SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
GLAUMAX, 50g/ml, eye drop solution
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml solution contains 50µg of latanoprost as active ingredient.
INN. Latanoprostum
Excipient with known effect: Benzalkonium chloride 0.2 mg/ml.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Eye drops, solution.
The solution is a clear colourless liquid
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Reduction of intraocular pressure in patients with open angle glaucoma and ocular hypertension.
Reduction of intraocular pressure in paediatric patients with elevated intraocular pressure and paediatric glaucoma.
4.2 Posology and method of administration
For ocular use.
Posology
Recommended dosage for adults (including the elderly):
To administer one drop of medicine in the affected eye once a day. Optimal effect is obtained if GLAUMAX is
administered in the evening.
Paediatric population:
GLAUMAX eye drops may be used in children at the same posology as in adults. No data are available for use of
latanoprost in premature infants (at the gestational age less than 36 weeks). Information on use in children under 1
year is limited (4 patients) (see section 5.1).
Studies have shown that more frequent than once daily administration of latanoprost reduces the intraocular pressure
lowering effect.
If one dose is missed, treatment should be continued with the next dose as usual.
Method of administration
After instillation is recommended to keep your eyes closed for a minute and press your index finger lightly against the
nasal corner of the eyelid. This reduces the systemic absorption and the possibility of systemic side effects.
Contact lenses should be removed before instillation. They can be reinserted not earlier than 15 minutes after using
this medicine.
If more than one topical ophthalmic drug is being used, the drugs must be administered at least five minutes apart.
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4.3 Contraindications
Known hypersensitivity to latanoprost or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Latanoprost may cause a gradual change in eye colour by increasing the number of melanosomes in melanocytes.
Before starting treatment, patients should be informed of the possibility of a permanent change in eye colour.
Unilateral treatment can result in permanent heterocromia.
Colour change occurs more frequently in patients with mixed coloured irides (blue-brown, grey-brown, green-brown
or yellow-brown). Eye colour change occurs mostly within the first 8 months of treatment, but few patients can
manifest the colour change later. In 4-year clinical study, 30% of patients developed the iris colour change. In most
cases, the iris colour change is slight and may not be clinically apparent. Among patients with mixed coloured irides,
the colour change is higher and it may occur more frequently in patients with yellow-brown irides. In patients with
homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown
eye colour, the change has rarely been reported.
The eye colour change is not caused by number increase of melanocytes, but due to increased melanin content in the
stromal melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the
periphery in affected eye, but the whole iris or part of it may exhibit darker brown colour. After discontinuation of
therapy, no further increase in brown iris pigment has been observed. Studies have shown that this phenomenon is not
any symptom or patological change.
Latanoprost does not affect either naevi or freckles of the iris. Studies have not shown any pigment accumulation in
the trabecular meshwork or the anterior chamber. According to 5 years clinical experience with latanoprost, increased
iris pigmentation has no adverse clinical results and GLAUMAX can be continuously used if iris pigmenation occurs.
However, patients should be regularly monitored and, depending on the clinical conditions, GLAUMAX treatment
may be withdrawn.
Latanoprost may gradually change eyelashes in the treated eye. Changes include increased length, thickness,
pigmentation and/or number of lashes. The changes are reversible upon discontinuation of treatment.
There are limited data on the use of latanoprost in chronic angle closure glaucoma, open angle glaucoma of
pseudophakic patients and in pigmentary glaucoma. There is no experience with the use of latanoprost in
inflammatory and neovascular glaucoma, ocular inflammatory diseases, or primary congenital glaucoma (PCG).
Effect of latanoprost on the pupil is an absent or minimal, but there is no experience in the treatment of acute angleclosure glaucoma. Therefore, it is recommended to use GLAUMAX with caution in these conditions.
There are limited data on the use of latanoprost during the peri-operative period prior to cataract removal. These
patients should be using GLAUMAX with caution.
Latanoprost should be administered with special caution to patients with a history of herpetic keratitis, and should be
avoided in cases of active herpex simplex keratitis and in case of recurrent herpetic keratitis specifically associated
with prostaglandin analogues.
Caution is required for using GLAUMAX in aphakic patients, in pseudophakic patients with torn posterior lens
capsule or anterior chamber lens, and in patients known to have high risk factors for cystoid macular oedema (see
section 4.8).
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GLAUMAX should be used with caution in patients who are predisposed to developing iritis/uveitis.
There is no experience regarding treatment of patients with severe or unstable asthma, therefore such patients must be
treated with caution (see section 4.8).
Periorbital skin discolouration has been reported, particularly in patients of Japanese origin. Currently available
experience suggests that a change in skin colour is not permanent and in some cases has reversed while continuing use
of latanoprost.
GLAUMAX contains benzalkonium chloride (preservative). It has been observed that benzalkonium chloride causes
punctate keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and discolour soft contact lenses.
Patients with dry eye syndrome and damaged cornea should be closely monitored with frequent or prolonged use of
GLAUMAX. Since contact lenses may absorb benzalkonium chloride, they must be removed before applying
GLAUMAX and may be reinserted after 15 minutes (see section 4.2).
Paediatric population
The efficacy and safety of GLAUMAX in the age group up to 1 year (olny 4 patients) are incomplete (see section
5.1). No efficacy or safety data are available for premature infants (at the gestational age less than 36 weeks).
For children between the age of birth and 3 years being diagnosed with primary congenital glaucoma (PCG), the firstline treatment remains surgery, i.e. trabeculotomy or goniotomy.
Long-term safety data on the use of Latanoprost in children are not available.
4.5 Interaction with other medicinal products and other forms of interaction
There is no evidence of interaction.
Simultaneous ophthalmic administration of two or more prostaglandin analogues may cause paradoxical increase in
intraocular pressure, therefore the concomitant use of several prostaglandins, prostaglandin analogues or
prostaglandin derivatives should be avoided.
Paediatric population
Interaction studies have been conducted only in adults, studies on children have not been performed.
4.6 Fertility, pregnancy and lactation
Pregnancy
Latanoprost safety during pregnancy has not been established. Since the risk on the course of pregnancy, the fetus or
the neonate cannot be ruled out, GLAUMAX should not be used during pregnancy.
Lactation
Latanoprost and its metabolites may pass into breast milk and therefore should not be used during breast feeding or
breast feeding should be discontinued.
Fertility
Latanoprost has not been found to have any effect on male or female fertility in animal studies.
4.7 Effects on ability to drive and use machines
As with other eye medicines, instillation of eye drops may cause transient blurring of vision.
Until this has resolved, patients should be advised not to drive a car or operate machinery.
4.8 Undesirable effects
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The majority of adverse effects occur in the eyes.
The incidence of adverse reactions are classified as follows: very common (≥1/10), common (≥1/100, <1/10);
uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000). Frequencies are not known (cannot
be estimated from available data). Frequencies for occuring post-marketing adverse events cannot be determined
because they originate from spontaneous reports.
MedDRA System Organ Class
Infections and infestations
Frequency
Unknown
Undesirable effects
herpetic keratitis
increased iris pigmentation
mild to moderate conjunctival hyperaemia
Very common
eye irritation (mild foreign body sensation)
eyelash changes (increased pigmentation, thickness,
length, number of eyelashes)*
* in most cases, in patients of Japanese origin
transient
punctate
asymptomatic)
Common
epithelial
erosions
(mostly
blepharitis
eye pain
Eye disorders
Uncommon
eyelid swelling: dry eye, keratitis, blurred vision,
conjunctivitis
iritis/uveitis (as a rule, in patients with predisposing
factors, see section 4.4)
macular oedema
Rare
symptomatic corneal oedema and erosions
periorbital oedema
misdirected eyelashes, which can sometimes cause eye
irritation
Nervous system disorders
Cardiac disorders
Respiratory,
thoracic
mediastinal disorders
and
Unknown
iris cyst
Unknown
headache, dizziness
Very rare
aggravation of pre-existing angina
Unknown
palpitations
Rare
Uncommon
Skin and subcutaneous tissue
disorders
asthma, asthma exacerbation and dyspnoea
skin rash
eyelid skin darkening
Rare
localised skin reactions on the eyelids
Musculoskeletal and connective
tissue disorders
General
disorders
and
administration site conditions
Unknown
myalgia, arthralgia
Very rare
chest pain
Macular oedema has been reported uncommonly during latanoprost treatment. Macular oedema has occurred mainly
in aphakic and pseudophakic (known risk factor for macular oedema) patients with torn posterior lens capsule or
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anterior chamber lens, also in patients with diabetic retinopathy and retinal vascular occlusion. An association
between the use of latanoprost and unexplained macular oedema cannot be excluded.
Rare cases of asthma, exacerbation of asthma and dyspnoea have been reported during latanoprost treatment. There is
limited experience from patients with asthma, but latanoprost has not been found to affect the lung function in patients
suffering from moderate asthma and receiving steroid and nonsteroid therapy. There is no experience in patients with
severe or unstable asthma, therefore they should be treated with caution.
Paediatric population
In two short-term clinical trials the safety profile of GLAUMAX was similar to that in adults, thus no new adverse
events were detected. The short-term safety profiles in different subgroups of children coincided as well (see section
5.1). The study involved 93 children (25 and 68) and lasted less than 12 weeks.
The following side effects occur more frequently in children than in adults: nasopharyngitis (5,9%), conjunctival
hyperaemia (4,4%) and pyrexia (2,9%).
4.9 Overdose
Apart from ocular irritation and conjunctival hyperaemia, no other side effects were seen.
If GLAUMAX is dosed orally, the following information is required: one dropper-bottle contains 125 g of
latanoprost. More than 90% is metabolised during the first pass through the liver. Intravenous drug infusion in 3
g/kg did not induce any symptoms, a dose of 5,5 -10 g/kg caused nausea, abdominal pain, dizziness, fatigue, hot
flushes and sweating. Administration of latanoprost in monkeys in doses of up to 500 g/kg has not been associated
with any serious side effects on the cardiovascular system.
Intravenous administration of latanoprost in monkeys has been associated with transient bronchoconstriction.
However, in patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost when
applied topically (on the eyes) in a dose of seven times the therapeutic dose.
Therapy
If overdosage with latanoprost occurs, symptomatic therapy should take place.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiglaucoma preparations and miotics, ATC-kood: S01EE01.
Mechanism of action
Latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist. Latanoprost reduces the
intraocular pressure by increasing the outflow of aqueous humour. Reduction of the intraocular pressure starts
approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours. Pressure
reduction is maintained for at least 24 hours.
Studies in animals and humans indicate that the main mechanism of action of latanoprost is increased uveoscleral
outflow, although some decrease in outflow resistance has been reported in humans as well.
Pharmacodynamic properties
Studies have shown the efficacy of latanoprost in monotherapy. In addition, studies investigating combination use of
latanoprost with other drugs have been performed, indicating that latanoprost is effective in combination with betaadrenergic antagonists (timolol). Short-term studies (1 or 2 weeks) show that the combination of latanoprost with
adrenergic agonists (dipivalyl epinephrine) and oral carbonic anhydrase inhibitors (acetazolamide) has an additive
effect. Combination of latanoprost with cholinergic agonists (pilocarpine) has partly additive effect.
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Latanoprost has no significant effect on the production of aqueous humour and does not have any effect on the bloodaqueous barrier. Experiments in monkeys suggest that when used at the clinical dose latanoprost has no or negligible
effects on the intraocular blood circulation. Topical administration may cause mild to moderate conjunctival or
episcleral hyperaemia.
Fluorescein angiography has determined that chronic treatment with latanoprost in monkey eyes, which had
undergone extracapsular lens extraction, did not affect the retinal blood vessels.
Latanoprost has not induced during short-term treatment fluorescein leakage in the posterior segment of pseudophakic
human eyes.
Latanoprost has not been found in clinical doses to have any significant pharmacological effects on the cardiovascular
and respiratory system.
Paediatric population
The efficacy of latanoprost versus timolol was demonstrated in 12 week double-blind clinical trial. A total of 107
patients aged less than 18 years diagnosed with ocular hypertension and paediatric glaucoma were enrolled in this
study. The minimum gestational age acceptable for neonates was 36 weeks. Administration schedule was as follows:
latanoprost 0,005% once daily or timolol 0,5% (optionally 0.25% for children under 3 years of age) twice daily. The
primary efficacy result was the mean reduction in intraocular pressure (IOP) from baseline at week 12 of the study.
The average IOP reduction in both groups of the investigational medicinal product was similar. In all age groups
studied (0 to < 3 years, 3 to < 12 years and 12 to 18 years of age) the average IOP reduction at week 12 in the
latanoprost group was similar to that in the timolol group. Efficacy data in the age group 0 to < 3 years were based on
13 patients treated with latanoprost. No data are available for preterm infants (less than 36 weeks gestational age).
IOP reduction between the latanoprost group and the timolol group was identical to the subset of patients who had a
primary congenital/infantile glaucoma (PCG), as well as non-PCG (ie juvenile open angle glaucoma and aphakic
glaucoma) subgroup.
The primary effect on IOP was seen after the first week of treatment and was maintained throughout the 12 week
period of study, as in adults (see Table).
Table. IOP reduction (mmHg) at week 12 by active treatment group and baseline diagnosis
Baseline Mean (SE)
Week 12 change from Baseline Mean † (SE)
p-value vs. timolol 0,2056
Baseline Mean (SE)
Week 12 change from Baseline Mean† (SE)
p-value vs. timolol 0,2056
Latanoprost
N = 53
27,3 (0,75)
–7,18 (0,81)
PCG
N = 28
26,5 (0,72)
–5,90
0,6957
SE: standard error.
† Adjusted estimate based on an analysis of covariance (ANCOVA) model.
5.2 Pharmacokinetic properties
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Non-PCG
N = 25
28,2 (1,37)
–8,66 (1,25)
0,1317
Timolol
N = 54
27,8 (0,84)
–5,72 (0,81)
0,2056
PCG
N = 26
26,3 (0,95)
– 5,34 (1,02)
Non-PCG
N = 28
29,1 (1,33)
–6,02 (1,18)
Latanoprost is an isopropyl ester, inactive prodrug, which becomes biologically active after hydrolysis to the acid of
latanoprost. The prodrug is well absorbed through the cornea entering the aqueous humour and hydrolyses during the
passage. The peak concentration in the aqueous humour is reached in two hours after topical administration.
Latanoprost is distributed mainly in the anterior segment of the eye, the conjunctiva and the eyelids. Only negligible
amounts of drug reach the posterior segment.
The acid of latanoprost has practically no metabolism in the eye. The main metabolism occurs in the liver. The
resultant metabolites (the 1,2-dinor and 1,2,3,4-tetranor) do not have a significant biological effect. The half-life in
plasma is 17 minutes. The metabolites are excreted primarily in the urine.
Paediatric population
An open pharmacokinetic study of plasma latanoprost acid concentrations was undertaken in 22 adults and 25
children (from birth to < 18 years of age), diagnosed with ocular hypertension and glaucoma. All age groups were
receiving 1 drop of latanoprost 0.005% daily in both eyes for 2 weeks. Latanoprost acid systemic exposure was
approximately 2-fold higher in 3 to < 12 year-olds and 6-fold higher in children < 3 years old than in adults, but a
wide safety margin for systemic adverse effects remained the same (see section 4.9). The average time to reach peak
plasma concentration was 5 minutes after drug administration in all age groups. The mean plasma elimination half-life
was equally short (less than 20 minutes) in both children and adults, which resulted in no accumulation of latanoprost
acid in the systemic circulation under steady-state conditions.
5.3 Preclinical safety data
The ocular and systemic effects of latanoprost have been studied in several species of animals. Generally, latanoprost
is well tolerated with a broad safety range. The systemic toxic dose is at least 1000 times the clinical ocular dose.
Increase of respiratory frequency was found in monkeys given high-dose (about 100 times the clinical dose/kg body
weight) of latanoprost via intravenous injection without anesthesia, possibly reflecting the manifestation of transient
bronchoconstriction. No hypersensitization was found in animal tests of latanoprost.
In rabbits and monkeys, no ocular toxicity was found at doses of latanoprost up to 100 μg/eye/day (the clinical dose is
1.5 μg/day). Animal studies have shown that latanoprost increases iris pigmentation in monkeys.
The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris,
with no proliferative changes observed. The change in iris colour may be permanent.
In chronic ocular toxicity study, ocular administration of latanoprost at a dose of 6 µg/eye/day has been shown to
induce increased palpebral fissure. This effect is reversible and occurs at doses above the therapeutic level. This effect
has not been observed in humans.
Latanoprost gave negative results in bacterial reverse mutation test, mouse lymphoma gene mutation test and mouse
micronucleus test. Chromosomal aberration was observed in vitro with human lymphocytes. Similar effects were
observed with existing in normal conditions prostaglandin F2α , indicating that this effect is common to substances in
prostaglandin group.
Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were negative and indicate that
latanoprost does not have mutagenic effect. Carcinogenicity studies in mice and rats were negative.
Latanoprost has not been found to have any effect on male or female fertility in animal studies. Intravenous
administration of latanoprost (at doses 5 g/kg, 50 g/kg and 250 μg/kg/day) did not demonstrate any embryonic
toxicity. However, latanoprost induced embryonic death in rabbits at doses of 5 g/kg /day and above.
No teratogenic effects have been determined.
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6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride;
Benzalkonium chloride (0,2 mg/ml);
Sodium dihydrogen phosphate dihydrate;
Disodium phosphate, anhydrous;
Water for injections.
6.2 Incompatibilities
In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with
latanoprost.
If such drugs are used, the eye drops should be administered with an interval of at least 5 minutes.
6.3 Shelf life
2 years.
After first opening of bottle: 4 weeks.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Protect from light.
After opening the bottle, store it below +25°C .
Shelf-life after first opening the medicine: see in section 6.3.
6.5 Nature and contents of container
50 g/ml eye drops in dropper-bottle (5ml), dropper, screw cap.
Each dropper-bottle contains 2,5 ml eye drops solution corresponding to approximately 80 drops of solution.
6.6 Special precautions for disposal and other handling
Remove the outer screw cap before use.
7. MARKETING AUTHORISATION HOLDER
AS Kevelt
Teaduspargi 3/1
12618 Tallinn
Estonia
8. MARKETING AUTHORISATION NUMBER
553107
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
Date of first authorisation: 24/08/2007
Date of last renewal: 24/08/2012
10. DATE OF REVISION OF THE TEXT
Confirmed by the State Agency of Medicines
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