Latanoprost / Timolol 50 microgram/5.0 mg per ml Eye Drops Solution

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Latanoprost; Timolol
Available from:
Accord Healthcare Ireland Ltd.
ATC code:
S01ED; S01ED51
INN (International Name):
Latanoprost; Timolol
Dosage:
50 mcg/ml + 5 milligram(s)/millilitre
Pharmaceutical form:
Eye drops, solution
Therapeutic area:
Beta blocking agents1); timolol, combinations
Authorization status:
Marketed
Authorization number:
PA2315/024/001
Authorization date:
2011-08-26

Package leaflet: Information for the user

Latanoprost/Timolol 50 microgram/5.0 mg per ml Eye Drops Solution

Latanoprost/timolol

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

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

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

1.

What Latanoprost/Timolol is and what it is used for

2.

What you need to know before you use Latanoprost/Timolol

3.

How to use Latanoprost/Timolol

4.

Possible side effects

5.

How to store Latanoprost/Timolol

6.

Contents of the pack and other information

1.

What Latanoprost/Timolol is and what it is used for

Latanoprost/Timolol contains two medicines: latanoprost and timolol. Latanoprost belongs to a group

of medicines known as prostaglandin analogues. Timolol belongs to a group of medicines known as

beta-blockers. Latanoprost works by increasing the natural outflow of fluid from the eye into the

bloodstream. Timolol works by slowing the formation of fluid in the eye.

Latanoprost/Timolol is used to reduce the pressure in your eye if you have conditions known as open

angle glaucoma or ocular hypertension. Both these conditions are linked to an increase in the pressure

within your eye, eventually affecting your eyesight. Your doctor will usually prescribe you

Latanoprost/Timolol when other medicines have not worked adequately.

2.

What you need to know before you use Latanoprost/Timolol

Latanoprost/Timolol can be used in adult men and women (including the elderly), but is not

recommended for use if you are less than 18 years of age.

Do not use Latanoprost/Timolol:

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

ingredients of this medicine (listed in section 6);

if you have now or have had in the past respiratory problems such as asthma or severe chronic

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

and/or long-standing cough);

if you suffer from certain heart disorders, e.g. slow heartbeat (sinus bradycardia, second or

third-degree atrioventricular block), a weak heart (manifest cardiac insufficiency) or in acute or

chronic heart failure (cardiogenic shock).

Warnings and precautions

Talk to your doctor or pharmacist before using Latanoprost/Timolol . Tell your doctor or pharmacist

if you have now or have had in the past:

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

you are about to have any kind of eye surgery (including cataract surgery) or have had any kind

of eye surgery in the past

you suffer from eye problems (such as eye pain, eye irritation, eye inflammation or blurred

vision)

you know that you suffer from dry eyes

you wear contact lenses. You can still use Latanoprost/Timolol but follow the instructions for

contact lens wearers in Section 3

you know that you suffer from angina (particularly a type known as Prinzmetal’s angina)

you know that you suffer from severe allergic reactions that would usually require hospital

treatment

you have suffered or are currently suffering from a viral infection of the eye caused by the

herpes simplex virus (HSV)

Tell your doctor before you have an operation that you are using Latanoprost/Timolol

as timolol may

change effects of some medicines used during anaesthesia.

Other medicines and Latanoprost/Timolol

Latanoprost/Timolol can affect or be affected by other medicines you are using, including other eye

drops for the treatment of glaucoma. Tell your doctor if you are using or intend to use other medicines

to lower blood pressure, heart medicine or medicines to treat diabetes. Please tell your doctor or

pharmacist if you are taking or have recently taken any other medicines, including medicines obtained

without a prescription.

In particular, speak to your doctor or pharmacist if you know you are taking any of the following

types of medicines:

Prostaglandins, prostaglandin analogues or prostaglandin derivates

Beta-blockers

Epinephrine

Medicines used to treat high blood pressure such as oral calcium channel blockers,

guanethidine,

Digitalis glycosides (medicines used to relieve heart failure or treat abnormal heartbeat, e.g.

digoxin)

Medicines to enable you to urinate more easily or in order to restore normal bowel movements

(parasympathomimetics)

Clonidine; if you are taking a medicine called clonidine with Latanoprost/Timolol and then you

suddenly stop taking clonidine, your blood pressure may rise

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

Antidepressants known as fluoxetine and paroxetine

Latanoprost/Timolol with food and drink

Normal meals, food or drink have no effect on when or how you should use Latanoprost/Timolol .

Pregnancy, breast-feeding and fertility

Pregnancy

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Do not use Latanoprost/Timolol if you are pregnant unless your doctor considers it necessary.

Breast-feeding

Do not use Latanoprost/Timolol if you are breast-feeding. Latanoprost/Timolol may get into your

milk. Ask your doctor for advice before taking any medicine during breast-feeding.

Fertility

Latanoprost and Timolol have been found to have no effect on male or female fertility in animal

studies.

Driving and using machines

When you use Latanoprost/Timolol your vision may become blurred for a short time. If this happens

to you, do not drive or use any tools or machines until your vision becomes clear again.

Latanoprost/Timolol eye drops, solution contains benzalkonium chloride and phosphate buffers

This medicinal product contains benzalkonium chloride which may cause eye irritation. Avoid contact

with soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes

before putting them back in. Benzalkonium chloride is known to discolour soft contact lenses.

Benzalkonium chloride may also cause eye irritation, especially if you have dry eyes or

disorders of the cornea (the clear layer at the front of the eye). If you feel abnormal eye

sensation, stinging or pain in the eye after using this medicine, talk to your doctor.

If you suffer from severe damage to the clear layer at the front of the eye (the cornea),

phosphates may cause in very rare cases cloudy patches on the cornea due to calcium build-up

during treatment.

3.

How to use Latanoprost/Timolol

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

The usual dosage for adults (including the elderly) is one drop once a day into the affected eye(s).

Do not use Latanoprost/Timolol more than once a day, because the effectiveness of the treatment can

be reduced if you administer it more often.

Use Latanoprost/Timolol as instructed by your doctor until your doctor tells you to stop.

Your doctor may want you to have extra checks on your heart and circulation if you use

Latanoprost/Timolol .

Contact lens wearers

If you wear contact lenses, you should remove them before using Latanoprost/Timolol . After using

Latanoprost/Timolol you should wait 15 minutes before putting your contact lenses back in.

Instructions for use

Wash your hands and sit or stand comfortably.

Twist off the colourless protective cap with the “wings”.

Unscrew the cap.

Use your finger to gently pull down the lower eyelid of your affected eye (figure 1).

Place the tip of the bottle close to, but not touching your eye (figure 1).

Squeeze the bottle gently so that only one drop goes into your eye, then

release the lower eyelid (figure 1).

After using Latanoprost/Timolol , press a finger into the corner of your

eye, by the nose (figure 2) for 2 minutes. This helps to stop

latanoprost/timolol getting into the rest of the body.

Repeat in your other eye if your doctor has told you to do this.

Put the protective inner cap back on the bottle.

Children

There is limited experience with Latanoprost/Timolol in children and adolescents.

If you use Latanoprost/Timolol with other eye drops

Wait at least 5 minutes between using Latanoprost/Timolol and using the other eye drops.

If you use more Latanoprost/Timolol than you should

If you put too many drops in your eye you may experience some minor irritation in your eye and your

eyes may water and turn red. This should pass but if you are worried contact your doctor for advice.

If you swallow Latanoprost/Timolol

If you swallow Latanoprost/Timolol accidentally you should contact your doctor for advice. If you

swallow a lot of Latanoprost/Timolol you may feel sick, have stomach pains, feel tired, flushed and

dizzy and start to sweat.

If you forget to use Latanoprost/Timolol

Carry on with the usual dosage at the usual time. Do not take a double dose to make up for the dose

you have forgotten. If you are unsure about anything talk to your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets 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 Latanoprost/Timolol without speaking to your doctor.

Listed below are the known side effects of using Latanoprost/Timolol . The most important side-effect

is the possibility of a gradual, permanent change in your eye colour. It is also possible that

Latanoprost/Timolol might cause serious changes in the way your heart works. If you notice changes

in your heart rate or heart function you should speak to a doctor and tell them you have been using

Latanoprost/Timolol .

The following are known side effects of using Latanoprost/Timolol :

Very common (may affect more than 1 in 10 people):

A gradual change in your eye colour by increasing the amount of brown pigment in the

coloured part of the eye known as the iris. If you have mixed-colour eyes (blue-brown, grey-

brown, yellow-brown or green-brown) you are more likely to see this change than if you have

eyes of one colour (blue, grey, green or brown eyes). Any changes in your eye colour may take

years to develop. The colour change may be permanent and may be more noticeable if you use

Latanoprost/Timolol in only one eye. There appears to be no problems associated with the

change in eye colour. The eye colour change does not continue after Latanoprost/Timolol

treatment is stopped.

Common (may affect up to 1 in 10 people):

Eye irritation (a feeling of burning, grittiness, itching, stinging or the sensation of a foreign

body in the eye) and eye pain.

Uncommon (may affect up to 1 in 100 people):

Headache

Redness of the eye, eye infection (conjunctivitis), blurred vision, watery eyes, inflammation of

the eyelids, irritation or disruption of the surface of the eye

Skin rashes or itching (pruritus)

Other side effects

Like other medicines used in the eyes, Latanoprost/Timolol is absorbed into the

blood. The incidence of side effects after using eye drops is lower than when medicines are, for

example, taken by mouth or injected.

Although not seen with Latanoprost/Timolol , the following additional side effects have been seen

with the medicines in Latanoprost/Timolol (latanoprost and timolol) and therefore might occur

when you use Latanoprost/Timolol .

The listed side effects include reactions seen within the class of

beta-blockers (e.g. timolol) when used for treating eye conditions:

Developing a viral infection of the eye caused by the herpes simplex virus (HSV)

Dizziness

Changes to the eyelashes and fine hairs around the eye (increased number, length, thickness

and darkening), changes to the direction of eyelash growth, swelling around the eye, swelling

of the coloured part of the eye (iritis/uveitis), swelling at the back of the eye (macular

oedema),inflammation/irritation of the surface of the eye (keratitis), dry eyes, fluid filled cyst

within the coloured part of the eye (iris cyst), light sensitivity (photophobia), sunken eye

appearance (deepening of the eye sulcus)

Worsening of angina, awareness of heart rhythm (palpitations)

Asthma, worsening of asthma, shortness of breath

Darkening of the skin around the eyes

Joint pain, muscle pain

Chest pain

Generalized 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

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 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

Whistling/ringing in the ears (tinnitus).

Slow heart rate, chest pain, palpitations (awareness of heart rhythm), 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, Raynaud's phenomenon, cold hands and feet.

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

difficulty breathing, cough.

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

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

of psoriasis, skin rash.

Muscle pain not caused by exercise.

Sexual dysfunction, decreased libido.

Muscle weakness/tiredness.

In very rare cases, some patients with severe damage to the clear layer at the front of the eye

(the cornea) have developed cloudy patches on the cornea due to calcium build-up during

treatment.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance,

Earlsfort

Terrace,

Dublin

Tel:

+353

6764971;

Fax:

+353

6762517.

Website:

www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can help provide more

information on the safety of this medicine.

5.

How to store Latanoprost/Timolol

Keep this medicine out of the sight and reach of children.

Before Latanoprost/Timolol is first opened, it should be stored and transported refrigerated (2°C -

8°C).

Once the bottle has been opened, Latanoprost/Timolol can be kept at room temperature (below 25°C)

for up to 28 days.

Keep the bottle in the outer carton in order to protect from light.

Do not use this medicine after the expiry date which is stated on the carton and the dropper after

‘EXP’. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Latanoprost/Timolol contains

Each millilitre (1 ml) of Latanoprost/Timolol contains:

Active substances:

50 microgram latanoprost and timolol maleate corresponding to 5 mg timolol.

Other ingredients:

sodium dihydrogen phosphate, monohydrate, sodium chloride, disodium

phosphate, anhydrous, benzalkonium chloride (preservative) and water for

injections.

Each bottle of Latanoprost/Timolol contains 2.5 ml eye drops.

What Latanoprost/Timolol Eye drops, solution looks like and contents of the pack

Latanoprost/Timolol is a clear, colourless liquid. It is supplied in a bottle containing 2.5 ml eye drops

solution. The bottles are singly packed.

Latanoprost/Timolol is available in the following pack sizes:

1 bottle x 2.5 ml

3 bottles x 2.5 ml

6 bottles x 2.5 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare Ireland Ltd,

Euro House,

Euro Business Park,

Little Island,

Cork T45 K857,

Ireland

Manufacturer

HBM Pharma s. r. o., Sklabinska 30, 036 80 Martin, Slovakia

This leaflet was last revised in January 2020

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Latanoprost / Timolol 50 microgram/5.0 mg per ml Eye Drops Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 50 microgram latanoprost and 6.8 mg timolol maleate equivalent to 5 mg timolol.

Excipient with known effect:

Benzalkonium chloride 0.2 mg/ml (see section 4.4).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Eye drops, solution.

The solution is a clear, colourless liquid.

Osmolality: 280~320 mOsmol/kg

pH: 5.0 – 7.0

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Latanoprost-Timolol is indicated in adults (including the elderly) for the reduction of intraocular pressure (IOP) in patients with

open angle glaucoma and ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin

analogues.

4.2 Posology and method of administration

Posology

Recommended dosage for adults (including the elderly):

Recommended therapy is one eye drop in the affected eye(s) once daily.

If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the

affected eye(s) daily.

Paediatric population:

The safety and efficacy of Latanoprost-Timolol in children and adolescents has not been established.

Method of administration:

Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes (see section 4.4).

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.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

4.3 Contraindications

Latanoprost-Timolol is contraindicated in patients with:

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary

disease.

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- Sinus bradycardia, sick sinus syndrome sino-atrial block, second or third degree atrioventricular block not controlled with

pace-maker, overt cardiac failure, cardiogenic shock.

4.4 Special warnings and precautions for use

Systemic effects:

Like other topically applied ophthalmic agents, latanoprost/timolol is absorbed systemically. Due to the beta-adrenergic

component timolol, the same types of cardiovascular, pulmonary and other adverse reactions as 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 section 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 reactions, and rarely, death in association with cardiac failures have been reported following administration of timolol.

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:

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in

association with cardiac failures, have been reported following administration of some ophthalmic beta-blockers.

Latanoprost/timolol 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.

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).

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 to the usual doses of adrenaline used to

treat anaphylactic reactions.

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 adrenaline. The anaesthesiologist

should be informed when the patient is receiving timolol.

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Concomitant therapy:

Timolol may interact with other drugs see section 4.5.

Other prostaglandin analogues

The concomitant use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not

recommended (see section 4.5).

Iris Pigmentation changes:

Latanoprost may gradually change eye colour by increasing the amount of brown pigment in the iris. Similar to experience with

latanoprost eye drops, increased iris pigmentation was seen in 16-20% of all patients treated with latanoprost/timolol eye

drops, solution for up to one year (based on photographs). 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 homogeneously 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 the treatment.

Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed but patients

should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation

ensues.

Before treatment is instituted patients should be informed of the possibility of a change in eye colour. Unilateral treatment can

result in permanent heterochromia.

Eyelid and eyelash changes

Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost. Latanoprost may

gradually change eyelashes and veilus hair in the treated eye; these changes include increased length, thickness, pigmentation,

and number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of

treatment.

Glaucoma

There is no documented experience with latanoprost 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 documented experience in acute attacks of closed angle glaucoma. Therefore it is recommended

that latanoprost/timolol should be used with caution in these conditions until more experience is obtained.

Herpetic keratitis

Latanoprost should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of

active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with

prostaglandin analogues.

Macular oedema

Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost. These reports have

mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk

factors for macular oedema. Latanoprost/timolol should be used with caution in these patients.

Preservative:

Latanoprost/Timolol Eye drops, solution contains benzalkonium chloride, which is commonly used as a preservative in

ophthalmic products. Benzalkonium chloride has been reported to cause punctuate keratopathy and/or toxic ulcerative

keratopathy and may cause eye irritation. Close monitoring is required with frequent or prolonged use of latanoprost/timolol

eye drops, solution in dry eye patients, or in conditions where the cornea is compromised.

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Contact lenses

Contact lenses may absorb benzalkonium chloride which is known to discolour soft contact lenses. Contact lenses should be

removed before applying eye drops, solution but may be reinserted after 15 minutes (see section 4.2).

4.5 Interaction with other medicinal products and other forms of interactions

No specific drug product interaction studies have not been performed with latanoprost / timolol eye drops, solution.

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.

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, 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 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.

Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported

occasionally .

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.

Beta-blockers may increase the hypoglycaemic effect of anti-diabetic agents. Beta-blockers can mask the signs and symptoms

of hypoglycaemia (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Latanoprost:

There are no adequate data from the use of latanoprost in pregnant women. Studies in animals have shown reproductive

toxicity (see section 5.3). The potential risk for humans is unknown.

Timolol:

There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless

clearly necessary. To reduce the systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when

betablockers 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 latanoprost/timolol is administered until delivery, the neonate should be carefully monitored

during the first days of life.

Consequently latanoprost/timolol should not be used during pregnancy unless clearly necessary (see section 5.3).

Breastfeeding

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient

amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic

absorption, see section 4.2.

Latanoprost and its metabolites may pass into breast milk.

Latanoprost/timolol Eye drops, solution should therefore not be used in women who are breast feeding.

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Fertility

Neither Latanoprost nor timolol have been found to have any effect on male or female fertility in animal studies.

4.7 Effects on ability to drive and use machines

Latanoprost/timolol has minor influence on the ability to drive and use machines. In common with other eye preparations,

instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use

machines.

4.8 Undesirable effects

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.

For latanoprost, the majority of adverse events relate to the ocular system. In data from the extension phase of the

latanoprost/timolol eye drops, solution pivotal trials, 16-20% of patients developed increased iris pigmentation, which may be

permanent. In an open 5 year latanoprost safety study, 33% of patients developed iris pigmentation (see section 4.4). Other

ocular adverse events are generally transient and occur on dose administration.

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 drugs, timolol is absorbed into the systemic circulation. This may cause similar

undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic

administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of

ophthalmic beta-blockers.

Treatment related adverse events seen in clinical trials with latanoprost / timolol eye drops, solution are listed below.

Adverse events are categorized by frequency as follows:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (frequency cannot be estimated from the available data)

Nervous system disorders:

Uncommon: Headache

Eye disorders:

Very common: Increased iris pigmentation

Common: Eye irritation (including stinging, burning and itching, foreign body sensation), Eye pain

Uncommon: Eye hyperaemia, conjunctivitis, vision blurred, lacrimation increased, blepharitis, corneal disorders

Skin and subcutaneous tissue disorders:

Uncommon: Skin rash, pruritus

Additional adverse events have been reported specific to the use of the individual components of latanoprost/timolol eye

drops, solution in either in clinical studies, spontaneous reports or in the available literature.

For latanoprost, these are:

Infections and infestations:

Herpetic keratitis

Nervous system disorders:

Dizziness

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Eye disorders:

Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes),

punctatekeratitis, periorbital oedema, iritis/uveitis, macular oedema (including cystoid macular oedema dry eye; keratitis;

corneal oedema; corneal erosions; trichiasis; iris cyst; photophobia; periorbital and lid changes resulting in deepening of the

eyelid sulcus; eyelid oedema; localised skin reaction on the eyelids; pseudopemphigoid of the ocular conjunctiva

; darkening

of the palpebral skin.

Cardiac disorders:

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

Respiratory, thoracic and mediastinal disorders:

Asthma, asthma aggravation, dyspnoea

Skin and subcutaneous tissue disorders:

Darkening of palpebral skin

Musculoskeletal and connective tissue disorders:

Myalgia; arthralgia

General disorders and administration site conditions:

Chest pain

May be potentially related to the preservative benzalkonium chloride

For timolol, these are:

Immune system disorders:

Systemic allergic reactions including angioedema, urticaria, and localized and generalized rash, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders

Hypoglycaemia

Psychiatric disorders:

Insomnia, depression, nightmares, memory loss

Nervous system disorders:

Syncope, cerebrovascular accident, cerebral ischaemia, increase in signs and symptoms of myasthenia gravis, dizziness,

parasthesia and headache.

Eye disorders:

Choroidal detachment following filtration surgery (see section 4.4), corneal erosion, keratitis, diplopia, decreased corneal

sensitivity, signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing and redness), dry eyes, blepharitis,

blurred vision, ptosis.

Ear and labyrinth disorders:

Tinnitus

Cardiac disorders:

Bradycardia, chest pain, palpitations, oedema arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, cardiac

failure

Vascular disorders:

Hypotension, Raynaud's phenomenon, cold hands and feet

Respiratory, thoracic and mediastinal disorders:

Bronchospasm (predominately in patients with pre-existing bronchospastic disease), dyspnoea, cough

Gastrointestinal disorders:

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Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting

Skin and subcutaneous tissue disorders:

Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash

Musculoskeletal and connective tissue disorders

Myalgia

Reproductive system and breast disorders

Sexual dysfunction, decreased libido

General disorders and administration site conditions:

Asthenia/fatigue

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

No data are available in humans with regard to overdose with latanoprost/timolol eye drops, solution.

Symptoms

Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac arrest. Apart from ocular

irritation and conjunctival hyperaemia, no other ocular or systemic side effects are known if latanoprost is overdosed.

Treatment:

If symptoms of overdose occur the treatment should be symptomatic and supportive. If latanoprost is accidentally ingested

orally the following information may be useful:

Symptomatic treatment:

Studies have shown that timolol does not dialyse readily. Gastric lavage if needed. Latanoprost is extensively metabolized

during the first pass through the liver. Intravenous infusion of 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmological-beta blocking agents - Timolol, combinations

ATC code: S01E D51

Mechanism of action:

Latanoprost/timolol eye drops, solution 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, a prostaglandin F2 alpha analogue, is a selective prostanoid FP receptor agonist that reduces the IOP by

increasing the outflow of aqueous humour. The main mechanism of action is increased uveoscleral outflow. Additionally, 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, the blood-aqueous barrier or the intraocular blood circulation. 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.

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Timolol is a beta-1 and beta-2 (non-selective) adrenergic receptor blocking agent that has no significant intrinsic

sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Timolol lowers IOP by decreasing the

formation of aqueous in the ciliary epithelium.

The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by

endogenous beta-adrenergic stimulation is probable. Timolol has not been found to significantly affect the permeability of the

blood-aqueous barrier to plasma proteins. In rabbits, timolol was without effect on the regional ocular blood flow after chronic

treatment.

Pharmacodynamic effects

Clinical efficacy and safety

In dose finding studies, latanoprost/timolol eye drops, solution produced significantly greater decreases in mean diurnal IOP

compared to latanoprost and timolol administered once daily as monotherapy. In two well controlled, double masked

six-month clinical studies the IOP reducing effect of latanoprost / timolol eye drops, solution was compared with latanoprost

and timolol monotherapy in patients with an IOP of at least 25 mm Hg or greater. Following a 2-4 week run-in with timolol

(mean decrease in IOP from enrollment of 5 mm Hg), additional decreases in mean diurnal IOP of 3.1, 2.0 and 0.6 mm Hg were

observed after 6 months of treatment for latanoprost/timolol eye drops, solution, latanoprost and timolol (twice daily),

respectively. The IOP lowering effect of latanoprost / timolol eye drops, solution was maintained in 6 month open label

extension of these studies.

Existing data suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, when

considering a recommendation of either morning or evening dosing, sufficient consideration should be given to the lifestyle of

the patient and their likely compliance.

It should be kept in mind that in case of insufficient efficacy of the fixed combination, results from studies indicate that the use

of unfixed administration of timolol and latanoprost once a day might be still efficient.

Onset of action of latanoprost/tmolol eye drops, solution is within one hour and maximal effect occurs within six to eight hours.

Adequate IOP reducing effect has been shown to be present up to 24 hours post dosage after multiple treatments.

5.2 Pharmacokinetic properties

Latanoprost

Absorption

Latanoprost is an isopropyl ester prodrug, which per se is inactive but after hydrolysis by esterases in the cornea to the acid of

latanoprost, becomes biologically active. The prodrug is well absorbed through the cornea and all drugs that enter the

aqueous humor is hydrolysed during the passage through the cornea.

Distribution

Studies in man indicate that the maximum concentration in the aqueous humour, approximately 15-30 ng/ml, is reached about

2 hours after topical administration of latanoprost alone. After topical application in monkeys latanoprost is distributed

primarily in the anterior segment, the conjunctiva and the eye lids.

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%.

Biotransformation and elimination

There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The main

metabolites, the 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or only weak biological activity in animal studies and are

excreted primarily in the urine.

Timolol

Absorption and distribtion

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 ng/ml is reached 10-20 minutes

after topical administration of one eye drop to each eye once daily (300 microgram/day).

Biotransformation

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The half life of timolol in plasma is about 6 hours. timolol is extensively metabolised in the liver.

Elimination

The metabolites are excreted in the urine together with some unchanged timolol.

Latanoprost/timolol eye drops, solution

Pharmacokinetic/pharmacodynamics relationship

No pharmacokinetic interactions between latanoprost and timolol were observed, although there was an approximate 2-fold

increased concentration of the acid of latanoprost in aqueous humour 1-4 hours after administration of latanoprost/timolol

eye drops, solution compared to monotherapy.

5.3 Preclinical safety data

The ocular and systemic safety profile of the individual components is well established. No adverse ocular or systemic effects

were seen in rabbits treated topically with the fixed combination or with concomitantly administered latanoprost and timolol

ophthalmic solutions. Safety pharmacology, genotoxicity and carcinogenicity studies with each of the components revealed no

special hazards for humans. Latanoprost did not affect corneal wound healing in the rabbit eye, whereas timolol inhibited the

process in the rabbit and the monkey eye when administered more frequently than once a day.

For latanoprost, no effects on male and female fertility in rats and no teratogenic potential in rats and rabbits have been

established. No embryotoxicity was observed in rats after intravenous doses of up to 250 microgram/kg/day. However,

latanoprost caused embryo fetal toxicity, characterized by increased incidence of late resorption and abortion and by reduced

foetal weight, in rabbits at intravenous doses of 5 microgram/kg/day (approximately 100 times the clinical dose) and above.

Timolol showed no effects on male and female fertility in rats or teratogenic potential in mice, rats and rabbits.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium dihydrogen phosphate, monohydrate

Sodium chloride

Disodium phosphate, anhydrous

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with latanoprost/timolol

eye drops, solution. If such drugs are used concomitantly with latanoprost/timolol eye drops, solution, the eye drops should be

administered with an interval of at least five minutes.

6.3 Shelf life

Unopened: 2 years

Shelf life after first opening: 28 days

Storage after first opening: Do not store above 25°C. Keep the bottle in the outer carton in order to protect from light.

6.4 Special precautions for storage

Store and transport refrigerated (2°C - 8°C).

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

LDPE bottle (5 ml) and dropper applicator (dropper tip), HDPE screw cap and tamper evident LDPE overcap.

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Each bottle contains 2.5 ml eye drop solution.

The eye drops, solution is available in the following pack sizes:

1 bottle x 2.5 ml

3 bottles x 2.5 ml

6 bottles x 2.5 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The tamper evident over cap should be removed before use.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Accord Healthcare Ireland Ltd.

Euro House

Euro Business Park

Little Island

Cork T45 K857

Ireland

8 MARKETING AUTHORISATION NUMBER

PA2315/024/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26

August 2011

Date of last renewal: 28

February 2014

10 DATE OF REVISION OF THE TEXT

January 2020

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