timolol Sandoz 50/5 eye drops 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 Latanoprost/Timolol Sandoz 50/5 eye drops given once daily. Latanoprost/Timolol Sandoz 50/5 eye drops should not be used to initiate therapy.
Latanoprost/Timolol Sandoz 50/5 eye drops should not be given more than once daily because latanoprost is most effective at this dosage. If there is inadequate response to Latanoprost/Timolol Sandoz 50/5 eye drops, consideration should be given to using the individual agents with timolol dose twice daily.
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 Precautions).

Overdosage

Contact the Poisons Information Centre on 131 126 (Australia) for advice on management of overdose.
There is no human data available on overdosage with latanoprost and 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.
In case of overdose treatment should be supportive and symptomatic.
Studies have shown that timolol is not readily dialyzable. If Latanoprost/Timolol Sandoz 50/5 eye drops 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.

Presentation

Eye drops (sterile solution), latanoprost 50 microgram/mL, timolol 5 mg/mL (≡ latanoprost 1.5 microgram, timolol 150 microgram per drop): 2.5 mL (5 mL bottle with dropper, screw cap).

Storage

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

Poison Schedule

S4.