5.1 Pigmentation

XALATAN has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes. Pigmentation is expected to increase as long as latanoprost is administered.

The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of latanoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. Beyond 5 years the effects of increased pigmentation are not known [see Clinical Studies (14.2)].

Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with XALATAN can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

5.2 Eyelash Changes

XALATAN may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment.

5.3 Intraocular Inflammation

XALATAN should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation because inflammation may be exacerbated.

5.4 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with XALATAN. XALATAN should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

5.5 Herpetic Keratitis

Reactivation of herpes simplex keratitis has been reported during treatment with XALATAN. XALATAN should be used with caution in patients with a history of herpetic keratitis. XALATAN should be avoided in cases of active herpes simplex keratitis because inflammation may be exacerbated.

5.6 Bacterial Keratitis

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

5.7 Contact Lens Use

XALATAN contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to the administration of XALATAN, and may be reinserted 15 minutes after administration.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

XALATAN was studied in three multicenter, randomized, controlled clinical trials. Patients received 50 mcg/mL XALATAN once daily or 5 mg/mL active-comparator (timolol) twice daily. The patient population studied had a mean age of 65±10 years. Seven percent of patients withdrew before the 6-month endpoint.

Less than 1% of the patients treated with XALATAN required discontinuation of therapy because of intolerance to conjunctival hyperemia.

6.2 Postmarketing Experience

The following reactions have been identified during postmarketing use of XALATAN in clinical practice. Because they are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to XALATAN, or a combination of these factors, include:

Nervous System Disorders: Dizziness; headache; toxic epidermal necrolysis

Eye Disorders: Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis); macular edema, including cystoid macular edema; trichiasis; periorbital and lid changes resulting in deepening of the eyelid sulcus; iris cyst; eyelid skin darkening; localized skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular conjunctiva.

Respiratory, Thoracic and Mediastinal Disorders: Asthma and exacerbation of asthma; dyspnea

Gastrointestinal Disorders: Nausea; vomiting

Skin and Subcutaneous Tissue Disorders: Pruritis

Infections and Infestations: Herpes keratitis

Cardiac Disorders: Angina; palpitations; angina unstable

General Disorders and Administration Site Conditions: Chest pain

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

12.1 Mechanism of Action

Latanoprost is a prostaglandin F2α analogue that is believed to reduce the IOP by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

12.2 Pharmacodynamics

Reduction of the IOP in man starts about 3-4 hours after administration and maximum effect is reached after 8-12 hours. IOP reduction is present for at least 24 hours.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum human dose) for up to 20 and 24 months, respectively.

Mutagenesis

Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests. Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.

Impairment of Fertility

Latanoprost has not been found to have any effect on male or female fertility in rat studies at IV doses up to 250 mcg/kg/day (811 times the maximum RHOD, on a mg/m2 basis, assuming 100% absorption).

14.1 Elevated Baseline IOP

Patients with mean baseline IOP of 24 – 25 mmHg who were treated for 6 months in multi-center, randomized, controlled trials demonstrated 6 – 8 mmHg reductions in IOP. This IOP reduction with XALATAN 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily.

14.2 Progression of Increased Iris Pigmentation

A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of XALATAN once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was based on observed-cases population of the 380 patients who continued in the extension phase.

Results showed that the onset of noticeable increased iris pigmentation occurred within the first year of treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the 5 years of the study. Observation of increased iris pigmentation did not affect the incidence, nature, or severity of adverse events (other than increased iris pigmentation) recorded in the study. IOP reduction was similar regardless of the development of increased iris pigmentation during the study.