- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Use in adults, including elderly populationThe dose is one drop of TRAVATAN in the conjunctival sac of the affected eye(s) once daily. Optimal effect is obtained if the dose is administered in the evening.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 medicinal product with TRAVATAN, the other medicinal product should be discontinued and TRAVATAN should be started the following day.
Hepatic and renal impairmentTRAVATAN 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 (see section 5.2).
Paediatric populationTRAVATAN can be used in paediatric patients from 2 months to < 18 years at the same posology as in adults. However, data in the age group 2 months to < 3 years (9 patients) is limited (see section 5.1).The safety and efficacy of TRAVATAN in children below the age of 2 months have not been established. No data are available.
Method of AdministrationFor ocular use.For patients who wear contact lenses, please refer to section 4.4.The patient should remove the protective overwrap immediately prior to initial use. After cap is removed, if the tamper evident snap collar is loose, remove before using the medicinal product. 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.
Eye colour changeTRAVATAN 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.
Periorbital and eye lid changesIn controlled clinical trials, periorbital and/or eyelid skin darkening in association with the use of TRAVATAN has been reported in 0.4% of patients. Periorbital and lid changes including deepening of the eyelid sulcus have also been observed with prostaglandin analogues.TRAVATAN 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.TRAVATAN 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 TRAVATAN 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. TRAVATAN should therefore be used with caution in patients with active intraocular inflammation.
Aphakic patientsMacular oedema has been reported during treatment with prostaglandin F2a analogues. Caution is recommended when using Travatan 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.
Iritis/uveitisIn patients with known predisposing risk factors for iritis/uveitis, TRAVATAN should be used with caution.
Contact with the skinSkin contact with TRAVATAN must be avoided as transdermal absorption of travoprost has been demonstrated in rabbits.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.
Contact lensesPatients must be instructed to remove contact lenses prior to application of TRAVATAN and wait 15 minutes after instillation of the dose before reinsertion.ExcipientsTRAVATAN contains propylene glycol which may cause skin irritation. TRAVATAN contains polyoxyethylene hydrogenated castor oil 40 which may cause skin reactions.
Paediatric populationEfficacy and safety data in the age group 2 months to < 3 years (9 patients) is limited (see section 5.1). No data are available for children below the age of 2 months.In children < 3 years old that mainly suffer from PCG (primary congenital glaucoma), surgery (e.g. trabeculotomy/goniotomy) remains the first line treatment.No long-term safety data are available in the paediatric population.
Women of child-bearing potential/contraceptionTRAVATAN must not be used in women of child bearing age/potential unless adequate contraceptive measures are in place (see section 5.3).
PregnancyTravoprost has harmful pharmacological effects on pregnancy and/or the fetus/new-born child. TRAVATAN should not be used during pregnancy unless clearly necessary.
BreastfeedingIt is unknown whether travoprost from the eye drops is excreted in human breast milk. Animal studies have shown excretion of travoprost and metabolites in breast milk. The use of TRAVATAN by breast-feeding mothers is not recommended.
FertilityThere are no data on the effects of TRAVATAN on human fertility. Animal studies showed no effect of travoprost on fertility at doses more than 250 times the maximum recommended human ocular dose.
Summary of the safety profileIn clinical trials with TRAVATAN, the most common adverse reactions were ocular hypearemia and iris hyperpigmentation, occurring in approximately 20% and 6% of patients respectively.
Tabulated list of adverse reactionsThe following adverse reactions 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<1/1,000), very rare <1/10,000), or not known (frequency cannot be estimated from the available data). Within each frequency group, adverse reactions are presented in decreasing order of seriousness. The adverse reactions were obtained from clinical studies and post- marketing data with TRAVATAN.
|System Organ Class||Frequency||Adverse Reactions|
|Infections and infestations||Rare||herpes simplex, keratitis herpetic|
|Immune system disorders||Uncommon||hypersensitivity, seasonal allergy|
|Psychiatric disorders||Not known||depression, anxiety|
|Nervous system disorder||Uncommon||headache, dizziness, visual field defect|
|Eye disorders||Very common||ocular hyperaemia,|
|Common||iris hyperpigmentation, eye pain, ocular discomfort, dry eye, eye pruritus, eye irritation|
|Uncommon||corneal erosion, uveitis, iritis, anterior chamber inflammation, keratitis, punctate keratitis, photophobia, eye discharge , blepharitis, erythema of eyelid, periorbital oedema, eyelids pruritus, visual acuity reduced, vision blurred, lacrimation increased, conjunctivitis, ectropioncataract, eyelid margin crusting, growth of eyelashes, eyelash discolouration, asthenopia|
|Rare||iridocyclitis, eye inflammation, photopsia, eczema eyelids, conjunctival oedema, halo vision, conjunctival follicles, hypoaesthesia eye, meibomianitis, anterior chamber pigmentation, mydriasis, eyelash thickening|
|Not known||macular oedema, sunken eyes|
|Ear and labyrinth disorders||Not known||vertigo, tinnitus|
|Rare||heart rate irregular, heart rate decreased|
|Not known||chest pain, bradycardia, tachycardia|
|Vascular disorders||Rare||blood pressure diastolic decreased, blood pressure systolic increased, hypotension, hypertension|
|Respiratory, thoracic and mediastinal disorders||Uncommon||dyspnoea, asthma, nasal congestion, throat irritation|
|Rare||respiratory disorder, oropharyngeal pain, cough, dysphonia|
|Not known||asthma aggravated|
|Gastrointestinal disorders||Rare||peptic ulcer reactivated, gastrointestinal disorder, constipation, dry mouth|
|Not known||diarrhoea, abdominal pain, nausea|
|Skin and subcutaneous tissue disorders||Uncommom||skin hyperpigmentation (periocular), skin discolouration, hair texture abnormal, hypertrichosis|
|Rare||dermatitis allergic, dermatitis contact, erythema, rash, hair colour changes, madarosis|
|Not known||pruritus, hair growth abnormal|
|Musculoskeletal and connective tissue disorders||Rare||musculoskeletal pain|
|Renal and urinary disorders||Not known||dysuria, urinary incontinence|
|General disorders and administration site conditions||Rare||asthenia|
|Investigations||Not known||prostatic specific antigen increased|
Paediatric PopulationIn a 3 month phase 3 study and a 7 days pharmacokinetic study, involving 102 paediatric patients exposed to TRAVATAN, the types and characteristics of adverse reactions reported were similar to what has been observed in adult patients. The short-term safety profiles in the different paediatric subsets were also similar (see section 5.1). The most frequent adverse reactions reported in the paediatric population were ocular hyperaemia (16.9%) and growth of eyelashes (6.5%). In a similar 3 month study in adult patients, these events occurred at an incidence of 11.4% and 0.0%, respectively. Additional adverse drug reactions reported in paediatric patients in the 3 month paediatric study (n=77) compared to a similar trial in adults (n=185) included erythema of eyelid, keratitis, lacrimation increased, and photophobia all reported as single events with an incidence of 1.3% versus 0.0% seen in adults.
Reporting of suspected adverse reactionsReporting 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:
United KingdomYellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
IrelandHPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: firstname.lastname@example.org
MaltaADR ReportingThe Medicines Authority Post-Licensing Directorate203 Level 3, Rue D'ArgensGŻR-1368 GżiraWebsite: www.medicinesauthority.gov.mte-mail: email@example.com
Mechanism of actionTravoprost, 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.
Clinical efficacy and safetyIn a clinical trial, patients with open-angle glaucoma or ocular hypertension who were treated with TRAVATAN (polyquaternium-preserved) dosed once-daily in the evening demonstrated 8 to 9 mmHg reductions (approximately 33%) in intraocular pressure from 24 to 26 mmHg baseline. Data on adjunctive administration of TRAVATAN with timolol 0.5% and limited data with brimonidine 0.2% were collected during clinical trials that showed an additive effect of TRAVATAN with these glaucoma medications. No clinical data are available on adjunctive use with other ocular hypotensive medications.
Secondary pharmacologyTravoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topical ocular administration (1.4 micrograms, once-daily).TRAVATAN preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.
Paediatric populationThe efficacy of TRAVATAN in paediatric patients from 2 months to less than 18 years of age was demonstrated in a 12-week, double-masked clinical study of travoprost compared with timolol in 152 patients diagnosed with ocular hypertension or paediatric glaucoma. Patients received either travoprost 0.004% once daily or timolol 0.5% (or 0.25% for subjects younger than 3 years old) twice daily. The primary efficacy endpoint was the intraocular pressure (IOP) change from baseline at Week 12 of the study. Mean IOP reductions in the travoprost and timolol groups were similar (see Table 1). In the age groups 3 to < 12 years (n=36) and 12 to <18 years (n=26), mean IOP reduction at Week 12 in the travoprost group was similar to that in the timolol group. Mean IOP reduction at Week 12 in the 2 months to < 3 years of age group was 1.8 mmHg in the travoprost group and 7.3 mmHg in the timolol group. IOP reductions for this group were based on only 6 patients in the timolol group and 9 patients in the travoprost group where 4 patients in the travoprost group versus 0 patients in the timolol group had no relevant mean IOP reduction at Week 12. No data are available for children less than 2 months old.The effect on IOP was seen after the second week of treatment and was consistently maintained throughout the 12 week period of study for all age groups.
Table 1 Comparison of Mean IOP Change from Baseline (mmHg) at Week 12
|N||Mean (SE)||N||Mean (SE)||Mean Differencea||(95% CI)|
|53||-6.4 (1.05)||60||-5.8 (0.96)||-0.5||(-2.1, 1.0)|
|SE = Standard Error; CI = Confidence Interval; aMean difference is Travoprost Timolol. Estimates based on least squares means derived from a statistical model that accounts for correlated IOP measurements within patient where primary diagnosis and baseline IOP stratum are in the model.|
AbsorptionTravoprost 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/mL of the free acid in aqueous humour one to two hours after topical dosing of TRAVATAN. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.
DistributionFollowing topical ocular administration of TRAVATAN 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.
BiotransformationMetabolism 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.
EliminationTravoprost free acid and its metabolites are mainly excreted by the kidneys. TRAVATAN 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.
Paediatric populationA pharmacokinetic study in paediatric patients aged 2 months to <18 years demonstrated very low plasma exposure to travoprost free acid, with concentrations ranging from below the 10 pg/mL assay limt of quantitation (BLQ) to 54.5 pg/mL. In 4 previous systemic pharmacokinetic studies in adult populations, travoprost free acid plasma concentrations ranged from BLQ to 52.0 pg/mL. While most of the plasma data across all studies was non-quantifiable, making statistical comparisons of systemic exposure across age groups unfeasible, the overall trend shows that plasma exposure to travoprost free acid following topical administration of TRAVATAN is extremely low across all age groups evaluated.
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