Travatan Z (Page 2 of 3)

8.2 Lactation

Risk Summary

There are no data on the effects of travoprost on the breastfed child or milk production. It is not known if travoprost is present in human milk following ophthalmic administration. A study in lactating rats demonstrated that radio-labeled travoprost and/or its metabolites were excreted in milk following subcutaneous administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRAVATAN Z and any potential adverse effects on the breast-fed child from TRAVATAN Z.

8.4 Pediatric Use

Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

8.5 Geriatric Use

No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

8.6 Hepatic and Renal Impairment

Travoprost ophthalmic solution 0.004% has been studied in patients with hepatic impairment and also in patients with renal impairment. No clinically relevant changes in hematology, blood chemistry, or urinalysis laboratory data were observed in these patients.

11 DESCRIPTION

Travoprost is a synthetic prostaglandin F analog. Its chemical name is [1R -[1α(Z),2β(1E ,3R *),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester. It has a molecular formula of C26 H35 F3 O6 and a molecular weight of 500.55 g/mol. The chemical structure of travoprost is:

chemical
(click image for full-size original)

Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water.

TRAVATAN Z is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg.

TRAVATAN Z contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, sof Zia® (boric acid, propylene glycol, sorbitol, zinc chloride), sodium hydroxide and/or hydrochloric acid (to adjust pH), and purified water, USP. Preserved in the bottle with an ionic buffered system, sof Zia®.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist, which is believed to reduce IOP by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.

12.3 Pharmacokinetics

Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from 4 multiple-dose pharmacokinetic studies (totaling 107 subjects) have shown that plasma concentrations of the free acid are below 0.01 ng/mL (the quantitation limit of the assay) in two-thirds of the subjects. In those individuals with quantifiable plasma concentrations (N = 38), the mean plasma Cmax was 0.018 ± 0.007 ng/mL (ranged 0.01 to 0.052 ng/mL) and was reached within 30 minutes. From these studies, travoprost is estimated to have a plasma half-life of 45 minutes. There was no difference in plasma concentrations between Days 1 and 7, indicating steady-state was reached early and that there was no significant accumulation.

Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to its biologically active free acid. Systemically, travoprost free acid is metabolized to inactive metabolites via beta-oxidation of the α (carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction of the 13, 14 double bond.

The elimination of travoprost free acid from plasma was rapid and levels were generally below the limit of quantification within one hour after dosing. The terminal elimination half-life of travoprost free acid was estimated from 14 subjects and ranged from 17 minutes to 86 minutes with the mean half-life of 45 minutes. Less than 2% of the topical ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free acid.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to exposure levels 326 times (mouse) and 547 times (rat) the human exposure at the MRHOD of 0.04 mcg/kg, based on estimated plasma Cmax for active travoprost free acid.

Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes.

Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 3 mcg/kg/day (18 times the MRHOD based on estimated plasma Cmax ). At 10 mcg/kg/day (60 times the MRHOD, based on estimated plasma Cmax ), the mean number of corpora lutea was reduced, and the post-implantation losses were increased.

14 CLINICAL STUDIES

In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 25 to 27 mmHg, who were treated with TRAVATAN or TRAVATAN Z dosed once daily in the evening, demonstrated 7 to 8 mmHg reductions in IOP. In sub-group analyses of these studies, mean IOP reduction in black patients was up to 1.8 mmHg greater than in non-black patients. It is not known at this time whether this difference is attributed to race or to heavily pigmented irides.

In a multi-center, randomized, controlled trial, patients with mean baseline IOP of 24 to 26 mmHg on TIMOPTIC** 0.5% twice daily who were treated with TRAVATAN dosed daily adjunctively to TIMOPTIC** 0.5% twice daily demonstrated 6 to 7 mmHg reductions in IOP.

16 HOW SUPPLIED/STORAGE AND HANDLING

TRAVATAN Z is a sterile, isotonic, buffered, preserved, aqueous solution of travoprost (0.04 mg/mL).

TRAVATAN Z is supplied as a 2.5 mL solution in a 4 mL and a 5 mL solution in a 7.5 mL oval natural polypropylene dispenser bottle with a natural polypropylene dropper tip and a turquoise polypropylene or high-density polyethylene overcap. Tamper evidence is provided with a shrink band around the closure and neck area of the package.

2.5 mL fill…………………NDC 0078-0946-40

5 mL fill……………………NDC 0078-0946-25

Storage: Store at 2°C to 25°C (36°F to 77°F).

After opening, TRAVATAN Z can be used until the expiration date on the bottle.

17 PATIENT COUNSELING INFORMATION

Potential for Pigmentation

Advise the patient about the potential for increased brown pigmentation of the iris, which may be permanent. Inform the patient about the possibility of eyelid skin darkening, which may be reversible after discontinuation of TRAVATAN Z [see Warnings and Precautions (5.1)].

Potential for Eyelash Changes

Inform the patient about the possibility of eyelash and vellus hair changes in the treated eye during treatment with TRAVATAN Z. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment [see Warnings and Precautions (5.2)].

Handling the Container

Instruct the patient to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions (5.6)].

When to Seek Physician Advice

Advise the patient that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of TRAVATAN Z [see Warnings and Precautions (5.3, 5.4, 5.5)].

Use with Contact Lenses

Contact lenses should be removed prior to instillation of TRAVATAN Z and may be reinserted 15 minutes following its administration [see Warnings and Precautions (5.7)].

Use with Other Ophthalmic Drugs

If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes between applications.

**TIMOPTIC is a registered trademark of Merck & Co., Inc.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

© Novartis

T2020-49

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