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TRAVOPROST SANDOZ 40 MICROGRAMS/ML EYE DROPS SOLUTION

Active substance(s): TRAVOPROST / TRAVOPROST / TRAVOPROST

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Travoprost Sandoz 40 micrograms/ml eye drops, solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 40 micrograms of travoprost.
Excipients with known effect: 1 ml of solution contains benzalkonium chloride
solution (equivalent to 0.15 mg benzalkonium chloride), 5 mg macrogolglycerol
hydroxystearate 40 (see section 4.4.).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Eye drops, solution.
Clear, colourless solution.
pH: 5.5 – 6.5.
Osmolality: 265-320 mOsmol/kg.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Decrease of elevated intraocular pressure in patients with ocular hypertension or
open-angle glaucoma (see section 5.1).

4.2

Posology and method of administration
For ocular use.
Posology
Use in adults, including the elderly population

The dose is one drop of Travoprost in the conjunctival sac of the affected eye(s) once
daily. Optimal effect is obtained if the dose is administered in the evening.
Paediatric population
The efficacy and safety of Travoprost in patients below the age of 18 years have not
been established and its use is not recommended in these patients until further data
become available.
Method of administration
Nasolacrimal occlusion or gently closing the eyelid after administration is
recommended. This may reduce the systemic absorption of medicinal products
administered via the ocular route and result in a decrease in systemic adverse
reactions.
If more than one topical ophthalmic medicinal product is being used, the medicinal
products must be administered at least 5 minutes apart (see section 4.5).
If a dose is missed, treatment should be continued with the next dose as planned. The
dose should not exceed one drop in the affected eye(s) daily.
When substituting another ophthalmic antiglaucoma agent with Travoprost, the other
agent should be discontinued and Travoprost should be started the following day.

Hepatic and renal impairment
Travoprost has been studied in patients with mild to severe hepatic impairment and in
patients with mild to severe renal impairment (creatinine clearance as low as
14 ml/min). No dosage adjustment is necessary in these patients.
The patient should remove the protective overwrap immediately prior to initial use.
To prevent contamination of the dropper tip and solution, care must be taken not to
touch the eyelids, surrounding areas or other surfaces with the dropper tip of the
bottle.

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
Travoprost may gradually change the eye colour by increasing the number of
melanosomes (pigment granules) in melanocytes. Before treatment is
instituted, patients must be informed of the possibility of a permanent change
in eye colour. Unilateral treatment can result in permanent heterochromia. The
long term effects on the melanocytes and any consequences thereof are
currently unknown. The change in iris colour occurs slowly and may not be
noticeable for months to years. The 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; however, it has also been observed in patients
with brown eyes. Typically, the brown pigmentation around the pupil spreads
concentrically towards the periphery in affected eyes, but the entire iris or
parts of it may be become more brownish. After discontinuation of therapy, no
further increase in brown iris pigment has been observed.
In controlled clinical trials, periorbital and/or eyelid skin darkening in
association with the use of travoprost has been reported in 0.4% of patients.
Travoprost may gradually change eyelashes in the treated eye(s); these
changes were observed in about half of the patients in clinical trials and
include: increased length, thickness, pigmentation, and/or number of lashes.
The mechanism of eyelash changes and their long term consequences are
currently unknown.
Travoprost has been shown to cause slight enlargement of the palpebral fissure
in studies in the monkey. However, this effect was not observed during the
clinical trials and is considered to be species specific.
There is no experience of travoprost in inflammatory ocular conditions; nor in
neovascular, angle-closure, narrow-angle or congenital glaucoma and only
limited experience in thyroid eye disease, in open-angle glaucoma of
pseudophakic patients and in pigmentary or pseudoexfoliative glaucoma.
Caution is recommended when using Travoprost in aphakic patients,
pseudophakic patients with a torn posterior lens capsule or anterior chamber
lenses, or in patients with known risk factors for cystoid macular oedema.
Skin contact with Travoprost must be avoided as transdermal absorption of
travoprost has been demonstrated in rabbits.
Benzalkonium chloride, which is commonly used as a preservative in
ophthalmic products, has been reported to cause punctate keratopathy and/or
toxic ulcerative keratopathy. Since Travoprost contains benzalkonium
chloride, close monitoring is required with frequent or prolonged use.
In patients with known predisposing risk factors for iritis/uveitis, Travoprost
can be used with caution.

Prostaglandins and prostaglandin analogues are biologically active materials
that may be absorbed through the skin. Women who are pregnant or
attempting to become pregnant should exercise appropriate precautions to
avoid direct exposure to the contents of the bottle. In the unlikely event of
coming in contact with a substantial portion of the contents of the bottle,
thoroughly cleanse the exposed area immediately
Travoprost contains benzalkonium chloride which may cause eye irritation and
is known to discolour soft contact lenses. Contact with soft contact lenses is to
be avoided.
Patients must be instructed to remove contact lenses prior to application of
Travoprost and wait 15 minutes after instillation of the dose before reinsertion.
Travoprost contains macrogolglycerol hydroxystearate 40 which may cause skin
reactions.

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.

4.6

Fertility, pregnancy and lactation
Women of child-bearing potential/contraception
Travoprost must not be used in women of child bearing age/potential unless adequate
contraceptive measures are in place (see section 5.3).
Pregnancy
Travoprost has harmful pharmacological effects on pregnancy and/or the foetus/new
born child. Travoprost should not be used during pregnancy unless clearly necessary.
Breastfeeding
It is unknown whether travoprost from eye drops is excreted in human breast milk.
Animal studies have shown excretion of travoprost and metabolites in breast milk.
The use of Travoprost by breast feeding mothers is not recommended.

4.7

Effects on ability to drive and use machines
Temporary blurred vision or other visual disturbances may affect the ability to drive
or use machines. If blurred vision occurs at instillation, the patient must wait until the
vision clears before driving or using machinery.

4.8

Undesirable effects
In clinical studies involving over 4400 patients, travoprost was administered once
daily as monotherapy or adjunctive therapy to timolol 0.5%. No serious ophthalmic or

systemic undesirable effects related to the product were reported in any of the clinical
studies. The most frequently reported treatment-related undesirable effect with
travoprost monotherapy was hyperaemia of the eye (22.0%), which included ocular,
conjunctival, or scleral hyperaemia. Hyperaemia was mild in 83.6% of those patients
who experienced it. Almost all patients (98%) who experienced hyperaemia did not
discontinue therapy as a result of this event. In phase III clinical studies ranging from
6 to 12 months in duration, hyperaemia decreased over time. In a post approval longterm clinical study of 5 years duration involving 502 patients, Travoprost was
administered once daily. No serious ophthalmic or systemic undesirable effects
related to travoprost were reported in the clinical study. The most frequently reported
treatment-related undesirable effect with travoprost was iris hyperpigmentation
(29.5%) (see section 4.4). Hyperaemia of the eye assessed as related to the use of
travoprost was reported at an incidence of 10.0% with 2% of patients reporting
hyperemia of the eye discontinuing study participation due to the undesirable effect.
The following undesirable effects were assessed to be treatment-related with
travoprost monotherapy and are classified according to the following convention:
very common (≥1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to ≤1/100),
rare (>1/10,000 to ≤1/1000), very rare (≤1/10,000), not known (cannot be estimated
from the available data). Within each frequency grouping, undesirable effects are
presented in decreasing order of seriousness.

System Organ
Classification

Frequency

Preferred Term

Infections and
infestations

Uncommon

herpes simplex, keratitis herpetic

Immune system
disorders

Uncommon

hypersensitivity, drug hypersensitivity,
seasonal allergy

Nervous system
disorder

Common

headache

Uncommon

dysgeusia, dizziness, visual field defect

Eye disorders

Very common

ocular hyperaemia, iris hyperpigmentation

Common

punctate keratitis, anterior chamber
inflammation, , eye pain, photophobia, eye
discharge, ocular discomfort, visual acuity
reduced, vision blurred, dry eye, eye pruritus,
lacrimation increased, erythema of eyelid,
eyelid oedema, growth of eyelashes, eyelash
discolouration

Uncommon

uveitis, keratitis, eye inflammation,
photopsia, blepharitis, conjunctival oedema,
halo vision, conjunctivitis, conjunctival
follicles, hypoaesthesia eye, meibomianitis,
ectropion, anterior chamber pigmentation,
mydriasis, cataract, eyelid margin crusting,
asthenopia, visual acuity reduced, lacrimation
increased, erythema of eyelid

Uncommon

heart rate irregular, palpitations, heart rate
decreased

Cardiac disorders

System Organ
Classification

Frequency

Preferred Term

Vascular disorders

Uncommon

blood pressure decreased, blood pressure
increased, hypotension, hypertension

Respiratory,
thoracic and
mediastinal
disorders

Uncommon

dyspnoea, asthma, respiratory disorder,
oropharyngeal pain, cough, dysphonia, nasal
congestion, throat irritation

Gastrointestinal
disorders

Uncommon

peptic ulcer reactivated, gastrointestinal
disorder, constipation, dry mouth

Skin and
subcutaneous tissue
disorders

Common

skin hyperpigmentation (periocular)

Uncommon

dermatitis allergic, periorbital oedema,
dermatitis contact, erythema, rash, hair
colour changes, hair texture abnormal,
hypertrichosis, madarosis

Musculoskeletal,
connective tissue
disorders

Uncommon

musculoskeletal pain

General disorders
and administrative
site conditions

Uncommon

asthenia, malaise

Adverse reactions identified from post-marketing experience that have not been
reported previously in clinical trials with travoprost as monotherapy include the
following.
Ocular: macular oedema (see also section 4.4), sunken eyes
Systemic: bradycardia, tachycardia, asthma aggravated, vertigo, tinnitus, PSA
increased, hair growth abnormal.
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 (www.mhra.gov.uk/yellowcard).

4.9

Overdose
No cases of overdose have been reported. A topical overdose is not likely to occur or
to be associated with toxicity. A topical overdose of Travoprost may be flushed from
the eye(s) with lukewarm water. Treatment of a suspected oral ingestion is
symptomatic and supportive.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group: Ophthalmologicals antiglaucoma preparations and
miotics prostaglandin analogues
ATC code: S01E E04
Mechanism of action
Travoprost, a prostaglandin F2α analogue, is a highly selective full agonist which has a
high affinity for the prostaglandin FP receptor, and reduces the intraocular pressure
by increasing the outflow of aqueous humour via trabecular meshwork and
uveoscleral pathways. Reduction of the intraocular pressure in man starts about 2
hours after administration and maximum effect is reached after 12 hours. Significant
lowering of intraocular pressure can be maintained for periods exceeding 24 hours
with a single dose.
Data on adjunctive administration of travoprost with timolol 0.5% and limited data
with brimonidine 0.2% were collected during clinical trials that showed an additive
effect of travoprost with these glaucoma medications. No clinical data are available
on adjunctive use with other ocular hypotensive medications.
Secondary pharmacology
Travoprost significantly increased optic nerve head blood flow in rabbits following 7
days of topical ocular administration (1.4 micrograms, once daily).

5.2

Pharmacokinetic properties
Absorption
Travoprost is an ester prodrug. It is absorbed through the cornea where the isopropyl
ester is hydrolysed to the active free acid. Studies in rabbits have shown peak
concentrations of 20 ng/g of the free acid in aqueous humour one to two hours after
topical dosing of travoprost. Aqueous humour concentrations declined with a half life
of approximately 1.5 hours.
Distribution
Following topical ocular administration of travoprost to healthy volunteers, low
systemic exposure to active free acid was demonstrated. Peak active free acid plasma
concentrations of 25 pg/ml or less were observed between 10 and 30 minutes post
dose. Thereafter, plasma levels declined rapidly to below the 10 pg/ml assay
quantitation limit before 1 hour post-administration. Due to the low plasma
concentrations and rapid elimination following topical dosing, the elimination half
life of active free acid in man could not be determined.

Biotransformation
Metabolism is the major route of elimination of both travoprost and the active free
acid. The systemic metabolic pathways parallel those of endogenous prostaglandin
F2α which are characterised by reduction of the 13 14 double bond, oxidation of the
15 hydroxyl and β-oxidative cleavages of the upper side chain.
Elimination
Travoprost free acid and its metabolites are mainly excreted by the kidneys.
Travoprost has been studied in patients with mild to severe hepatic impairment and in
patients with mild to severe renal impairment (creatinine clearance as low as 14
ml/min). No dosage adjustment is necessary in these patients.

5.3

Preclinical safety data
In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45
microgram, twice a day, was shown to induce increased palpebral fissure. Topical
ocular administration of travoprost to monkeys at concentrations of up to 0.012% to
the right eye, twice daily for one year resulted in no systemic toxicity.
Reproduction toxicity studies have been undertaken in rat, mice and rabbit by
systemic route. Findings are related to FP receptor agonist activity in uterus with
early embryo lethality, post implantation loss, foetotoxicity. In pregnant rat, systemic
administration of travoprost at doses more than 200 times the clinical dose during the
period of organogenesis resulted in an increased incidence of malformations. Low
levels of radioactivity were measured in amniotic fluid and foetal tissues of pregnant
rats administered 3H travoprost. Reproduction and development studies have
demonstrated a potent effect on foetal loss with a high rate observed in rats and mice
at plasma levels of 180 pg/ml and 30 pg/ml , respectively corresponding to 1.2 to 6
times the clinical level (up to 25 pg/ml).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Benzalkonium chloride solution
Macrogolglycerol hydroxystearate 40
Trometamol
Disodium edetate
Boric acid (E284)
Mannitol (E421)
Sodium hydroxide and/or hydrochloric acid (to adjust pH)
Purified water

6.2

Incompatibilities
Not applicable.
Specific in vitro interaction studies were performed with this medicinal product and
medicinal products containing thiomersal. No evidence of precipitation was observed.

6.3

Shelf life
Unopened:
3 years.
After first opening: 4 weeks.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
2.5 ml oval dropper container with screw cap, all polypropylene, presented in an
overwrap.
Pack sizes: 1, 3 or 6 dropper containers.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park,
Frimley, Camberley,
Surrey,
GU16 7SR
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 04416/1354

9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
06/06/2014

10

DATE OF REVISION OF THE TEXT
01/10/2014

Expand Transcript

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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