Consumer medicine information

Timoptol

Timolol

BRAND INFORMATION

Brand name

Timoptol Eye drops

Active ingredient

Timolol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Timoptol.

What is in this leaflet

This leaflet answers some common questions about TIMOPTOL. 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 TIMOPTOL 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 TIMOPTOL is used for

TIMOPTOL 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. Also, some people with raised eye pressure may not have glaucoma.

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. The only way of knowing that you have glaucoma is to have your eye pressure, optic nerve and visual field checked by an eye specialist or optometrist. If glaucoma is not treated it can lead to serious problems. You may have no symptoms but eventually glaucoma can lead to total blindness. In fact, untreated glaucoma is one of the most common causes of blindness.

Although TIMOPTOL helps control your glaucoma it does not cure it.

For more information about glaucoma, contact Glaucoma Australia Inc., PO Box 420, Crows Nest 1585, telephone 1800 500 880, or at www.glaucoma.com.au.

TIMOPTOL is used, either alone or in combination with other eye drops or medicines, to lower raised pressure within your eye(s).

TIMOPTOL lowers pressure in the eye by reducing the production of fluid.

TIMOPTOL belongs to a family of medicines called beta-blockers.

TIMOPTOL is not addictive.

Before you use TIMOPTOL

When you must not use it

Do not use TIMOPTOL if you have an allergy to TIMOPTOL or any of the ingredients listed at the end of this leaflet.

Do not use TIMOPTOL if:

  • you have now or you have had in the past certain serious breathing problems such as asthma, or a history of asthma, chronic obstructive lung disease (emphysema), or other breathing problems
  • you have certain heart conditions, such as a slow heart rate, an irregular heart beat, or heart failure.

Do not use TIMOPTOL if you are breast-feeding or intend to breast-feed.

Your baby may absorb this medicine from breast milk and therefore there is a possibility of harm to the baby.

Do not put the eye drops into your eye(s) while you are wearing soft contact lenses.

The preservative in TIMOPTOL (benzalkonium chloride) may be deposited in soft contact lenses. You can put your soft contact lenses back into your eyes at least 15 minutes after you have used TIMOPTOL.

Do not use TIMOPTOL if:

  • the seal around the cap is broken
  • the bottle shows signs of tampering
  • the expiry date on the pack has passed.

If you use this medicine after the expiry date has passed, it may not work.

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

Do not use TIMOPTOL in a child.

The safety and effectiveness of TIMOPTOL in children have not been established.

Before you start to use it

Tell your doctor if:

  1. you are pregnant or intend to become pregnant
    Your doctor will discuss the possible risks and benefits of using TIMOPTOL during pregnancy and a decision can be made if you should or should not use it.
  2. you have now or have had in the past any medical conditions, especially the following:
  • heart problems (such as coronary heart disease, heart failure or low blood pressure)
  • heart rate disturbances (such as slow or irregular heart beats)
  • poor blood circulation problems (such as Raynaud's syndrome)
  • lung or breathing problems (such as asthma or chronic obstructive lung disease)
  • diabetes or other blood sugar problems
  • thyroid disease
  1. you are already using another beta-blocker eye drop
    It is not recommended to use two beta-blocker eye drops at the same time.
  2. you have a history of allergic problems, including eczema, hives or hay fever
  3. you have had an allergy to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you use TIMOPTOL.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and TIMOPTOL may interfere with each other.

These include:

  • medicines for high blood pressure or heart conditions, including a group of medicines called beta-blockers
  • digoxin, a medicine used to treat heart failure
  • quinidine, a medicine used to treat irregular heart beats
  • medicines to treat depression
  • medicines to treat diabetes

These medicines may be affected by TIMOPTOL, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How to use TIMOPTOL

How much to use

Your doctor will tell you how many drops you need to use each day.

Use TIMOPTOL only when prescribed by your doctor.

The usual dose for adults is one drop of TIMOPTOL twice a day, in either one or both eyes.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

Use TIMOPTOL every day, at about the same time each day, unless your doctor tells you otherwise.

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

After using TIMOPTOL, wait at least 5 minutes before putting any other eye drops in your eye(s).

How to use it

Please refer to the instruction leaflet inside the TIMOPTOL pack for directions on how to use your eye drops.

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

If you are wearing contact lenses, remove them before putting the drops in your eye.

Wait at least 15 minutes before replacing your contact lenses.

Be careful not to touch the dropper tip against your eye, eyelid or anything else to avoid contaminating the eye drops.

Contaminated eye drops may give you an eye infection.

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

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

How long to use it

TIMOPTOL helps control your condition but does not cure it. Therefore TIMOPTOL must be used every day. Continue using TIMOPTOL for as long as your doctor prescribes.

If you forget to use it

If it is almost time for your next dose, skip the dose you missed and use your next dose when you are meant to. Otherwise, use the drops as soon as you remember, and then go back to using them as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

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

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

If you use too much (overdose)

If you think that you or anyone else may have swallowed any or all of the contents of a bottle of TIMOPTOL, or used too many drops, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to accident and emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

If TIMOPTOL 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.

While you are using TIMOPTOL

Things you must do

Have your eye pressure checked when your eye specialist says, to make sure TIMOPTOL is working.

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 TIMOPTOL because of possible contamination of the old one, or may advise you to stop your treatment with TIMOPTOL.

If you become pregnant while using TIMOPTOL tell your doctor.

Tell your doctor before you have an operation that you are using TIMOPTOL, as it may change the effects of some medicines during anaesthesia.

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

Things you must not do

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

Do not stop using TIMOPTOL without first talking to your doctor.

If you stop using your eye drops, your eye pressures may rise again and damage to your eye may occur.

Things to be careful of

Be careful driving or operating machinery until you know how TIMOPTOL affects you.

TIMOPTOL generally does not cause any problems with your ability to drive a car or operate machinery. However, TIMOPTOL may cause blurred vision or dizziness in some people. Make sure you know how you react to TIMOPTOL 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 TIMOPTOL.

TIMOPTOL helps most people with high eye pressure and 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 treatment if you get some of the side effects.

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

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

problems with your eye/s such as:

  • blurred vision, double vision or other visual problems
  • allergic reactions including redness, swelling and/or itching of the eye
  • burning and stinging of the eyes
  • conjunctivitis
  • irritation or feeling of having something in the eye, dry eyes
  • watering of the eyes or discharge
  • pain in the eye
  • drooping of eyelid/s

difficulty thinking or working because of:

  • headache
  • tiredness, weakness
  • ringing or buzzing in the ears
  • difficulty sleeping, nightmares
  • changes in mood such as depression, memory loss

stomach or bowel problems

  • feeling sick (nausea), upset stomach
  • diarrhoea
  • dry mouth
  • abdominal pain

changes in the way your hands and feet feel such as:

  • 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

hair loss or thinning

less desire for sex

sexual dysfunction

muscle weakness or muscle pain, not caused by exercise.

These are usually mild side effects of TIMOPTOL.

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

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

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

Serious side effects are rare.

If any of the following happen, stop using TIMOPTOL and tell your doctor immediately or go to accident and emergency at your nearest hospital:

  • wheezing, difficulty in breathing, shortness of breath
  • very slow pulse, chest pain
  • fainting
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in breathing or swallowing
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettlerash

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

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

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

After using TIMOPTOL

Storage

Keep your eye drops in a cool place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Do not carry the eye drops in pockets of your clothes.

Heat and dampness can destroy some medicines.

Keep the eye drops away from direct light.

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.

Do not leave the lid off the bottle for any length of time to avoid contaminating the eye drops.

Disposal

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

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. A new bottle should be opened.

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

Product description

How does it come?

TIMOPTOL comes as eye drops in a 5 mL dropper pack. It is available in two strengths.

Ingredients

Active ingredient:

  • TIMOPTOL 0.25% - timolol maleate, equivalent to timolol 0.25%
  • TIMOPTOL 0.5% - timolol maleate, equivalent to timolol 0.5%

Inactive ingredients:

  • dibasic sodium phosphate
  • monobasic sodium phosphate
  • sodium hydroxide
  • benzalkonium chloride as preservative

Supplier

TIMOPTOL is supplied in Australia by:

Mundipharma Pty Limited
88 Phillip Street
Sydney NSW 2000

This leaflet was prepared in April 2017.

Australian Register Numbers*:
TIMOPTOL 0.25% - AUST R 28776
TIMOPTOL 0.5% - AUST R 28775

* All strengths may not currently be available in Australia.

® TIMOPTOL is a registered trade mark.

Orbis RA-0111

BRAND INFORMATION

Brand name

Timoptol Eye drops

Active ingredient

Timolol

Schedule

S4

 

1 Name of Medicine

Timolol maleate.

2 Qualitative and Quantitative Composition

Each mL of Timoptol 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of Timoptol 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate).

List of excipient(s) with known effect.

Benzalkonium chloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Eye drops, solution.
Clear, colourless sterile solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Timoptol is indicated for the reduction of elevated intraocular pressure.
In clinical trials it has been shown to reduce intraocular pressure in:
patients with ocular hypertension;
patients with chronic open-angle glaucoma;
aphakic patients with glaucoma.

4.2 Dose and Method of Administration

Recommended therapy is one drop of 0.25% solution in the affected eye twice a day.
If clinical response is not adequate, dosage may be changed to one drop of 0.5% solution in each affected eye twice a day. If needed, concomitant therapy with miotics, adrenaline (epinephrine) and systemically administered carbonic anhydrase inhibitors may be instituted. The use of two topical beta-adrenergic blocking agents is not recommended (see Section 4.4 Special Warnings and Precautions for Use).
Since in some patients the pressure-lowering response to Timoptol may require a few weeks to stabilise, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Timoptol.
If the intraocular pressure is maintained at satisfactory levels, many patients can be placed on once-a-day therapy. Because of naturally occurring diurnal variations in intraocular pressure, satisfactory response is best determined by measuring the intraocular pressure at different times during the day.
Systemic absorption of drugs from ophthalmic solutions may be minimised by pressure on the tear-duct immediately after application. This may result in increased local activity.

How to transfer patients from other therapy.

When patients are being transferred from other antiglaucoma agents, monitoring of intraocular pressure is recommended.
When a patient is transferred from another topical ophthalmic β-adrenergic blocking agent, that agent should be discontinued after proper dosing on one day and treatment with Timoptol started on the following day with one drop of 0.25% Timoptol in the affected eye twice a day. The dose may be increased to one drop of 0.5% Timoptol twice a day if the clinical response is not adequate.
When a patient is transferred from a single antiglaucoma agent, other than a topical ophthalmic beta-adrenergic blocking agent, on the first day continue with the agent already being used and add one drop of 0.25% Timoptol in each affected eye twice a day. On the following day, discontinue the previously used antiglaucoma agent completely and continue with Timoptol. If a higher dosage of Timoptol is required substitute one drop of 0.5% solution in each affected eye twice a day.
When a patient is transferred from several concomitantly administered antiglaucoma agents, individualisation is required.
The physician may be able to discontinue some or all of the other antiglaucoma agents. Adjustments should involve one agent at a time.
Clinical trials have shown the addition of Timoptol to be useful in patients who respond inadequately to the maximum tolerable antiglaucoma drug therapy.

4.3 Contraindications

Timoptol is contraindicated in patients with:
Reactive airway disease, bronchospasm, bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease.
Sinus bradycardia; sino-atrial block; second and third degree atrioventricular block; overt cardiac failure; cardiogenic shock.
Hypersensitivity to Timoptol or any component of this product.

4.4 Special Warnings and Precautions for Use

As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration.

Cardio-respiratory reactions.

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.
In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Timoptol should be discontinued.
Cardiac failure should be adequately controlled before beginning therapy with Timoptol. Patients with a history of cardiovascular disease, including cardiac failure should be watched for signs of deterioration of these diseases, and pulse rates should be checked.
Due to its negative effect on conduction time, beta-blockers should be given with caution to patients with first degree heart block.
Because of potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timoptol, alternative therapy should be considered.

Muscle weakness.

Beta-adrenergic blockage has been reported to increase muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalised weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenic symptoms.
Respiratory complications, including exacerbation of asthma and death due to bronchospasm in patients with asthma, and cardiac complications, including rarely death in association with cardiac failure, have been reported following administration of Timoptol.
In patients with mild/moderate chronic obstructive pulmonary disease (COPD), Timoptol should be used with caution, and only if the potential benefit outweighs the potential risk.

Vascular disorders.

Patients with severe peripheral circulatory disturbance/disorders (e.g. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Masking of hypoglycemic symptoms in patients with diabetes mellitus.

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia.

Masking of thyrotoxicosis.

Beta-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g. tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.

Surgical anesthesia.

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists (see Section 4.9 Overdose).

Other.

Patients who are already receiving a beta-adrenergic blocking agent orally and who are given Timoptol should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade. The use of two topical beta-adrenergic blocking agents is not recommended.
In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Timoptol has little or no effect on the pupil. When Timoptol is used to reduce elevated intraocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Timoptol contains the preservative benzalkonium chloride, which may be deposited in soft contact lenses; therefore, Timoptol should not be used while wearing these lenses. The lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.
Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection) or any ocular reactions, particularly conjunctivitis and lid reactions, they should immediately seek their physician's advice concerning the continued use of the product.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or disruption of the ocular epithelial surface.

Risk from anaphylactic reaction.

While taking β-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 epinephrine use to treat anaphylactic reactions.

Use in the elderly.

No data available.

Paediatric use.

Safety and effectiveness in children have not been established by adequate and well controlled studies.

Effects on laboratory tests.

Clinically important changes in standard laboratory parameters were rarely associated with the administration of systemic timolol maleate. Slight increases in blood urea nitrogen, serum potassium, serum uric acid and triglycerides and slight decreases in haemoglobin, haematocrit and HDL-cholesterol occurred, but were not progressive or associated with clinical manifestations.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Although Timoptol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timoptol and adrenaline (epinephrine) has been reported occasionally.
Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRI's) and timolol.
Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope or postural hypotension.
Oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.
The potential exists for hypotension, AV conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium entry blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker.
The potential exists for additive effects and production of hypotension and/or marked bradycardia when Timoptol is administered together with an oral calcium entry blockers, catecholamine-depleting drugs, antiarrhythmics, parasympathomimetics or beta-adrenergic blocking agents.
Intravenous calcium entry blockers should be used with caution in patients receiving beta-adrenergic blocking agents.
The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging AV conduction time.
β-Adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. Caution should be exercised in patients using these drugs concomitantly. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 100 mg/kg/day.
(Category C)
Beta-adrenergic blocking agents may cause bradycardia in the fetus and newborn infant. During the final part of pregnancy and parturition these drugs should therefore only be given after weighing the needs of the mother against the risk to the fetus.
Timoptol has not been studied in human pregnancy. The use of Timoptol requires that the anticipated benefit be weighed against possible hazards.
Timolol is detectable in human milk. Because of the potential for serious adverse reactions from timolol 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

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Timoptol is usually well tolerated. The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulations, either in clinical trials or since the drug has been marketed.

Special senses.

Signs and symptoms of ocular irritation, including burning and stinging, conjunctivitis, blepharitis, keratitis, blepharoptosis, and decreased corneal sensitivity and dry eyes. Visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia and choroidal detachment following filtration surgery (see Section 4.4 Special Warnings and Precautions for Use), tinnitus.

Cardiovascular.

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

Respiratory.

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), exacerbation of asthma, respiratory failure, dyspnoea, cough.

Body as a whole.

Headache, asthenia, fatigue, chest pain.

Integumentary.

Alopecia, psoriasiform rash or exacerbation of psoriasis.

Hypersensitivity.

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

Nervous system/psychiatric.

Dizziness, depression, insomnia, nightmares, memory loss, increase in signs and symptoms of myasthenia gravis, paraesthesia.

Digestive.

Nausea, diarrhoea, dyspepsia, dry mouth, abdominal pain.

Urogenital.

Decreased libido, Peyronie's disease, sexual dysfunction.

Immunologic.

Systemic lupus erythematosus have been reported.

Musculoskeletal.

Myalgia.

Potential adverse effects.

The following adverse effects have been reported in clinical experience with oral timolol maleate and may be considered potential adverse effects of ophthalmic timolol maleate.

Body as a whole.

Extremity pain, decreased exercise tolerance.

Cardiovascular.

AV block (2nd or 3rd degree), sinoatrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.

Digestive.

Vomiting.

Endocrine.

Hyperglycaemia, hypoglycaemia.

Integumentary.

Pruritus, sweating, exfoliative dermatitis.

Musculoskeletal.

Arthralgia.

Nervous system.

Vertigo, local weakness.

Psychiatric.

Diminished concentration, increased dreaming.

Haematologic.

Nonthrombocytopenic purpura.

Respiratory.

Rales.

Urogenital.

Impotence, micturition difficulties.

Causal relationship unknown.

The following adverse effects have been reported but a causal relationship to therapy with Timoptol has not been established: aphakic cystoid macular oedema, nasal congestion, anorexia, CNS effects (e.g. behavioural changes including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence and other psychic disturbances), hypertension, retroperitoneal fibrosis, and pseudopemphigoid.

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

There have been reports of inadvertent overdosage with Timoptol resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents, such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see Section 4.8 Adverse Effects (Undesirable Effects)).
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.

The precise mechanism of action of Timoptol in lowering intraocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that its predominant action may be related to reduced aqueous formation. However, in some studies, a slight increase in outflow facility was also observed.
Unlike miotics, Timoptol reduces intraocular pressure with little or no effect on accommodation or pupil size. Thus, changes in visual acuity due to increased accommodation are uncommon, and dim or blurred vision and night blindness produced by miotics are not evident. In addition, in patients with cataracts, the inability to see around lenticular opacities when the pupil is constricted by miotics is avoided. When changing patients from miotics to Timoptol a refraction might be necessary when these effects of the miotic have passed.

Clinical trials.

In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, Timoptol 0.25% or 0.5% administered twice a day produced a greater reduction in intraocular pressure than 1, 2, 3 or 4% pilocarpine solution administered four times a day or 0.5, 1 or 2% adrenaline hydrochloride solution administered twice a day.
In the multiclinic studies comparing Timoptol with pilocarpine, 61% of patients treated with Timoptol had intraocular pressure reduced to less than 22 mmHg compared to 32% of patients treated with pilocarpine.
For patients completing these studies, the mean reduction in pressure at the end of the study from pretreatment was 30.7% for patients treated with Timoptol and 21.7% for patients treated with pilocarpine.
In the multiclinic studies comparing Timoptol with adrenaline, 69% of patients treated with Timoptol had intraocular pressure reduced to less than 22 mmHg compared to 42% of patients treated with adrenaline. For patients completing these studies, the mean reduction in pressure at the end of the study from pretreatment was 33.2% for patients treated with Timoptol and 28.1% for patients treated with adrenaline.
In clinical studies Timoptol produced fewer and less severe adverse effects than either pilocarpine or adrenaline.
As with the use of other antiglaucoma drugs, diminished responsiveness to Timoptol after prolonged therapy has been reported in some patients. However, in one long-term study in which 96 patients have been followed for at least 3 years, no significant difference in mean intraocular pressure has been observed after initial stabilisation.
Timoptol has also been used in patients with glaucoma wearing conventional hard contact lenses, and has generally been well tolerated. Timoptol has not been studied in patients wearing lenses made with materials other than polymethylmethacrylate.

5.2 Pharmacokinetic Properties

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 nanogram/mL and following afternoon dosing was less than the lower limit of quantification of the assay, 0.375 nanogram/mL.
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant or local anaesthetic (membrane stabilising) activity. Timolol maleate combines reversibly with a part of the cell membrane, the beta-adrenergic receptor, and thus inhibits the usual biological response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic receptors by catecholamines having beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of the agonist, which will restore the usual biological response.
Timoptol (timolol maleate) reduces elevated and normal intraocular pressure whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.
Onset of action of Timoptol is usually rapid, occurring approximately 20 minutes after topical application to the eye. Maximum reduction of intra-ocular pressure occurs in one to two hours. Significant lowering of intraocular pressure has been maintained for as long as 24 hours with 0.25% or 0.5% Timoptol. This extended duration of action permits control of intraocular pressure over the usual sleeping hours. Repeated observations over a period of one year indicate that the intraocular pressure lowering effect of Timoptol is well maintained.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro and in vivo studies (Ames test, neoplastic cell transformation assay, cytogenetic assay and micronucleus test in mice) showed no genotoxicity of timolol.

Carcinogenicity.

In a 2-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day. Similar differences were not observed in rats administered oral doses of 100 mg/kg/day.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumours, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, but not at 50 mg/kg/day. In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumours was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg, but not at doses of 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

6 Pharmaceutical Particulars

6.1 List of Excipients

Monobasic sodium phosphate, dibasic sodium phosphate dodecahydrate, sodium hydroxide, water for injections and benzalkonium chloride (0.01% as preservative).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.
Timoptol is stable at room temperature.

6.5 Nature and Contents of Container

Timoptol 0.25% and 0.5% are available in bottles; pack size: 1 x 5 mL bottle packs.
All strengths may not currently be marketed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Timolol maleate has a molecular weight of 432.50. It is a white, odourless, crystalline powder which is soluble in water, methanol and alcohol. Timoptol is stable at room temperature.

Chemical structure.

Timolol maleate is described chemically as (S)-1-((1,1-dimethylethyl)amino)- 3-((4-(4-morpholinyl) - 1,2,5-thiadiazol-3-yl)oxy)- 2-propanol, (Z)-butenedioate (1:1) salt. Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The empirical formula is C13H24N4O3S.C4H4O4 and the structural formula is:

CAS number.

26921-17-5.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes