TILOPTIC 0.5 %

Israel - English - Ministry of Health

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Active ingredient:
TIMOLOL AS MALEATE
Available from:
RAFA LABORATORIES LTD
ATC code:
S01ED01
Pharmaceutical form:
EYE DROPS
Composition:
TIMOLOL AS MALEATE 5 MG/ML
Administration route:
OCULAR
Prescription type:
Required
Manufactured by:
LABORATORIES MERCK,SHARP & DOHME-CHIBRET (MIRABEL), FRANCE
Therapeutic group:
TIMOLOL
Therapeutic area:
TIMOLOL
Therapeutic indications:
For the reduction of elevated intraocular pressure may be used in patients with chronic open-angle glaucoma, aphakic glaucoma, some patients with secondary glaucoma and patients with ocular hypertension
Authorization number:
113 20 22175 00
Authorization date:
2013-12-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

17-08-2016

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS'

REGULATIONS (PREPARATIONS) – 1986

This medicine can be sold under doctor's prescription only

TILOPTIC

®

0.5%

Ophthalmic Solution

The ophthalmic solution contains: Timolol (as maleate)

5 mg/ml

For a list of inactive ingredients see section 6.1 "What TILOPTIC contains". See also section 2.6

Important information about some of the ingredients of TILOPTIC”.

Read all of this leaflet carefully before you start using this medicine.

This leaflet contains concise information about TILOPTIC. If you have any further questions, ask

your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their medical condition seems similar to yours.

This medicine is not intended for use in children and infants.

1. WHAT TILOPTIC IS AND WHAT IT IS USED FOR?

Timolol lowers the intraocular pressure. TILOPTIC is used to treat glaucoma and to reduce elevated

intraocular pressure.

Therapeutic group: beta blockers.

TIC

BEFORE YOU USE TILOP

2.

2.1 Do not use TILOPTIC if:

you are hypersensitive (allergic) to timolol, beta-blockers or any of the other ingredients of TILOPTIC

(for a list of inactive ingredients, see section 6.1).

you are suffering or have suffered in the past from respiratory problems such as asthma, severe chronic

obstructive bronchitis (severe lung disease which may cause wheeziness, difficulty in breathing and/or

long-standing cough)

you have heart problems

slow heartbeat

disorders of heart rhythm (irregular heartbeats)

heart failure

“cardiogenic shock” – a serious heart condition caused by very low blood pressure, which may result in

the following symptoms: dizziness and lightheadedness, fast pulse rate, white skin, sweating,

restlessness, loss of consciousness.

If you are not sure whether you should use TILOPTIC talk to your doctor or pharmacist

2.2 Special warnings concerning use of TILOPTIC

Before starting treatment with TILOPTIC, tell your doctor if you are suffering or have suffered in the

past from:

coronary heart disease (symptoms can include chest pain or tightness, breathlessness or choking),

heart failure

low blood pressure

disturbances of heart rate such as slow heart beat

breathing problems, asthma or chronic obstructive pulmonary disease

poor blood circulation disease (such as Raynaud's disease or Raynaud's syndrome)

diabetes as timolol may mask signs and symptoms of low blood sugar

overactivity of the thyroid gland as timolol may mask signs and symptoms

if you wear soft contact lenses. Your eye drops contain a preservative which can be deposited on soft

contact lenses. It is important that your lenses are removed before using your eye drops and not put

back into your eyes for 15 minute.

Tell your doctor before you have an operation that you are using TILOPTIC as timolol may change effects

of some medicines used during anaesthesia

If your eye becomes irritated or any new eye problems come on, talk to your doctor straight away. Eye

problems could include redness of the eye or swelling of the eyelids (see Section 4 “SIDE EFFECTS”).

If you suspect that TILOPTIC is causing an allergic reaction or hypersensitivity (for example, skin rash, or

redness and itching of the eye), stop using TILOPTIC and contact your doctor immediately

Tell your doctor if

you get an eye infection

you injure your eye or have an operation on it

your eye problems get worse or you get any new symptoms.

2.3 Taking other medicines

If you are taking or have recently taken other medicines, including non-prescription medicines and

nutritional supplements, you should tell the attending doctor or pharmacist.

ESPECIALLY INFORM YOUR DOCTOR OR PHARMACIST IF YOU ARE TAKING:

Other eye drops for the treatment of glaucoma or any other eye drops, medicine to lower blood pressure,

heart medicines or medicines to treat diabetes.

It is important to tell your doctor before using TILOPTIC if you are taking one or more of the following

medicines:

a calcium antagonist, such as nifedipine, verapamil or diltiazem, often used to treat high blood

pressure, angina, an abnormal heartbeat or Raynaud’s syndrome

digoxin, a medicine used to relieve heart failure or treat abnormal heartbeat

medicines known as catecholamine-depleting agents, such as rauwolfia alkaloids or reserpine, used for

high blood pressure

medicines called pressor amines, such as adrenaline used to treat severe allergic reaction

quinidine (used to treat heart conditions and some types of malaria)

antidepressants known as fluoxetine and paroxetine

clonidine, a medicine used to treat high blood pressure

other beta-blockers taken by mouth or used as eye drops, because they belong to the same group of

medicines as TILOPTIC and could have an additive effect.

2.4 Pregnancy and breast-feeding

Consult your doctor or pharmacist before taking any medicine.

Use in pregnancy

Do not use TILOPTIC if you are pregnant unless your doctor considers it necessary.

Use in breast-feeding

Do not use TILOPTIC if you are breast-feeding. Timolol may get into your milk. Ask your doctor for advice

before taking any medicine during breast-feeding

2.5 Driving and using machines

There are possible side effects associated with TILOPTIC, such as dizziness, tiredness and changes in

your eyesight, such as blurred vision, drooping of the upper eyelid (making the eye stay half closed), double

vision which may affect your ability to drive and/or operate machinery. Do not drive and/or operate

machinery until you feel well and your vision is clear.

2.6 Important information about some of the ingredients of TILOPTIC

TILOPTIC contains 0.01% benzalkonium chloride, which may be deposited in soft contact lenses (See also

section 2.2 “Special warnings concerning use of TILOPTIC”).

3. HOW TO USE TILOPTIC

Always use TILOPTIC as instructed by the doctor. You should check with your doctor or pharmacist if you

are not sure.

The dosage and duration of treatment will be determined by the doctor only.

The usually recommended dose is:

One drop in the affected eye(s) twice each day:

one in the morning

one in the evening.

Do not exceed the recommended dose.

This medicine is intended for external use only.

Do not allow the tip of the container to touch the eye or areas around the eye. It may become contaminated

with bacteria that can cause eye infection leading to serious damage of the eye, even loss of vision. To

avoid possible contamination of the container, keep the tip of the container away from contact with any

surface.

INSTRUCTIONS FOR USE

1. Before putting in your eye drops wash your hands thoroughly.

2. Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is

unbroken. A gap between the bottle and the cap is normal for an unopened bottle.

3. Tear off the Safety Strip to break the seal.

4. To open the bottle, unscrew the cap by turning as indicated by the arrows on the top of the cap. Do not

pull the cap directly up and away from the bottle. Pulling the cap directly up will prevent your dispenser

from operating properly.

5. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and

your eye.

6. Invert the bottle and press lightly with the thumb or index finger over the “Finger Push Area” (as shown)

until a single drop is dispensed into the eye as directed by your doctor. DO NOT TOUCH YOUR EYE

OR EYELID WITH THE DROPPER TIP.

7. After using TILOPTIC, press a finger into the corner of your eye, by the nose for 2 minutes. This helps to

stop timolol getting into the rest of your body and therefore helps to prevent side effects.

Ophthalmic medications, if handled improperly, can become contaminated by common bacteria known to

cause infections. Serious damage to the eye and subsequent loss of vision may result from using

contaminated ophthalmic medications. If you think your medication may be contaminated, or if you

develop an eye infection, contact your doctor immediately concerning continued use of this bottle.

8. If drop dispensing is difficult after opening for the first time, replace the cap on the bottle and tighten

(do not overtighten) and then remove by turning the cap in the opposite direction as indicated by the

arrows on top of the cap.

9. Repeat steps 5, 6 and 7 with the other eye if instructed to do so by your doctor.

10. Replace the cap by turning until it is firmly touching the bottle. The arrow on the left side of the cap

must be aligned with the arrow on the left side of the bottle label for proper closure. Do not

overtighten the cap or you may damage the bottle and cap.

11. The dispenser tip is designed to provide a single pre-measured drop; therefore, do NOT enlarge the

hole of the dispenser tip.

12. After you have used all the doses there may be some TILOPTIC left in the bottle. You should not be

concerned since an extra amount of TILOPTIC has been added in order to ensure that you get the

full amount of TILOPTIC that your doctor prescribed. Do not attempt to remove excess medicine

from the bottle.

Do not bring the bottle within a direct contact with the eye or the area around the eye.

Examinations and monitoring

During treatment with this medicine, intraocular pressure tests should be performed.

Duration of treatment:

Your doctor will decide for how long the eye drops will be needed.

If you use more TILOPTIC than you should

If you put too many drops in your eye or swallow any of the drops, you may:

have a headache

feel dizzy or light-headed

have difficulty breathing

chest pain

feel that your heart rate has slowed down

If this happens, contact your doctor immediately

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately

to a hospital emergency room and bring the package of the medicine with you.

If you forget to take TILOPTIC

It is important to take TILOPTIC as prescribed by your doctor.

If you miss a dose, use the drops as soon as possible.

If it is almost time for the next dose, skip the missed dose and take the next dose at the usual

time.

Do not take a double dose to make up for the forgotten dose.

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your health, do not discontinue use of this medicine before

consulting your doctor.

If you stop using TILOPTIC

If you want to stop using this medicine talk to your doctor first.

How can you contribute to the success of the treatment?

In order to prevent infection make sure the dispenser tip does not come in contact with any

surface (including the eye itself). The bottle should be kept well closed.

The bottle may be not completely full; this is in order to enable a better control on the dripping

pace.

How to use the eye drops: See section INSTRUCTIONS FOR USE.

After using the medicine wash your hands thoroughly in order to clean them from medicine

residues.

To prevent spreading contamination the same bottle must not be used for more than one

person.

Do not take medicines in the dark! Check the label and the dose each time you take your

medicine. Wear glasses if you need them.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. SIDE EFFECTS

Like all medicines, TILOPTIC can cause side effects, in some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

You can usually carry on taking the drops, unless the effects are serious. If you're worried, talk to

a doctor or pharmacist. Do not stop using TILOPTIC without speaking to your doctor.

Like other medicines applied into eyes, timolol is absorbed into the blood. This may cause similar

side effects as seen with intravenous and/or oral beta-blocking agents. Incidence of side effects

after topical ophthalmic administration is lower than when medicines are, for example taken by

mouth or injected. Listed side effects include reactions seen within the class of beta-blockers

when used for treating eye conditions.

Stop using TILOPTIC and seek medical attention immediately, if you develop any of the

following signs:

allergic reactions including swelling beneath the skin that can occur in areas such as the face

and limbs, and can obstruct the airway which may cause difficulty swallowing or breathing,

hives or itchy rash, localized and generalized rash, itchiness, severe sudden life-threatening

allergic reaction.

Additional side effects

Low blood glucose levels.

Difficulty sleeping (insomnia), depression, nightmares, memory loss.

Fainting, stroke, reduced blood supply to the brain, increases in signs and symptoms of

myasthenia gravis (muscle disorder), dizziness, unusual sensations like tingling or pins and

needles, and headache.

Signs and symptoms of eye irritation (e.g. burning, stinging, itching, tearing, redness),

inflammation of the eyelid, inflammation in the cornea, blurred vision and detachment of the

layer below the retina that contains blood vessels following filtration surgery which may cause

visual disturbances, decreased corneal sensitivity, dry eyes, corneal erosion (damage to the

front layer of the eyeball), drooping of the upper eyelid (making the eye stay half closed)

double vision, sensitivity to light, discharge from the eye, pain in the eye.

Ringing sound in the ears.

Slow heart rate, chest pain, palpitations, oedema (fluid build up), changes in the rhythm or

speed of the heartbeat, congestive heart failure (heart disease with shortness of breath and

swelling of the feet and legs due to fluid build up), a type of heart rhythm disorder, heart

attack, heart failure.

Low blood pressure, fainting, interference with the blood supply to the brain which may lead

to a stroke, Raynaud's phenomenon, cold hands and feet, limping because there is a reduced

blood supply to your legs

Constriction of the airways in the lungs (predominantly in patients with pre-existing disease),

difficulty breathing, shortness of breath, wheezing, cough

Taste disturbances, nausea, indigestion, diarrhoea, dry mouth, abdominal pain, vomiting

Sexual dysfunction, decreased sex drive, decreased libido. In men a condition which effects

your penis called Peyronie’s disease. The signs may be abnormal curve, pain or hardening of

the tissue of your penis

Hair loss, skin rash with white silvery coloured appearance (psoriasiform rash) or worsening

of psoriasis, skin rash, itching

Muscle weakness/tiredness, muscle pain not caused by exercise

A condition called lupus (systemic lupus erythematosus).

If a side effect appears, if any of the side effects gets serious or if you suffer from a side effect not

mentioned in this leaflet, consult your doctor.

Adverse events can be reported to the Ministry of Health using the online form in the following link:

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.

health.gov.il

5. HOW TO STORE TILOPTIC

Avoid Poisoning! This medicine, as all other medicine, must be stored in a safe place out of the reach

of children and/or infants, in order to avoid poisoning. Do not induce vomiting unless explicitly instructed

to do so by a doctor!

Do not use TILOPTIC after the expiry date (exp. date) which is stated on the pack. The expiry date

refers to the last day of the indicated month.

Storage conditions: Store below 25°C. Do not Freeze. Protect from light. Do not use this

medicine for more than 30

days after the bottle is first opened.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

6.1 What TILOPTIC contains

In addition to the active ingredient the medicine also contains: Dibasic Sodium Phosphate,

Monobasic Sodium Phosphate, Benzalkonium chloride, Sodium hydroxide, Water for injections.

See also section 2.6 “Important information about some of the ingredients of TILOPTIC”.

6.2 What TILOPTIC looks like and contents of the pack

TILOPTIC is a clear colourless to light yellow sterile eye drops solution.

Pack size: 5ml bottle.

Marketing authorization holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

Manufacturer: Laboratories Merck Sharp & Dohme - Chibret, France

This Leaflet was checked and approved by the Ministry of Health on July 2015.

Drug registration no. listed in the official registry of the Ministry of Health:

113.20.22175

Tiloptic-DL-July 2015-Sep 2016-01

1.

NAME OF THE MEDICINAL PRODUCT

TILOPTIC® 0.5 %

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

‘Tiloptic’ 0.5% w/v Eye Drops Solution contains timolol maleate equivalent to 0.5%

w/v solution of timolol with preservative.

3.

PHARMACEUTICAL FORM

Eye drops solution.

Clear, colourless to light yellow, sterile eye drops solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

For the reduction of elevated intraocular pressure may be used in patients with chronic

open angle glaucoma, aphakic glaucoma, some patients with secondary glaucoma and

patients with ocular hypertension.

4.2

Posology and method of administration

Recommended therapy is one drop in the affected eye twice a day.

needed,

‘Tiloptic’

used

with

other

agent(s)

lowering

intra-ocular

pressure. The use of two topical beta-adrenergic blocking agents is not recommended

(see 4.4 ‘Special warnings and precautions for use’).

Intra-ocular pressure should be reassessed approximately four weeks after starting

treatment because response to ‘Tiloptic’ may take a few weeks to stabilise.

Provided that the intra-ocular pressure is maintained at satisfactory levels, many

patients can then be placed on once-a-day therapy.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic

absorption is reduced. This may result in a decrease in systemic side effects and an

increase in local activity.

Transfer from other agents

When another topical beta-blocking agent is being used, discontinue its use after a full

day of therapy and start treatment the next day with one drop of ‘Tiloptic’ in each

affected eye twice a day.

When transferring a patient from a single anti-glaucoma agent other than a topical

beta-blocking agent, continue the agent and add one drop of ‘Tiloptic’ in each affected

eye twice a day. On the following day, discontinue the previous agent completely, and

continue with the ‘Tiloptic’.

Use in the elderly

: there has been wide experience with the use of timolol maleate in

elderly patients. The dosage recommendations given above reflect the clinical data

derived from this experience.

Paediatric Population:

Safety and effectiveness in pediatric patients have not been established.

4.3

Contraindications

Reactive airway disease including bronchial asthma or a history of bronchial asthma,

severe chronic obstructive pulmonary disease; sinus bradycardia, sick sinus syndrome,

sino-atrial block, second- and third-degree atrioventricular block not controlled with

pace-maker, overt cardiac failure, cardiogenic shock.

Hypersensitivity to the active substance or to any of the excipients.

4.4

Special warnings and precautions for use

Like other topically applied ophthalmic agents, timolol is absorbed systemically. Due

to beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary

and other adverse reactions seen with systemic beta-adrenergic blocking agents may

occur. Incidence of systemic ADRs after topical ophthalmic administration is lower

than for systemic administration. To reduce the systemic absorption, see 4.2.

Cardiac disorders:

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 the 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.

Due to its negative effect on conduction time, beta-blockers should only be given with

caution to patients with first degree heart block.

Cardiac

failure

should

adequately

controlled

before

beginning

therapy

with

‘Tiloptic’. Patients with a history of severe cardiac disease should be watched for signs

of cardiac failure and have their pulse rates monitored.

Vascular disorders

Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of

Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.

Respiratory disorders:

Respiratoryreactions, including death due to bronchospasm in patients with asthma

have been reported following administration of some ophthalmic beta-blockers.

‘Tiloptic’should

used

with

caution,

patients

with

mild/moderate

chronic

obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the

potential risk.

Hypoglycaemia/diabetes

Beta-blockers should be administered with caution in patients subject to spontaneous

hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs

and symptoms of acute hypoglycaemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases

should be treated with caution.

Other beta-blocking agents

The effect on intra-ocular pressure or the known effects of systemic beta-blockade

may be potentiated when timolol is given to the patients already receiving a systemic

beta-blocking agent. The response of these patients should be closely observed. The

use of two topical beta-adrenergic blocking agents is not recommended (see section

4.5).

There have been reports of skin rashes and/or dry eyes associated with the use of

beta-adrenoreceptor blocking drugs. The reported incidence is small and in most cases

the symptoms have cleared when treatment was withdrawn. Discontinuation of the

drug should be considered if any such reaction is not otherwise explicable. Cessation

of therapy involving beta-blockade should be gradual.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant

therapy (e.g. timolol, acetazolamide) after filtration procedures.

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects

e.g. of epinephrine (adrenaline). The anaesthesiologist should be informed when the

patient is receiving timolol.

‘Tiloptic’ has been generally well tolerated in glaucoma patients wearing conventional

hard contact lenses. ‘Tiloptic’ has not been studied in patients wearing lenses made

with material other than polymethylmethacrylate (PMMA), which is used to make

hard contact lenses.

‘Tiloptic’ contains benzalkonium chloride as a preservative which may be deposited in

soft contact lenses; therefore ‘Tiloptic’ should not be used while wearing these lenses.

The lenses should be removed before application of the drops and not reinserted

earlier than 15 minutes after use.

In patients with angle-closure glaucoma, the immediate objective of treatment is to

reopen the angle. This requires constricting the pupil with a miotic. ‘Tiloptic’ has little

or no effect on the pupil. When ‘Tiloptic’ is used to reduce elevated intra-ocular

pressure in angle-closure glaucoma it should be used with a miotic and not alone.

Patients should be advised that if they develop an intercurrent ocular condition (e.g.

trauma, ocular surgery or infection), they should immediately seek their physician’s

advice concerning the continued use of the present multidose container (see 6.6

‘Special precautions for disposal and other handling’).

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 a

disruption of the ocular epithelial surface.

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

and,

unresponsive

usual

dose

epinephrine (adrenaline) used to treat anaphylactic reactions.

4.5

Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been performed with timolol maleate.

There is a potential for additive effects resulting in hypotension and/or marked

bradycardia when ophthalmic beta-blockers solution is administered concomitantly

with oral calcium-channel blockers, beta-adrenergic blocking agents, antiarrhythmics

(including

amiodarone),

digitalis

glycosides,

rauwolfia

alkaloids,

parasympathomimetics, guanethidine.

Although ‘Tiloptic’ alone has little or no effect on pupil size, mydriasis resulting from

concomitant use of ophthalmic beta-blockers and epinephrine (adrenaline) 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,

fluoxetine, paroxetine) and timolol.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which

can follow the withdrawal of clonidine.

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

production

hypotension

and/or

marked

bradycardia, which may produce vertigo, syncope, or postural hypotension.

Oral calcium-channel 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-

channel blocker is added to the treatment regimen. The nature of any cardiovascular

adverse

effects

tends

depend

type

calcium-channel

blocker

used.

Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas

verapamil

diltiazem

have

greater

propensity

lead

conduction

disturbances or left ventricular failure when used with a beta-blocker.

Intravenous

calcium

channel

blockers

should

used

with

caution

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.

4.6

Pregnancy and lactation

Pregnancy

There are no adequate data for the use of timolol maleate in pregnant women.

‘Tiloptic’should not be used during pregnancy unless clearly necessary. To reduce the

systemic absorption, see 4.2.

Epidemiological studies have not revealed malformative effects but show a risk for

intra uterine growth retardation when beta-blockers are administered by the oral route.

In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension,

respiratory distress and hypoglycaemia) have been observed in the neonate when

beta-blockers have been administered until delivery. If ‘Tiloptic’ is administered until

delivery, the neonate should be carefully monitored during the first days of life.

Lactation

Timolol is detectable in human milk. A decision for breastfeeding mothers, either to

stop taking ‘Tiloptic’ or stop nursing, should be based on the importance of the drug to

the mother.

4.7

Effects on the ability to drive and use machines

Possible

side

effects

such

dizziness,

visual

disturbances,

refractive

changes,

diplopia, ptosis, frequent episodes of mild and transient blurred vision and fatigue may

affect some patients’ ability to drive or operate machinery.

4.8

Undesirable effects

Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic

circulation.

This

cause

similar

undesirable

effects

seen

with

systemic

beta-blocking

agents.

Incidence

systemic

ADRs

after

topical

ophthalmic

administration

lower

than

systemic

administration.

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.

Additional side effects have been reported in clinical experiences with

systemic

timolol maleate,

considered

potential

effects

ophthalmic

timolol

maleate. Also listed are adverse reactions seen within the class of ophthalmic beta-

blockers and may potentially occur with ‘Tiloptic’.

Eye disorders

ocular

: signs and symptoms of ocular irritation, (e.g. burning, stinging, itching,

tearing, redness), conjunctivitis, blepharitis, keratitis, dry eyes, decreased corneal

sensitivity, blurred vision, corneal erosion. Visual disturbances, including refractive

changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and

choroidal detachment following filtration surgery (see 4.4 ‘Special warnings and

precautions for use’).

Ear and labyrinth disorders:

Ocular:

tinnitus

Cardiac disorders

ocular

: bradycardia, chest pain, arrhythmia, heart block, congestive heart failure,

palpitations, cardiac arrest, atrioventricular block,cardiac failure, oedema;

systemic

AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening

of arterial insufficiency, worsening of angina pectoris, vasodilation.

Vascular disorders:

ocular

: claudication, hypotension, Raynaud's phenomenon, cold hands and feet.

Respiratory, thoracic and mediastinal disorders

ocular

: bronchospasm (predominantly in patients with pre-existing bronchospastic

disease), respiratory failure, dyspnoea, cough;

systemic

: rales.

General disorders and administration site conditions:

ocular

: asthenia, fatigue;

systemic

: extremity pain, decreased exercise tolerance.

Skin and subcutaneous tissue disorders:

ocular

: alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash;

systemic

: sweating, exfoliative dermatitis.

Immune system disorders:

ocular:

systemic lupus erythematosus, pruritus;

systemic

signs

symptoms

allergic

reactions

including

anaphylaxis,

angioedema, urticaria, localised and generalised rash, anaphylactic reaction.

Psychiatric disorders:

ocular:

depression, insomnia, nightmares, memory loss;

systemic:

diminished concentration, increased dreaming.

Nervous system disorders

ocular

: syncope, cerebrovascular accident, cerebral ischemia, headache, dizziness,

increase in signs and symptoms of myasthenia gravis, paraesthesia;

systemic

: vertigo, local weakness

Gastrointestinal disorders:

ocular

: nausea, diarrhoea, dyspepsia, dry mouth, dysgeusia, abdominal pain, vomiting.

Reproductive system and breast disorders:

ocular

: decreased libido, Peyronie’s disease, sexual dysfunction such as impotence;

systemic

: micturition difficulties.

Metabolism and nutrition disorders:

ocular

: hypoglycaemia;

systemic

: hyperglycaemia.

Musculoskeletal and connective tissue disorders

ocular:

myalgia;

systemic

: arthralgia.

Blood and lymphatic system disorders:

systemic

: non-thrombocytopenic purpura.

Any suspected adverse events should be reported to the Ministry of Health according

to the National Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffect

Medic@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

4.9

Overdose

There

have

been

reports

inadvertent

overdosage

with

‘Tiloptic’

resulting

systemic effects similar to those seen with systemic beta-adrenergic blocking agents

such

dizziness,

headache,

shortness

breath,

bradycardia,

hypotension,

bronchospasm, acute cardiac insufficiency and cardiac arrest (see ‘Side effects’).

If overdosage occurs, the following measures should be considered:

Gastric lavage, if ingested. Studies have shown that timolol does not dialyse

readily.

Symptomatic bradycardia: atropine sulphate, 0.25 to 2 mg intravenously, should

be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline

hydrochloride should be administered cautiously. In refractory cases, the use of a

cardiac pacemaker may be considered.

Hypotension: a sympathomimetic pressor agent such as dopamine, dobutamine or

noradrenaline should be used. In refractory cases, the use of glucagon has been

reported to be useful.

Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy

with aminophylline may be considered.

Acute cardiac failure: conventional therapy with digitalis, diuretics, and oxygen

should be instituted immediately. In refractory cases, the use of intravenous

aminophylline is suggested. This may be followed, if necessary, by glucagon,

which has been reported useful.

Heart block (second- or third-degree): isoprenaline hydrochloride or a pacemaker

should be used.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does

not have significant intrinsic sympathomimetic, direct myocardial depressant, or local

anaesthetic activity. Timolol maleate combines reversibly with the beta-adrenergic

receptor,

this

inhibits

usual

biologic

response

that

would

occur

with

stimulation of that receptor. This specific competitive antagonism blocks stimulation

of the 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.

Unlike miotics, ‘Tiloptic’ reduces IOP with little or no effect on accommodation or

pupil size. In patients with cataracts, the inability to see around lenticular opacities

when the pupil is constricted is avoided. When changing patients from miotics to

‘Tiloptic’ a refraction might be necessary when the effects of the miotic have passed.

Diminished response after prolonged therapy with ‘Tiloptic’ has been reported in

some patients.

5.2

Pharmacokinetic properties

The onset of reduction in intra-ocular pressure can be detected within one-half hour

after a single dose. The maximum effect occurs in one or two hours; significant

lowering of IOP can be maintained for as long as 24 hours with a single dose.

5.3

Preclinical safety data

No adverse ocular effects were observed in rabbits and dogs administered ‘Tiloptic’

topically in studies lasting one and two years, respectively. The oral LD

of the drug

is 1,190 and 900 mg/kg in female mice and female rats, respectively.

Carcinogenesis, mutagenesis, impairment of fertility

In a two-year oral study of timolol maleate in rats there was a statistically significant

0.05) increase in the incidence of adrenal phaeochromocytomas in male rats

administered 300 mg/kg/day (300 times the maximum recommended human oral

dose). Similar differences were not observed in rats administered oral doses equivalent

to 25 or 100 times the maximum recommended human oral dose.

In a lifetime oral study in mice, there were statistically significant (p

0.05) increases

in the incidence of benign and malignant pulmonary tumours, benign uterine polyps

and mammary adenocarcinoma in female mice at 500 mg/kg/day (500 times the

maximum recommended human dose), but not at 5 or 50 mg/kg/day. In a subsequent

study in female mice, in which post-mortem examinations were limited to uterus and

lungs, a statistically significant increase in the incidence of pulmonary tumours was

again observed at 500 mg/kg/day.

increased

occurrence

mammary

adenocarcinoma

associated

with

elevations in serum prolactin which occurred in female mice administered timolol at

500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of

mammary adenocarcinomas in rodents has been associated with administration of

several other therapeutic agents which elevate serum prolactin, but no correlation

between serum prolactin levels and mammary tumours has been established in man.

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.

Timolol maleate was devoid of mutagenic potential when evaluated

in vivo

(mouse) in

the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and

in vitro

in a

neoplastic cell transformation assay (up to 100 mcg/ml). In Ames tests the highest

concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with

statistically significant (p

0.05) elevations of revertants observed with tester strain

TA100 (in seven replicate assays) but not in the remaining three strains. In the assays

with tester strain TA100, no consistent dose-response relationship was observed, nor

did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the

criterion for a positive Ames test.

Reproduction and fertility studies in rats showed no adverse effect on male or female

fertility at doses up to 150 times the maximum recommended human oral dose.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Monobasic Sodium Phosphate

Dibasic Sodium Phosphate

Sodium hydroxide

Benzalkonium chloride

Water for injections

6.2

Incompatibilities

None known.

6.3

Shelf life

24 months

Discard ‘Tiloptic’ Eye Drops Solution 30 days after first opening the bottle.

6.4

Special precautions for storage

Store below 25°C. Do not Freeze. Protect from light.

6.5

Nature and contents of container

The dispenser consists of a translucent high-density polyethylene container with a

sealed dropper tip, a flexible fluted side area, which is depressed to dispense the drops,

and a two-piece cap assembly. The two-piece cap mechanism punctures the sealed

dropper tip upon initial use, then locks together to provide a single cap during the

usage period. Tamper evidence is provided by two perforated tabs on the container

label extending on to the cap. The dispenser contains 5 ml of solution.

6.6

Special precautions for disposal and other handling

Patients should be instructed to avoid allowing the tip of the dispensing container to

contact the eye or surrounding structures.

Patients should also be instructed that 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.

7.

REGISTRATION

HOLDER

Rafa Laboratories Ltd., P.O.Box 405, Jerusalem 9100301.

8.

REGISTRATION NUMBER(S)

113 20 22175

9.

MANUFACTURER

Laboratories Merck Sharp & Dohme-Chibret (Mirabel) Route de Marsat, 63963

Clermont-Ferrand, Cedex 9, France

The format of this leaflet was determined by the Ministry of Health and its content was

checked and approved in

July 2015

)תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ(

05.2013

_____ ךיראת

26

-

Jun-2014

___

תילגנאב רישכת םש

TILOPTIC 0.5

%

םושירה רפסמ

113

20

22175

00

םושירה לעב םש

Merck Sharp & Dohme (Israel – 1996) Company Ltd

.

! דבלב תורמחהה טורפל דעוימ הז ספוט ןכרצל ןולעב תושקובמה תורמחהה ןולעב קרפ טסקט יחכונ שדח טסקט ןיא יתמ שמתשהל ?רישכתב

-

)רידס אל בל בצק( בלה בצקב תוערפה

רשא ,ךומנ םד ץחלמ םרגנה בלב רומח בצמ – "ינגוידרק םלה" רוע ,ריהמ בל בצק ,תרוחרחס :םיאבה םינימסתל םורגל לולע .הרכה ןדבוא ,החונמ רסוח ,העזה ,ןבל שמתשהל ןיא ילבמ הפורתב ץעוויהל ינפל אפורב תלחתה :לופיטה םא ךלש אפורל רפס ,קיטפוליטב לופיטה ינפל תלבס וא לבוס התא :מ רבעב

ךומנ םד ץחל

יטיא בל בצק ןוגכ בלה בצקב תוערפה

)ונייר תנומסת וא ונייר תלחמ ןוגכ( השלח םד תמירז תלחמ

רכוס לש םינימסתו םינמיס ךסמל לולע לולומיטו רחאמ ,תרכוס םדב ךומנ

לולע לולומיטו רחאמ ,)דיאורית( סירתה תטולב לש רתי תוליעפ .םינימסתהו םינמיסה תא ךסמל ןיב תובוגת :תויתופורת :חקול התא םא חקורה וא אפורה תא עדייל שי דחוימב ,תורחא םייניע תופיט לכ וא המוקואלגב לופיטל תורחא םייניע תופיט וא בלל תופורת ,םד-ץחל תדרוהל תופורת תרכוסב לופיטל תופורת

ב שומישה ינפל אפורל רפסל בושח קיטפוליט רתוי וא תחא חקול התא םא :תואבה תופורתהמ

םישמשמה ,םזאיטליד ,לימאפארו ,ןיפידפינ ןוגכ ,ןדיס םסוח ןיקת אל בל בצק ,הקועת ,הובג םד ץחלב לופיטל תובורק םיתיעל ונייר תנומסת וא

לופיטל וא בל תקיפס-יאב הלקהל תשמשמה הפורת ,ןיסקוגיד ןיקת אל בל בצקב

דיאולקלא ןוגכ ,םינימאלוכטק יתיחפמ םירמוחכ תועודיה תופורת הובג םד ץחלל תושמשמה ,ןיפרסר וא היפלוואר

לופיטל שמשמה ןילנרדא ןוגכ ,םינימא-רוסרפ תוארקנה תופורת הרומח תיגרלא הבוגתב

לש םימיוסמ םיגוסו בלב תויעבב לופיטל תשמשמה( ןידיניכ )הירלמ

ןיטסקוראפו ןיטסקואולפ םינוכמה ןואכיד ידגונ

הובג םד ץחלב לופיטל תשמשמה תופורת ,ןידינולק

תופיטכ םישמשמה וא הפה ךרד םיחקלנה םירחא אטב ימסוח ומכ תופורת תצובק התואל םיכייש םהו רחאמ ,םייניע קיטפוליט תרבטצמ העפשה םהל תויהל הלוכיו

שמתשת דציכ :הפורתב

לע ןמוסמל םאתהב קקפה תא בבוס ןוקובקבה תא חותפל ידכב .הסכמה לש ןוילעה וקלחב םיציחה הסכמה תא ךושמת לא יפלכ הסכמה תכישמ .ןוקובקבהמ קחרהו הלעמ יפלכ תורישי יוארכ לועפל תפטפטהמ ענמת הלעמ

ב שומישה רחאל קיטפוליט דיל ,ןיעה תיוז לע עבצאה םע ץחל , ךשמל ףאה

ףוגה ראשל לולומיט תגיפס תעינמב רוזעי הז .תוקד יאוול תועפות תעינמב רוזעי ןכלו ךלש

חתפמ התא םא וא ,המהדזה ךלש הפורתהש בשוח התא םא .ןוקובקבב שומיש ךשמהל עגונב דימ אפורל הנפ ,ןיעב תקלד תועפות :יאוול

םדב תוכומנ זוקולג תומר

לש םינימסתו םינמיסב היילע ,חומל םדה תקפסאב הדירי ,ץבש ,)םירירשה דוקפתב הערפה( סיברג הינתסאימ

,תינרקב תקלד ,םייפעפעב תקלד

תחתמ הבכשה תודרפיהו יושע רשא היצרטליפ חותינמ האצותכ םד ילכ הליכמה תיתשרל ,תינרקה תושיגרב הדירי ,הייאר שוטשטל םורגל

ףעפעה תחינצ ,)ןיעה לגלג לש ימדקה קלחל קזנ( תינרקה תקיחש ,)היצחב הרוגס ראשיהל ןיעל םרוג רשא( ןוילעה

,רואל תושיגר .ןיעב באכ ,ןיעהמ תושרפה

הלולע רשא חומל םדה תקפסאב הערפה ,ןופליע ,ךומנ םד ץחל העילצ ,תורק םיילגרו םיידי תופכ ,ונייר תעפות ,ץבשל ליבוהל םיילגרל םדה תקפסאב הדירי ללגב

,)תמייק הלחמ םע םילוחב רקיעב( ,תואירב המישנה יכרד תורציה ,םיפוצפצ ,המישנ רצוק ,המישנב ישוק

,םעטב תוערפה

.תואקה ,ןטב באכ

,ינימה דוקפתב תויעב ןיפה תמקע ארקנו ךלש ןימה רביא לע עיפשמה בצמ ,םירבגב ,הגירח תוימומקע תויהל םילוכי םינמיסה .)ינורייפ םש לע הלחמ( .ךלש ןיפב תומקרה תושקתה וא באכ

תייומד החירפ( ףוסכ-ןבל עבצב הארמ תלעב תירוע החירפ ,סיזאירוספ לש הרמחה וא )סיזאירוספ

האצותכ םרגנ אל רשא םירירשב באכ ,םירירש תופייע/תשלוח תינפוג תוליעפמ

)תיתכרעמ תיתנמדא תבאז( תבאז ארקנה בצמ

אפורל ןולעב תושקובמה תורמחהה ןולעב קרפ טסקט יחכונ שדח טסקט

Contra-

Indications

sick sinus syndrome, sino-atrial block,

second- and third-degree

atrioventricular block not controlled with pace-maker,

Posology, dosage

& administration

Section 4.2 Posology and method of administration:

When using nasolacrimal occlusion or closing the eyelids

for 2 minutes, the systemic absorption is reduced. This may

result in a decrease in systemic side effects and an

increase in local activity.

Special Warnings

and Special

Precautions for

Use

To reduce the systemic absorption, see 4.2.

Vascular disorders

Patients with severe peripheral circulatory

disturbance/disorders )i.e. severe forms of Raynaud’s

disease or Raynaud’s syndrome( should be treated with

caution.

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes.

Patients with corneal diseases should be treated with

caution.

There have been reports of skin rashes and/or dry eyes associated with the

use of beta-adrenoreceptor blocking drugs. The reported incidence is

small and in most cases the symptoms have cleared when treatment was

withdrawn. Discontinuation of the drug should be considered if any such

reaction is not otherwise explicable. Cessation of therapy involving beta-

blockade should be gradual.

Interaction with

Other

Medicaments and

No specific drug interaction studies have been performed

with timolol maleate.

There is a potential for additive effects resulting in

Other Forms of

Interaction

hypotension and/or marked bradycardia when ophthalmic

beta-blockers solution is administered concomitantly with

oral calcium-channel blockers, beta-adrenergic blocking

agents, antiarrhythmics )including amiodarone(, digitalis

glycosides, rauwolfia alkaloids, parasympathomimetics,

guanethidine.

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 potential exists for hypotension, AV conduction disturbances and left

ventricular failure to occur in patients receiving a beta-blocking agent

when an oral calcium-channel blocker is added to the treatment regimen.

The nature of any cardiovascular adverse effects tends to depend on the

type of calcium-channel 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

Fertility,

pregnancy and

Lactation

To reduce the systemic absorption, see 4.2.

Epidemiological studies have not revealed malformative

effects but show a risk for intra uterine growth retardation

when beta-blockers are administered by the oral route. In

addition, signs and symptoms of beta-blockade )e.g.

bradycardia, hypotension, respiratory distress and

hypoglycaemia( have been observed in the neonate when

beta-blockers have been administered until delivery. If

‘Tiloptic’

is administered until delivery, the neonate should

be carefully monitored during the first days of life.

Effects on the

ability to drive

and use machines

Possible side effects such as dizziness, visual disturbances, refractive

changes, diplopia, ptosis, frequent episodes of mild and transient blurred

vision and fatigue may affect some patients’ ability to drive or operate

machinery.

Adverse events

Eye disorders: blurred vision, corneal erosion

Cardiac disorder:

ocular: congestive heart failure, atrioventricular block

systemic: AV block (second- or third-degree), sino-atrial block,

Skin and subcutaneous tissue disorders:

ocular: skin rash

systemic: exfoliative dermatitis.

Psychiatric disorders:

systemic: increased dreaming.

Gastrointestinal disorders

:

ocular: dysgeusia, abdominal pain, vomiting

Musculoskeletal and connective tissue disorders:

ocular:myalgia;

4.9

Overdose

(additional systemic effects)

hypotension, acute cardiac insufficiency

5.1

Pharmacodynamic

properties

Diminished response after prolonged therapy with ‘Tiloptic’ has been

reported in some patients.

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