Fixopost 50 mikrogram/ml + 5 mg/ml Ögondroppar, lösning i endosbehållare

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

03-06-2020

Produktens egenskaper Produktens egenskaper (SPC)

24-09-2018

Aktiva substanser:
latanoprost; timololmaleat
Tillgänglig från:
Laboratoires THEA
ATC-kod:
S01ED51
INN (International namn):
latanoprost; timolol maleate
Dos:
50 mikrogram/ml + 5 mg/ml
Läkemedelsform:
Ögondroppar, lösning i endosbehållare
Sammansättning:
sorbitol Hjälpämne; makrogolglycerolhydroxistearat Hjälpämne; timololmaleat 6,83 mg Aktiv substans; latanoprost 50 mikrog Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Endosbehållare, 30 st (6 x 5 st); Endosbehållare, 90 st (18 x 5 st)
Bemyndigande status:
Godkänd
Godkännandenummer:
55579
Tillstånd datum:
2018-09-24

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

06-05-2020

Produktens egenskaper Produktens egenskaper - engelska

06-05-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

26-04-2018

Läs hela dokumentet

Package leaflet: Information for the patient

Fixopost 50 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container

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, pharmacist or nurse.

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, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Fixopost is and what it is used for

What you need to know before you use Fixopost

How to use Fixopost

Possible side effects

How to store Fixopost

Contents of the pack and other information

1.

What Fixopost is and what it is used for

Fixopost

contains

medicines:

latanoprost

timolol.

Latanoprost

belongs

group

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.

Fixopost 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 Fixopost

when other medicines have not worked adequately.

2.

What you need to know before you use Fixopost

Fixopost 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 Fixopost:

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, severe chronic

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

and/or long-standing cough),

if you have serious heart problems or heart rhythm disorders.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Fixopost 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 Fixopost but follow the instructions for contact lens

wearers in section 3,

you know that you suffer from angina (particularly a type known as Prinzmetal 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 Fixopost

as timolol may change

effects of some medicines used during anaesthesia.

Other medicines and Fixopost

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

medicines, including using eye drops and medicines obtained without a prescription.

Fixopost 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 medicines to lower blood

pressure, heart medicine or medicines to treat diabetes.

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

types of medicine:

Prostaglandins, prostaglandin analogues or prostaglandin derivates,

Beta-blockers,

Epinephrine,

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

antiarrythmics, digitalis glycosides or parasympathomimetics,

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

Antidepressants known as fluoxetine and paroxetine.

Fixopost with food and drink

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

Pregnancy, breast-feeding and fertility

Do not use Fixopost

when you are pregnant or breast-feeding.

Fixopost may get into your milk.

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

studies.

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

your doctor for advice before taking this medicine.

Driving and using machines

When you use Fixopost 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.

Fixopost contains macrogolglycerol hydroxystearate

(derived from castor oil) which may cause

skin reactions.

3.

How to use Fixopost

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

or pharmacist if you are not sure.

The recommended dose for adults (including the elderly) is one drop once a day in the affected eye(s).

Do not use Fixopost more than once a day, because the effectiveness of the treatment can be reduced

if you administer it more often.

Use Fixopost 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 Fixopost.

Contact lens wearers

If you wear contact lenses, you should remove them before using Fixopost. After using Fixopost you

should wait 15 minutes before putting your contact lenses back in.

Instructions for use

This medicine is intended to be administered into the eye.

Please follow these instructions to use the drops:

Wash your hands and sit or stand comfortably.

Open the sachet containing 5 single-dose containers. Write down the date of first opening on the

sachet.

Break off one single-dose container from the strip.

Twist open the top of the single-dose container as shown. Do not touch the tip after opening the

container.

Use your finger to gently pull down the lower eyelid of your affected eye.

Place the tip of the single-dose container close to, but not touching your eye.

Squeeze the single-dose container gently so that only one drop goes into your eye, then release the

lower eyelid.

Press a finger against the corner of the affected eye by the nose. Hold for 2 minutes while keeping

the eye closed.

Repeat in your other eye if your doctor has told you to do this. Each single-dose container contains

enough solution for both eyes.

Discard the single-dose container after use. Do not keep it to use it again. Since sterility cannot

be maintained after the individual single-dose container is opened, a new container must be

opened prior to each use.

Place the unopened single-dose containers back in the sachet. Place the opened sachet in the

carton. The unopened containers must be used within 1 month after opening the sachet.

If you use Fixopost with other eye drops

Wait at least 5 minutes between using Fixopost and using the other eye drops.

If you use more Fixopost 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 Fixopost

If you swallow Fixopost accidentally you should contact your doctor for advice. If you swallow a lot

of Fixopost you may feel sick, have stomach pains, feel tired, flushed and dizzy and start to sweat.

If you forget to use Fixopost

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

have forgotten. If you are unsure 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 using the drops, unless the effects are serious. If you are worried, talk to a

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

Listed below are the known side effects of using Fixopost. The most important side-effect is the

possibility of a gradual, permanent change in your eye colour. It is also possible that Fixopost 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 him or her you have been using Fixopost.

The following are known side effects of using Fixopost:

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 Fixopost 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 Fixopost 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, Fixopost (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 Fixopost, the following additional side effects have been seen with the

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

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.

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 Fixopost

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 carton, sachet and single-dose

container. The expiry date refers to the last day of that month.

This medicine does not require any special temperature storage conditions.

After first opening of the sachet:

use the single-dose containers within 1 month.

Write down the date of first opening on the sachet.

After first opening of the single-dose container:

use immediately and discard the single-dose

container after use.

Keep the unused single-dose containers in the opened sachet in order to protect them from light.

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 Fixopost contains

The active substances are latanoprost 50 micrograms/ml and timolol (as timolol maleate) 5 mg/ml.

The other ingredients are: macrogolglycerol hydroxystearate, sorbitol, macrogol, carbomer, disodium

edetate, sodium hydroxide (for pH-adjustment), water for injections.

What Fixopost looks like and contents of the pack

This medicinal product is presented as an eye drops, solution in single-dose container. The solution is

a slightly yellow and opalescent preservative free solution, practically free from particles presented in

single-dose containers packed in a sachet of 5 units, each single-dose container holding 0.2 ml of

product.

A pack size contains 30 (6 x 5) or 90 (18 x 5) single-dose containers.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Laboratoires THEA

12 rue Louis Blériot

63017 Clermont-Ferrand Cedex 2

France

Manufacturer

EXCELVISION

27, rue de la Lombardière

07100 Annonay

France

Laboratoires THEA

12 rue Louis Blériot

63017 Clermont-Ferrand Cedex 2

France

This medicinal product is authorised in the Member States of the EEA under the following

names:

This leaflet was last revised 2020-04-30.

Detailed information on this medicine is available on the website of {name of MS Agency (link)}

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Fixopost

50 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

One drop contains approximately 1.5 micrograms of latanoprost and 0.15 mg of timolol.

Excipient with known effect

1 ml eye drops solution contains 50 mg of macrogolglycerol hydroxystearate (castor oil polyoxyl

hydrogenated).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Eye drops, solution in single-dose container.

Slightly yellow and opalescent solution, practically free from particles.

pH: 5.7 – 6.2

Osmolality: 300-340 mosmol/kg.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Fixopost 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

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 Fixopost in children and adolescents has not been established.

Method of administration

Ocular use.

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal

sac be compressed at the medial canthus (punctal occlusion) for two minutes. This should be

performed immediately following the instillation of each drop.

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

minutes.

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

administered at least five minutes apart.

A single-dose contains enough eye drops solution to treat both eyes.

For single use only.

This medicinal product is a sterile solution that does not contain a preservative. The solution from one

individual single dose container is to be used immediately after opening for administration to the

affected eye(s). Since sterility cannot be maintained after the individual single dose container is

opened, any remaining contents must be discarded immediately after administration.

Patients should be instructed:

to avoid contact between the dropper tip and the eye or eyelids,

to use the eye drops solution immediately after first opening the single-dose container and to

discard the single-dose after use,

to store the unopened single-dose containers in the sachet.

4.3

Contraindications

Fixopost is contraindicated in patients with:

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.

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

4.4

Special warnings and precautions for use

Systemic effects

Like other topically applied ophthalmic agents, Fixopost 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 for 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. Fixopost 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.

Hypoglycemia/diabetes

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

or in patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute

hypoglycaemia.

Hyperthyroidism

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.

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).

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 ophthalmic preparations may block systemic beta-agonist effects e.g. of adrenaline.

The anaesthetist should be informed when the patient is receiving timolol.

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 the combined latanoprost/timolol preserved reference product 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 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 Fixopost 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,

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. Fixopost

should be used with caution in these patients.

Excipients

Fixopost contains macrogolglycerol hydroxystearate (castor oil polyoxyl hydrogenated) which may

cause skin reactions. No long-term safety data are currently available on this excipient.

4.5

Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been performed with Fixopost.

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 an

ophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers,

beta-adrenergic

blocking

agents,

antiarrhythmics

(including

amiodarone),

digitalis

glycosides,

parasympathomimetics or 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 Fixopost 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.

hypertensive

reaction

sudden

withdrawal

clonidine

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 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

Fixopost is administered until delivery, the neonate should be carefully monitored during the first

days of life.

Consequently Fixopost 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.

Fixopost 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.

4.7

Effects on ability to drive and use machines

Fixopost has minor influence on the ability to drive and use machines. 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

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

extension phase of pivotal trials on the combined latanoprost/timolol preserved reference product,

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 reactions are generally transient and occur on dose administration. For timolol, the most

serious adverse reactions 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 reactions seen in clinical trials with the combined latanoprost/timolol

preserved reference product 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) and very rare (<1/10,000), not

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

Table 1: Adverse reactions seen in clinical 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,itching,

foreign

body

sensation)

Corneal disorders,

conjunctivitis,

blepharitis, eye

hyperaemia, vision

blurred, lacrimation

increased

Skin and

subcutaneous tissue

disorders

Rash, pruritus

Additional adverse events have been reported specific to the use of the individual components of

Fixopost 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

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

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 Fixopost.

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 accidentally ingested orally the following information may be useful:

Studies have shown that timolol does not dialyse readily. Gastric lavage if needed.

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,

code: S01ED51

Mechanism of action

Fixopost 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

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

determined

fluorescein

angiography.

Latanoprost

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 combined latanoprost/timolol preserved reference product 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 combined latanoprost/timolol preserved reference product 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 combined latanoprost/timolol preserved reference product, latanoprost and timolol

(twice daily), respectively. The IOP lowering effect of the combined latanoprost/timolol preserved

reference product was maintained in a 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 bid and latanoprost once a day

might still be efficient.

Onset of action of the combined latanoprost/timolol preserved reference product 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.

Clinical efficacy and safety

Preservative-free Fixopost was evaluated in a 3-month, randomised, investigator-masked study in

comparison with the preserved latanoprost/timolol 50 micrograms/5mg per ml reference product in

242 patients with ocular hypertension or open angle glaucoma, confirmed as being insufficiently

controlled on monotherapy. Before study start, patients were treated and controlled by the reference

product or generics (fixed combination latanoprost/timolol 50 micrograms/5mg per ml preserved eye

drops) for at least 2 months.

The primary efficacy variable was the change from baseline in mean intraocular pressure (IOP) on

Day 84.

On Day 84, the mean change from baseline IOP was -0.49 mmHg with Fixopost, and was similar to

that of the preserved latanoprost/timolol 50 micrograms/5mg per ml reference product.

Worse eye

(mITT population)

Fixopost

Reference Product

Baseline (D0)

Mean ± SD

15.6 ± 2.1

15.7 ± 2.1

Mean ± SD

15.1 ± 2.4

15.2 ± 2.2

Mean change (D0 – D84)

Mean ± SD

[95% CI]

-0.49 ± 1.80

[-0.81 ; -0.17]

-0.49 ± 2.25

[-0.92 ; -0.07]

Statistical analysis

Adjusted mean difference ± SE

[95%CI]

0.01 ± 0.25

[-0.48; 0.50]

CI=confidence interval; N=number of patients in treatment group; mITT=modified intent-to-treat; n=number of patients with

data; SE=standard error; SD=standard deviation

This 3-month study showed that no ocular adverse events were identified for Fixopost besides those

already well documented with the BAK-preserved latanoprost/timolol reference product. Fixopost

associated

with

fewer

subjective

symptoms

upon

instillation

(irritation/burning/stinging: 20.5%

vs

41.8%, p<0.001; itching: 4.9%

vs

13.9%, p=0.010) as well as

subjective symptoms throughout the day independently of instillation (irritation/burning/stinging:

7.4%

vs

12.7 %, p=0.094; itching:

1.6%

vs

13.6%, p<0.001

) compared to the reference product.

A few systemic adverse reactions, already well known for timolol, but not seen in clinical trials with

the combined latanoprost/timolol preserved reference product (see section 4.8), have been observed at

an uncommon frequency: dysgeusia, arrhythmia and fatigue.

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 drug that enters the aqueous humour 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 distribution

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).

Biotransformation

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.

Combined latanoprost/timolol preserved reference product

Pharmacokinetic/pharmacodynamic 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 the combined latanoprost/timolol preserved reference product 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 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 showed no

effects on male and female fertility in rats or teratogenic potential in mice, rats and rabbits.

Ocular toxicity

Ocular administration of Fixopost eye drops to animals twice a day for 28 days did not demonstrate

any local or systemic toxic effect.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Macrogolglycerol hydroxystearate

Sorbitol

Macrogol

Carbomer

Disodium edetate

Sodium hydroxide (for pH-adjustment)

Water for injections

6.2

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other

medicinal products.

6.3

Shelf life

2 years

After opening of the sachet : use the single-dose container within 1 month.

After opening of the single-dose container: use immediately and discard the single-dose container

after use.

The unused single dose containers should be stored in the opened sachet in order to protect from light.

6.4

Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Keep the single-dose container in the sachet, in order to protect from light.

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

6.5

Nature and contents of container

5 single-dose containers (LDPE) containing 0.2 ml of eye drops solution are packed in sachet

(polyethylene/aluminium/polyester).

Pack sizes: 30 (6x5) or 90 (18x5) single-dose containers.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Laboratoires THEA

12 rue Louis Blériot

63017 Clermont-Ferrand Cedex 2

France

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2020-04-30

Detailed information on this medicinal product is available on the website of {name of MS Agency

(link)}

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