Xalatan: Package Insert and Label Information

XALATAN- latanoprost solution
Pfizer Laboratories Div Pfizer Inc

1 INDICATIONS AND USAGE

XALATAN is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

2 DOSAGE AND ADMINISTRATION

The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one dose is missed, treatment should continue with the next dose as normal.

The dosage of XALATAN should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including XALATAN is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the IOP lowering effect or cause paradoxical elevations in IOP.

Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours.

XALATAN may be used concomitantly with other topical ophthalmic drug products to lower IOP. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with XALATAN. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. Contact lenses should be removed prior to the administration of XALATAN, and may be reinserted 15 minutes after administration.

3 DOSAGE FORMS AND STRENGTHS

Ophthalmic solution containing latanoprost 50 mcg/mL (0.005%).

4 CONTRAINDICATIONS

Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this product.

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

The following adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the label:

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.

Table 1: Ocular Adverse Reactions and Ocular Signs/Symptoms Reported by 5–15% of Patients Receiving Latanoprost
Symptom/Finding Adverse Reactions (incidence (%))
Latanoprost
(n=460)
Timolol
(n=369)
Foreign body sensation 13 8
Punctate keratitis 10 9
Stinging 9 12
Conjunctival hyperemia 8 3
Blurred vision 8 8
Itching 8 8
Burning 7 8
Increased pigmentation of the Iris 7 0

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

Table 2: Adverse Reactions That Were Reported in 1–5% of Patients Receiving Latanoprost
Adverse Reactions (incidence (%))
Latanoprost
(n=460)
Timolol
(n=369)
Ocular Events/Signs and Symptoms
Excessive tearing 4 6
Eyelid discomfort/pain 4 2
Dry eye 3 3
Eye pain 3 3
Eyelid margin crusting 3 3
Erythema of the eyelid 3 2
Photophobia 2 1
Eyelid edema 1 3
Blepharitis 1 3
Systemic Events
Upper respiratory tract infection/nasopharyngitis/influenza 3 3
Myalgia/arthralgia/back pain 1 0.5
Rash/allergic skin reaction 1 0.3

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

Skin and Subcutaneous Tissue Disorders: Pruritus

Infections and Infestations: Herpes keratitis

Cardiac Disorders: Angina; palpitations; angina unstable

General Disorders and Administration Site Conditions: Chest pain

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of XALATAN administration in pregnant women.to inform drug-associated risks.

In animal reproduction studies, intravenous (IV) administration of latanoprost to pregnant rabbits and rats throughout the period of organogenesis produced malformations, embryofetal lethality and spontaneous abortion at clinically relevant doses [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Animal Data

Embryofetal studies were conducted in pregnant rabbits administered latanoprost daily by IV injection on gestation days 6 through 18, to target the period of organogenesis. A no observed adverse effect level (NOAEL) was not established for rabbit developmental toxicity. Post-implantation loss due to late resorption was shown as doses ≥0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [RHOD], on a mg/m2 basis, assuming 100% absorption). Spina bifida and abortion occurred at 5 mcg/kg/day (equivalent to 32 times the maximum RHOD). Total litter loss due to early resorption was observed at doses ≥50 mcg/kg/day (324 times the maximum RHOD). Transient signs of maternal toxicity were observed after IV dosing (increased breathing, muscle tremors, slight motor incoordination) at 300 mcg/kg/day (1946 times the maximum RHOD). No maternal toxicity was observed at doses up to 50 mcg/kg/day.

Embryofetal studies were conducted in pregnant rats administered latanoprost daily by IV injection on gestation days 6 through 15, to target the period of organogenesis. A NOAEL for rat developmental toxicity was not established. Cleft palate was observed at 1 mcg/kg (equivalent to 3.2 times the maximum RHOD, on a mg/m2 basis, assuming 100% absorption). Brain porencephalic cyst(s) were observed ≥50 mcg/kg (162 times the maximum RHOD). Skeletal anomalies were observed at 250 mcg/kg (811 times the maximum RHOD). No maternal toxicity was detectable at 250 mcg/kg/day.

Prenatal and postnatal development was assessed in rats. Pregnant rats were administered latanoprost daily by IV injection from gestation day 15, through delivery, until weaning (lactation Day 21). No adverse effects on rat offspring were observed at doses up to 10 mcg/kg/day (32 times the maximum RHOD, on a mg/m2 basis, assuming 100% absorption). At 100 mcg/kg/day (324 times the maximum RHOD), maternal deaths and pup mortality occurred.

8.2 Lactation

Risk Summary

It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XALATAN is administered to a nursing woman.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XALATAN and any potential adverse effects on the breastfed child from XALATAN.

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.

10 OVERDOSAGE

IV infusion of up to 3 mcg/kg of latanoprost in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment with XALATAN and no adverse reactions were observed. IV dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea, and sweating.

If overdosage with XALATAN occurs, treatment should be symptomatic.

11 DESCRIPTION

Latanoprost is a prostaglandin F2 α analogue. Its chemical name is isopropyl-(Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. Its molecular formula is C26 H40 O5 and its chemical structure is:

M.W. 432.58
Chemical Structure
(click image for full-size original)

Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically insoluble in water.

XALATAN (latanoprost ophthalmic solution) 0.005% is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of XALATAN contains 50 mcg of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injection. One drop contains approximately 1.5 mcg of latanoprost.

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