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MEDIZOL 0.005% W/V EYE DROPS SOLUTION

Active substance(s): LATANOPROST

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Medizol 0.005% w/v eye drops, solution.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each millilitre (ml) of eye drops, solution contains 50 mcg of latanoprost.
One drop contains approximately 1.5 micrograms latanoprost.
Excipient with known effect: Benzalkonium chloride 0.02% w/v as a preservative.
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 elevated intraocular pressure in patients with open angle
glaucoma and ocular hypertension.
Reduction of elevated intraocular pressure in paediatric patients with elevated
intraocular pressure and paediatric glaucoma.

4.2

Posology and method of administration
Posology
Recommended dosage for adults (including the elderly):
Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal
effect is obtained if Medizol is administered in the evening.
The dosage of Medizol should not exceed once daily since it has been shown that
more frequent administration decreases the intraocular pressure lowering effect.
If one dose is missed, treatment should continue with the next dose as normal.
Paediatric population

Medizol may be used in paediatric patients at the same posology as in adults. No data
are available for preterm infants (less than 36 weeks gestational age). Data in the age
group < 1 year (4 patients) are limited (see section 5.1).
Method of administration
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
one minute. 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 drug is being used, the drugs should be
administered at least five minutes apart.

4.3

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

4.4

Special warnings and precautions for use
Medizol may gradually change eye colour by increasing the amount of brown
pigment in the iris. Before treatment is instituted, patients should be informed of the
possibility of a permanent change in eye colour. Unilateral treatment can result in
permanent heterochromia.
This change in eye colour has predominantly been seen in patients with mixed
coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In
clinical studies with latanoprost, the onset of the change is usually within the first 8
months of treatment, rarely during the second or third year, and has not been seen
after the fourth year of treatment. The rate of progression of iris pigmentation
decreases with time and is stable for five years. The effect of increased pigmentation
beyond five years has not been evaluated. In an open 5-year latanoprost safety study,
33% of patients developed iris pigmentation (see section 4.8). The iris colour change
is slight in the majority of cases and often not observed clinically. The incidence in
patients with mixed colour irides ranged from 7 to 85%, with yellow-brown irides
having the highest incidence. In patients with homogeneously blue eyes, no change
has been observed and in patients with homogeneously grey, green or brown eyes, the
change has only rarely been seen.
The colour change is due to increased melanin content in the stromal melanocytes of
the iris and not to an increase in number of melanocytes. 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. No further
increase in brown iris pigment has been observed after discontinuation of treatment. It
has not been associated with any symptom or pathological changes in clinical trials to
date.
Neither naevi nor freckles of the iris have been affected by treatment. Accumulation
of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not
been observed in clinical trials. Based on 5 years clinical experience, increased iris
pigmentation has not been shown to have any negative clinical sequelae and Medizol

can be continued if iris pigmentation ensues. However, patients should be monitored
regularly and if the clinical situation warrants, Medizol treatment may be
discontinued.
There is limited experience of latanoprost in chronic angle closure glaucoma, open
angle glaucoma of pseudophakic patients and in pigmentary glaucoma. There is no
experience of latanoprost in inflammatory and neovascular glaucoma or inflammatory
ocular conditions. Medizol has no or little effect on the pupil, but there is no
experience in acute attacks of closed angle glaucoma. Therefore, it is recommended
that Medizol should be used with caution in these conditions until more experience is
obtained.
There are limited study data on the use of latanoprost during the peri-operative period
of cataract surgery. Medizol should be used with caution in these patients.
Medizol 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.
Reports of macular oedema have occurred (see section 4.8) mainly in aphakic
patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber
lenses, or in patients with known risk factors for cystoid macular oedema (such as
diabetic retinopathy and retinal vein occlusion). Medizol should be used with caution
in aphakic patients, in pseudophakic patients with torn posterior lens capsule or
anterior chamber lenses, or in patients with known risk factors for cystoid macular
oedema.
In patients with known predisposing risk factors for iritis/uveitis, Medizol can be used
with caution.
There is limited experience from patients with asthma, but some cases of
exacerbation of asthma and/or dyspnoea were reported in post marketing experience.
Asthmatic patients should therefore be treated with caution until there is sufficient
experience (see also section 4.8).
Periorbital skin discolouration has been observed, the majority of reports being in
Japanese patients. Experience to date shows that periorbital skin discolouration is not
permanent and in some cases has reversed while continuing treatment with
latanoprost.
Latanoprost may gradually change eyelashes and vellus hair in the treated eye and
surrounding areas; these changes include increased length, thickness, pigmentation,
number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are
reversible upon discontinuation of treatment.
Medizol contains benzalkonium chloride, which is commonly used as a preservative
in ophthalmic products. Benzalkonium chloride has been reported to cause punctuate
keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and is
known to discolour soft contact lenses. Close monitoring is required with frequent or
prolonged use of Medizol in dry eye patients, or in conditions where the cornea is
compromised. Contact lenses may absorb benzalkonium chloride and these should be
removed before applying Medizol but may be reinserted after 15 minutes (see section
4.2).

Paediatric population
Efficacy and safety data in the age group < 1 year (4 patients) are very limited (see
section 5.1). No data are available for preterm infants (less than 36 weeks gestational
age).
In children from 0 to < 3 years old that mainly suffer from PCG (primary congenital
glaucoma), surgery (e.g. trabeculotomy/goniotomy) remains the first line treatment.
Long-term safety in children has not yet been established.

4.5

Interaction with other medicinal products and other forms of interaction
Definitive drug interaction data are not available.
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.
Paediatric population
Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation
Fertility
Latanoprost has not been found to have any effect on male or female fertility in
animal studies (see section 5.3).
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been
established. It has potential hazardous pharmacological effects with respect to the
course of pregnancy, to the unborn or the neonate. Therefore, Medizol should not be
used during pregnancy.
Breast-feeding
Latanoprost and its metabolites may pass into breast milk and Medizol should
therefore not be used in nursing women or breast feeding should be stopped.

4.7

Effects on ability to drive and use machines
In common with other eye preparations, instillation of eye drops may cause
transient blurring of vision. Until this has resolved, patients should not drive or
use machines.

4.8

Undesirable effects
a. Summary of the safety profile
The majority of adverse events relate to the ocular system. 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.
b. Tabulated list of adverse reactions
Adverse events are categorized by frequency as follows: very common (≥1/10),
common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000)
and very rare (<1/10,000). Not known (cannot be estimated from the available data).

Infections and
Infestations

Not known:

Herpetic keratitis

Nervous System
Disorders

Not known:

Headache, Dizziness

Eye Disorders

Very common:

Increased iris pigmentation; mild to moderate
conjunctival hyperaemia, eye irritation (burning,
grittiness, itching, stinging and foreign body sensation);
eyelash and vellus hair changes (increased length,
thickness, pigmentation and number) (vast majority of
reports in Japanese population).

Common:

Transient punctate epithelial keratitis, mostly without
symptoms; blepharitis; eye pain, photophobia.

Uncommon:

Eyelid oedema, dry eye; keratitis; vision blurred;
conjunctivitis.

Rare:

Iritis/uveitis (the majority of reports in patients with
concomitant predisposing factors); macular oedema;
symptomatic corneal oedema and erosions; periorbital
oedema; misdirected eyelashes sometimes resulting in
eye irritation; extra row of cilia at the aperture of the
meibomian glands (distichiasis).

Very rare:

Periorbital and lid changes resulting in deepening of the
eyelid sulcus.

Not known:

Iris cyst

Very rare:

Unstable angina.

Not known:

Palpitations.

Respiratory,
Thoracic and
Mediastinal
Disorders:

Rare:

Asthma, asthma exacerbation and dyspnoea.

Skin and
Subcutaneous
Tissue
Disorders:

Uncommon:

Skin rash.

Rare:

Localised skin reaction on the eyelids; darkening of the
palpebral skin of the eyelids.

Musculoskeletal
and Connective

Not known:

Myalgia; Arthralgia.

Cardiac
Disorders:

Tissue
Disorders:
General
Disorders and
Administration
Site Conditions:

Very rare:

Chest pain.

c. Description of selected adverse reactions
No information is provided.
d. Paediatric Population
In two short term clinical trials (≤ 12 weeks), involving 93 (25 and 68) paediatric
patients the safety profile was similar to that in adults and no new adverse events
were identified. The short term safety profiles in the different paediatric subsets
were also similar (see section 5.1). Adverse events seen more frequently in the
paediatric population as compared to adults are: nasopharyngitis and pyrexia.
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 Yellow Card Scheme Website:
www.mhra.gov.uk/yellowcard.

4.9

Overdose
Apart from ocular irritation and conjunctival hyperaemia, no other ocular side effects
are known if Medizol is overdosed.
If Medizol is accidentally ingested the following information may be useful: One
bottle contains 125 micrograms latanoprost. More than 90% is 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. In monkeys, latanoprost
has been infused intravenously in doses of up to 500 micrograms/kg without major
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 clinical dose of latanoprost.
If overdosage with Medizol occurs, treatment should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Prostaglandin analogues
ATC code: S01EE01
The active substance latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP
receptor agonist which reduces the intraocular pressure by increasing the outflow of aqueous
humour. Reduction of the intraocular pressure in man starts about three to four hours after
administration and maximum effect is reached after eight to twelve hours. Pressure reduction
is maintained for at least 24 hours.
Studies in animals and man indicate that the main mechanism of action is increased
uveoscleral outflow, although some increase in outflow facility (decrease in outflow
resistance) has been reported in man.
Pivotal studies have demonstrated that Medizol is effective as monotherapy. In addition,
clinical trials investigating combination use have been performed. These include studies that
show that latanoprost is effective in combination with beta-adrenergic antagonists (timolol).
Short-term (1 or 2 weeks) studies suggest that the effect of latanoprost is additive in
combination with adrenergic agonists (dipivalyl epinephrine), oral carbonic anhydrase
inhibitors (acetazolamide) and at least partly additive with cholinergic agonists (pilocarpine).
Clinical trials have shown that latanoprost has no significant effect on the production of
aqueous humour. Latanoprost has not been found to have any effect on the blood-aqueous
barrier.
Latanoprost has no or negligible effects on the intraocular blood circulation when used at the
clinical dose and studied in monkeys. However, mild to moderate conjunctival or episcleral
hyperaemia may occur during topical treatment.
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.
Latanoprost in clinical doses has not been found to have any significant pharmacological
effects on the cardiovascular or respiratory system.
Paediatric population
The efficacy of Medizol in paediatric patients ≤ 18 years of age was demonstrated in a 12week, double-masked clinical study of latanoprost compared with timolol in 107 patients

diagnosed with ocular hypertension and paediatric glaucoma. Neonates were required
to be at least 36 weeks gestational age. Patients received at random either latanoprost
50 mcg/ml once daily or timolol 0.5% (or optionally 0.25% for subjects younger than
3 years old) twice daily. The primary efficacy endpoint was the mean reduction in
intraocular pressure (IOP) from baseline at Week 12 of the study. Mean IOP
reductions in the latanoprost and timolol groups were similar. In all age groups
studied (0 to <3 years, 3 to < 12 years and 12 to 18 years of age) the mean IOP
reduction at Week 12 in the latanoprost group was similar to that in the timolol group.
Nevertheless, efficacy data in the age group 0 to < 3 years were based on only 13
patients for latanoprost and no relevant efficacy was shown from the 4 patients
representing the age group 0 to < 1 year old in the clinical paediatric study. No data
are available for preterm infants (less than 36 weeks gestational age).

IOP reductions among subjects in the primary congenital/infantile glaucoma (PCG)
subgroup were similar between the latanoprost group and the timolol group. The nonPCG (e.g. juvenile open angle glaucoma, aphakic glaucoma) subgroup showed
similar results as the PCG subgroup.
The effect on IOP was seen after the first week of treatment (see table) and was
maintained throughout the 12 week period of study, as in adults.
Table: IOP reduction (mmHg) at week 12 by active treatment group and
baseline diagnosis
Latanoprost

Timolol

N=53

N=54

Baseline Mean (SE)

27.3 (0.75)

27.8 (0.84)

Week 12 Change
from Baseline
Mean†(SE)

-7.18 (0.81)

-5.72 (0.81)

p-value vs. timolol

0.2056
PCG
N=28

NonPCG

PCG
N=26

N=25

NonPCG
N=28

Baseline Mean (SE)

26.5
(0.72)

28.2
(1.37)

26.3
(0.95)

29.1
(1.33)

Week 12 Change
from Baseline
Mean†(SE)

-5.90
(0.98)

-8.66
(1.25)

-5.34
(1.02)

-6.02
(1.18)

p-value vs. timolol

0.6957

0.1317

SE: standard error.


5.2

Adjusted estimate based on an analysis of covariance (ANCOVA) model.

Pharmacokinetic properties
Latanoprost (mw 432.58) is an isopropyl ester prodrug which per se is inactive, but
after hydrolysis 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.
Studies in man indicate that the peak concentration in the aqueous humour is reached
about two hours after topical administration. After topical application in monkeys,
latanoprost is distributed primarily in the anterior segment, the conjunctivae and the
eyelids. Only minute quantities of the drug reach the posterior segment.

There is practically no metabolism of the acid of latanoprost in the eye. The
main metabolism occurs in the liver. The half life in plasma is 17 minutes in
man. 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.
Paediatric population
An open-label pharmacokinetic study of plasma latanoprost acid
concentrations was undertaken in 22 adults and 25 paediatric patients (from
birth to < 18 years of age) with ocular hypertension and glaucoma. All age
groups were treated with latanoprost 50 mcg/ml, one drop daily in each eye for
a minimum of 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 compared with adults, but a wide safety margin for
systemic adverse effects was maintained (see section 4.9). Median time to
reach peak plasma concentration was 5 minutes post-dose across all age
groups. The median plasma elimination half-life was short (< 20 minutes),
similar for paediatric and adult patients, and resulted in no accumulation of
latanoprost acid in the systemic circulation under steady-state conditions.

5.3

Preclinical safety data
The ocular as well as systemic toxicity of latanoprost has been investigated in several
animal species. Generally, latanoprost is well tolerated with a safety margin between
clinical ocular dose and systemic toxicity of at least 1000 times. High doses of
latanoprost, approximately 100 times the clinical dose/kg body weight, administered
intravenously to unanaesthetised monkeys have been shown to increase the
respiration rate probably reflecting bronchoconstriction of short duration. In animal
studies, latanoprost has not been found to have sensitising properties.
In the eye, no toxic effects have been detected with doses of up to 100
micrograms/eye/day in rabbits or monkeys (clinical dose is approximately 1.5
micrograms/eye/day). In monkeys, however, latanoprost has been shown to induce
increased pigmentation of the iris.
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 studies, administration of latanoprost 6 micrograms/eye/day
has also been shown to induce increased palpebral fissure. This effect is reversible
and occurs at doses above the clinical dose level. The effect has not been seen in
humans.
Latanoprost was found negative in reverse mutation tests in bacteria, gene mutation in
mouse lymphoma and mouse micronucleus test. Chromosome aberrations were
observed in vitro with human lymphocytes. Similar effects were observed with

prostaglandin F2α, a naturally occurring prostaglandin, and indicates that this is a
class effect.
Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in
rats were negative and indicate that latanoprost does not have mutagenic potency.
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. In the embryotoxicity study in rats, no embryotoxicity was observed
at intravenous doses (5, 50 and 250 micrograms/kg/day) of latanoprost. However,
latanoprost induced embryolethal effects in rabbits at doses of 5 micrograms/kg/day
and above.
The dose of 5 micrograms/kg/day (approximately 100 times the clinical dose) caused
significant embryofetal toxicity characterised by increased incidence of late
resorption and abortion and by reduced fetal weight.

No teratogenic potential has been detected.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride
Benzalkonium chloride
Sodium dihydrogen phosphate monohydrate
Anhydrous disodium phosphate

Water for injections

6.2

Incompatibilities
In vitro studies have shown that precipitation occurs when eye drops containing
thiomersal are mixed with Medizol. If such drugs are used, the eye drops should be
administered with an interval of at least five minutes.

6.3

Shelf life
Shelf life: 36 months

Shelf life after opening of container: 4 weeks

6.4

Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Keep the bottle in the outer carton in order to protect from light.

After first opening the bottle: do not store above 25°C and use within four
weeks.

6.5

Nature and contents of container
Dropper container (5 ml) of polyethylene, screw cap, tamper evident overcap of
polyethylene.
Each dropper container contains 2.5 ml eye drops solution corresponding to
approximately 80 drops of solution.
Pack sizes: 1 x 2.5 ml, 3 x 2.5 ml.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
MEDICOM HEALTHCARE LTD
235 Hunts Pond Road, Titchfield Common, PO14 4PJ
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 18956/0021

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

06/04/2017

10

DATE OF REVISION OF THE TEXT
09/08/2017

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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