Latanoprost/Timolol 2care4 50 mikrogram/ml + 5 mg/ml Ögondroppar, lösning

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

20-01-2020

Produktens egenskaper Produktens egenskaper (SPC)

20-01-2020

Aktiva substanser:
latanoprost; timololmaleat
Tillgänglig från:
2care4 ApS,
ATC-kod:
S01ED51
INN (International namn):
latanoprost; timolol maleate
Dos:
50 mikrogram/ml + 5 mg/ml
Läkemedelsform:
Ögondroppar, lösning
Sammansättning:
timololmaleat 6,83 mg Aktiv substans; bensalkoniumklorid Hjälpämne; latanoprost 50 mikrog Aktiv substans
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
kombinationer
Bemyndigande status:
Avregistrerad
Godkännandenummer:
50852
Tillstånd datum:
2015-09-02

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

20-10-2020

Produktens egenskaper Produktens egenskaper - engelska

20-10-2020

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Package leaflet: Information for the user

Latiotim 50 micrograms/ml + 5 mg/ml eye drops, solution

latanoprost + timolol (as maleate)

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

What [nationally completed name] is and what it is used for

What you need to know before you use [nationally completed name]

How to use [nationally completed name]

Possible side effects

How to store [nationally completed name]

Contents of the pack and otherinformation

1.

What [Nationally completed name] is and what it is used for

[Nationally completed name] 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.

[Nationally completed name] 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

[Nationally completed name] when other medicines have not worked adequately.

2.

What you need to know before you use [Nationally completed name]

[Nationally completed name] 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 [Nationally completed name] if

you are allergic (hypersensitive) to either of the medicines in [Nationally completed name]

(latanoprost or timolol), beta-blockers or any of the other ingredients of this medicine (listed

in section 6)

you have now or have had in the past 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 serious heart problems or heart rhythm disorders

Warnings and precautions

Talk to your doctor or pharmacist before using [Nationally completed name] if you have now or have

had in the past any of the following:

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

eye surgery in the past

eye problems (such as eye pain, eye irritation, eye inflammation or blurred vision)

dry eyes

you wear contact lenses. You can still use [Nationally completed name] but follow the instructions

for contact lens wearers in Section 3

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

disturbances of the heart rate such as slow heart beat

heart failure

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

angina (particularly a type known as Prinzmetal angina)

low blood pressure

severe allergic reactions that would usually require hospital treatment

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 [Nationally completed name] as this

medicine may change effects of some medicines used during anaesthesia.

Other medicines and [Nationally completed name]

[Nationally completed name] can affect or be affected by other medicines you are using, including

other eye drops for the treatment of glaucoma.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

In particular, tell your doctor if you are using or intend to use any of the following medicines:

Prostaglandins, prostaglandin analogues or prostaglandin derivates

Medicines to lower blood pressure (e.g. beta-blockers)

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

clonidine antiarrythmics (e.g. amiodarone), digitalis glycosides or parasympathomimetics

Medicines to treat diabetes

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

Antidepressants known as fluoxetine and paroxetine

Medicines to prevent allergic anaphylactic shock (adrenalin/epinephrine)

[Nationally completed name] with food and drink

Normal meals, food or drink have no effect on when or how you should use [Nationally completed

name].

Pregnancy, breast-feeding and fertility

Do not use

[Nationally completed name] if you are pregnant unless your doctor considers it

necessary. Tell your doctor immediately if you are pregnant, think you are pregnant or are planning to

become pregnant.

Do not use

[Nationally completed name] if you are breast-feeding. The active substances of this

medicine may get into your milk. Ask your doctor for advice before taking any medicine during

breast-feeding.

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 [Nationally completed name] 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.

[Nationally completed name] contains benzalkonium chloride

This medicine contains 0.20 mg benzalkonium chloride in each ml, Benzalkonium chloride may be

absorbed by soft contact lenses and may change the colour of the contact lenses. You should remove

contact lenses before using this medicine and put them back 15 minutes afterwards.

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.

[Nationally completed name] contains phosphates

This medicine contains 6.3 mg phosphates in each ml. 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 [Nationally completed name]

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

you are not sure.

If this is the first time that you have used this bottle, write the date in the space provided on the carton

so that you will know when they should no longer be used because they are out of date.

Dose

The recommended dose is

One

drop

in the affected eye(s) once daily. The dose should not exceed one drop in the affected eye(s)

daily.

Using [Nationally completed name] with another eye drop

If you are using [Nationally completed name] as well as other eye drops, the different drops should be

instilled at least 5 minutes apart.

Instructions for Use

Please follow these instructions carefully when using [Nationally completed name] eye drops solution.

It is recommended that you wash your hands before putting in your eye drops.

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

contaminated with bacteria that can cause eye infections 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.

1. You must not use the bottle if the tamper-proof seal on the bottle neck is broken before you first use

2. To open the bottle unscrew the cap by turning it until the tamper-proof seal breaks.

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

and your eye (Fig. 1).

Fig. 1

4. Invert the bottle, and press gently as shown (Fig. 2 and 3) until a single drop as instructed by your

doctor is dispensed into your eye. DO NOT TOUCH YOUR EYE OR EYELID WITH THE TIP

OF THE CONTAINER.

Fig. 2

Fig. 3

5. Repeat steps 3 and 4 with the other eye if instructed to do so by your doctor.

6. After using [Nationally completed name], slowly close your eye(s) and press a finger into the inner

corner of your eye, by the nose for 2 minutes. This helps to stop [Nationally completed name]

getting into the rest of the body.

7. Reclose the bottle by turning the cap firmly immediately after use and return the bottle to the

original outer carton.

8. The dispenser tip is designed to provide a pre-measured drop; therefore, do not enlarge the hole of

the dispenser tip.

If you use more [Nationally completed name] than you should

It is important to keep to the dose your doctor has prescribed. If you put too many drops in your eye or

swallow any of the contents of the bottle, you may feel unwell, for example you may become light-

headed, have difficulty breathing, feel tired, flushed, have stomach pains or start to sweat. If you feel

any of the above effects, you should seek medical attention immediately.

If you forget to use [Nationally completed name]

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

dose.

If you stop using [Nationally completed name]

If you must stop or want to stop treatment, contact your doctor immediately.

If you have any further questions on the use of this medicine, ask 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 using the drops, unless the effects are serious. If you're worried, talk to a

doctor or pharmacist. Do not stop using [Nationally completed name] without speaking to your doctor.

Listed below are the known side effects of using [Nationally completed name]. The most important

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

[Nationally completed name] 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 [Nationally completed name].

The following have been seen with [Nationally completed name]:

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 [Nationally completed

name] 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 [Nationally completed name] treatment is stopped.

Common

(may affect up to 1 in 10 people)

eye irritation (including stinging, burning, itching, sensation of a foreign body in the eye)

eye pain

Uncommon

(may affect up to 1 in 100 people)

headache

pink/redness of the eye

blurred vision

watering eyes

inflammation of the eyelids

corneal disorders

skin rashes/itching

eye infection (conjunctivitis)

irritation or disruption of the surface of the eye

Other side effects

Like other medicines used in the eyes, Xalcom (latanoprost and 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 Xalcom, the following additional side effects have been seen with the

medicines in Xalcom (latanoprost and timolol) and therefore might occur when you use Xalcom. 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).

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.

Dizziness.

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

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

myasthenia gravis (muscle disorder), unusual sensations like pins and needles, and headache.

Swelling at the back of the eye (macular oedema), fluid filled cyst within the coloured part of the

eye (iris cyst), light sensitivity (photophobia), sunken eye appearance (deepening of the eye

sulcus).

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.

Darkening of the skin around the eyes, 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), scarring of the

surface of the eye.

Whistling/ringing in the ears (tinnitus).

Angina, worsening of angina in patients who already have heart disease

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, poor blood circulation which makes the fingers and toes numb and pale, cold

hands and feet.

Shortness of breath, constriction of the airways in the lungs (predominantly in patients with pre

existing disease), difficulty breathing, cough, asthma, worsening of asthma.

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.

Joint pain, muscle pain not caused by exercise, muscle weakness, tiredness.

Sexual dysfunction, decreased libido.

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 the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store [nationally completed name]

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

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The

expiry date refers to the last day of that month.

Storage conditions before first opening:

Store in a refrigerator (2°C -8 °C).

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

Storage conditions after first opening:

Do not store the bottle above 25 °C. Store the bottle in the outer carton in order to protect from light.

Shelf life after first opening:

28 days

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 protect the environment.

6.

Contents of the pack and other information

What [nationally completed name] contains

The active substances are latanoprost and timolol (as maleate).

Each ml contains 50 micrograms latanoprost and 5 mg timolol (as maleate).

The other ingredients are benzalkonium chloride, sodium dihydrogen phosphate dihydrate, disodium

phosphate anhydrous, sodium chloride, sodium hydroxide/hydrochloride acid (for pH-adjustment),

water for injection.

What [nationally completed name] looks like and contents of the pack

Eye drops, solution.

Colourless solution.

This medicinal product is available in transparent plastic bottles with a white screw cap.

Each bottle contains 2.5 ml eye drops.

Pack sizes

1 x 2.5 ml, 2 x 2.5 ml, 3 x 2.5 ml, 4 x 2.5 ml, 5 x 2.5 ml, 6 x 2.5 ml, 7 x 2.5 ml, 8 x 2.5 ml, 9 x 2.5 ml,

10 x 2.5 ml and 12 x 2.5 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

This medicinal product is authorized in the Member States of the EEA under the

following names:

[To be completed nationally]

This leaflet was last revised in {MM/YYYY}.

2020-06-04

[To be completed nationally]

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Latiotim 50 micrograms/ml + 5 mg/ml eye drops, solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml eye drops, solution contains 50 micrograms latanoprost and 5 mg timolol (as maleate).

Excipient with known effect

Each ml eye drops, solution contains 0.2 mg/ml benzalkonium chloride and 6.3 mg/ml phosphate (as

buffer).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Eye drops, solution.

Colourless solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

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

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

Safety and effectiveness in children and adolescents has not been established.

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.

Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15

minutes (see section 4.4).

If more than one topical ophthalmic medicinal product is being used, the medicinal products should be

administered at least 5 minutes apart.

4.3

Contraindications

[Nationally completed name] 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

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, [Nationally completed name] 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-blockers 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 the 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, including death due to bronchospasm in patients with asthma have been

reported following administration of some ophthalmic beta-blockers.

[Nationally completed name] 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 intraocular pressure or the known effects of systemic beta-blockade may be potentiated

when timolol is given to 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 dose 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.

Concomitant therapy

Timolol may interact with other medicinal products, 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 [Nationally completed name] 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 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 vellus hair in the treated eye; these changes include

increased length, thickness, pigmentation, and number of lashes or hairs, and misdirected growth of

eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Glaucoma

There is no documented experience with latanoprost in inflammatory, neovascular or chronic angle

closure 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 [Nationally completed name] should be

used with caution in these conditions until more experience is obtained.

Herpetic keratitis

[Nationally completed name] 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. [Nationally

completed name] should be used with caution in these patients.

[Nationally completed name] contains benzalkonium chloride

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect

the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where

the cornea may be compromised. Patients should be monitored in case of prolonged use.

Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of the

contact lenses. Patient should remove contact lenses before using this medicinal product and put them

back 15 minutes afterwards.

4.5

Interaction with other medicinal products and other forms of interaction

No specific medicinal product interaction studies have been performed with [Nationally completed

name].

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 [Nationally completed name] 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 antidiabetic 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 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

[Nationally completed name] is administered until delivery, the neonate should be carefully monitored

during the first days of life.

Consequently [Nationally completed name] should not be used during pregnancy (see section 5.3).

Breast-feeding

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. [Nationally completed name] should

therefore not be used in women who are breast feeding.

Fertility

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

animal studies (see section 5.3).

4.7

Effects on ability to drive and use machines

Instillation of eye drops may cause transient blurring of vision. Until this is resolved, patients should

not drive or use machines.

4.8

Undesirable effects

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

phase of the pivotal trials with a combination of latanoprost and timolol, 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 medicinal products, timolol is absorbed into the systemic

circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents.

Incidence of systemic 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 the combination of latanoprost and timolol

are listed below.

Adverse events are categorised 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)

Table 1: Adverse reactions seen in Latanoprost/Timolol’s trials

System Organ Class

Very common (≥

1/10)

Common (≥

1/100 to < 1/10)

Uncommon (≥ 1/1,000 to <

1/100)

Nervous system

disorders

Headache

Eye disorders

Iris

hyperpigmentation

Eye pain, eye

irritation

(including

stinging,

burning and

itching, foreign

body sensation)

Corneal disorders,

conjunctivitis, blepharitis,

eye hyperaemia, vision

blurred, lacrimation

increased

Skin and

subcutaneous tissue

disorders

Rash, pruritus

Additional adverse reactions have been reported specific to the use of the individual

components of Latanoprost/Timolol in either clinical studies, spontaneous reports or in the

available literature.

For latanoprost, these are:

Adverse Reaction Table 2: Latanoprost

System Organ Class

Adverse Reactions

Infections and infestations

Herpetic keratitis

Nervous system disorders

Dizziness

Eye disorders

Eyelash and vellus hair changes of the eyelid

(increased length, thickness, pigmentation, and

number of eyelashes); punctate keratitis,

periorbital oedema; iritis; uveitis; macular

oedema including cystoid macular oedema; dry

eye; keratitis; corneal oedema; corneal erosion;

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

Angina; angina unstable; palpitations

Respiratory, thoracic and mediastinal disorders

Asthma; asthma aggravation; dyspnoea

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:

Adverse Reaction Table 3: Timolol Maleate (ocular administration)

System Organ Class

Adverse Reactions

Immune system disorders

Systemic allergic reactions including anaphylactic reaction,

angioedema, urticaria, localised and generalised rash, pruritus

Metabolism and nutrition disorders

Hypoglycaemia

Psychiatric disorders

Memory loss, insomnia, depression, nightmares,

hallucination

Nervous system disorders

Cerebrovascular accident, cerebral ischaemia, dizziness,

increases in signs and symptoms of myasthenia gravis,

paraesthesia, headache, syncope

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, ptosis, blepharitis, blurred vision

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Cardiac arrest, cardiac failure, atrioventricular block,

congestive heart failure, chest pain, arrhythmia, bradycardia,

oedema, palpitations

Vascular disorders

Cold hands and feet, hypotension, Raynaud’s phenomenon

Respiratory, thoracic and

mediastinal disorders

Bronchospasm (predominately in patients with pre-existing

bronchospastic disease), cough, dyspnoea

Gastrointestinal disorders

Abdominal pain, vomiting, diarrhoea, dry mouth, dysgeusia,

dyspepsia, nausea

Skin and subcutaneous tissue

disorders

Skin rash, psoriasiform rash, exacerbation of psoriasis,

alopecia

Musculoskeletal and connective

tissue disorders

Myalgia

Reproductive system and breast

disorders

Sexual dysfunction, decreased libido

General disorders and administration

site conditions

Asthenia, fatigue

Cases of corneal calcification have been reported very rarely in association with the use of phosphate

containing eye drops in some patients with significantly damaged corneas.

Reporting 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 the national reporting system

listed in Appendix V.

4.9

Overdose

No data are available in humans with regard to overdose with [Nationally completed name].

Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac

arrest. If such symptoms occur the treatment should be symptomatic and supportive. Studies have

shown that timolol does not dialyse readily

.

Apart from ocular irritation and conjunctival hyperaemia no other ocular or systemic side effects are

known if latanoprost is overdosed.

If latanoprost is accidentally ingested orally the following information may be useful:

Treatment

Gastric lavage if needed. Symptomatic treatment. One bottle contains 125 micrograms latanoprost.

Latanoprost is extensively metabolised during the first pass through the liver. Intravenous infusion of

3 micrograms/kg in healthy volunteers induced no symptoms but a dose of 5.5-10 micrograms/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-betablocking agents - timolol, combinations

ATC code: S01E D51

Mechanism of action

‘Latanoprost/Timolol’ 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 F

2alpha

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.

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 effects

In dose finding studies, the combination of latanoprost and timolol 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 the combination of latantoprost and timolol 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 the combination

of latanoprost and timolol, latanoprost and timolol (twice daily), respectively. The IOP lowering effect

of the combination of latanoprost and timolol was maintained in 6 month open label extensions 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 twice daily and latanoprost once a

day might be still efficient.

Onset of action of the combination of latanoprost and timolol 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 dose after multiple treatments.

5.2

Pharmacokinetic properties

Latanoprost

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 medicinal product that enters the aqueous humor is hydrolysed during the

passage through the cornea.

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 eyelids.

The acid of latanoprost has a plasma clearance of 0.40 L/h/kg and a small volume of distribution, 0.16

L/kg, resulting in a rapid half life in plasma, 17 minutes. After topical ocular administration the

systemic bioavailability of the acid of latanoprost is 45%. The acid of latanoprost has a plasma protein

binding of 87%.

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

in the liver. The main metabolites, the 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or only

weak biological activity in animal studies and are excreted primarily in the urine.

Timolol

The maximum concentration of timolol in the aqueous humour is reached about 1 hour after topical

administration of eye drops. Part of the dose is absorbed systemically and a maximum plasma

concentration of 1 ng/mL is reached 10-20 minutes after topical administration of one eye drop to each

eye once daily (300 micrograms/day). The half life of timolol in plasma is about 6 hours. Timolol is

extensively metabolised in the liver. The metabolites are excreted in the urine together with some

unchanged timolol.

Combination of latanoprost and timolol 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 the combination of latanoprost and

timolol 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.

Latanoprost

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 micrograms/kg/day. However, latanoprost caused embryofetal toxicity, characterised by increased

incidence of late resorption and abortion and by reduced foetal weight, in rabbits at intravenous doses

of 5 micrograms/kg/day (approximately 100 times the clinical dose) and above.

Timolol

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

benzalkonium chloride

sodium dihydrogen phosphate dihydrate

disodium phosphate anhydrous

sodium chloride

water for injections

sodium hydroxide or hydrochloric acid are used for adjusting the pH value

6.2

Incompatibilities

In vitro

studies have shown that precipitation occurs when eye drops containing thiomersal are mixed

with ‘Latanoprost/Timolol’. If such drugs are used concomitantly with ‘Latanoprost/Timolol’, the eye

drops should be administered with an interval of at least ten minutes.

6.3

Shelf life

30 months

Shelf life after first opening of bottle:

28 days

Storage conditions after first opening of the bottle:

Do not store above 25°C. Store the bottle in the outer carton in order to protect from light.

6.4

Special precautions for storage

Store in a refrigerator (2°C - 8°C). Store in the original carton in order to protect from light.

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

6.5

Nature and contents of container

LDPE bottle (transparent; 5ml) with LDPE dropper (transparent) and HDPE cap (white).

Each bottle contains 2.5 ml eye drops, solution.

Pack sizes: 1 x 2.5 ml, 2 x 2.5 ml, 3 x 2.5 ml, 4 x 2.5 ml, 5 x 2.5 ml, 6 x 2.5 ml, 7 x 2.5 ml, 8 x 2.5 ml,

9 x 2.5 ml, 10 x 2.5 ml and 12 x 2.5 ml

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}

Date of latest renewal: {DD month YYYY}

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2020-06-04

[To be completed nationally]

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