Xalatan.com

Xalatan®
latanoprost ophthalmic solution

0.005% (50 µg/mL)
DESCRIPTION
Latanoprost is a prostaglandin F2α 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 C26H40O5 and its chemical structure is:
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 Sterile Ophthalmic Solution (latanoprost ophthalmic solution) 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 micrograms 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 µg of latanoprost.
CLINICAL PHARMACOLOGY

Mechanism of Action
Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the
intraocular pressure (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.
Pharmacokinetics/Pharmacodynamics
Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester
prodrug is hydrolyzed to the acid form to become biologically active. Studies in man
indicate that the peak concentration in the aqueous humor is reached about two hours
after topical administration.
Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration. Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation. Excretion: The elimination of the acid of latanoprost from human plasma is rapid (t1/2 =17 min) after both intravenous and topical administration. Systemic clearance is
approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly
eliminated via the kidneys. Approximately 88% and 98% of the administered dose is
recovered in the urine after topical and intravenous dosing, respectively.
Animal Studies
In monkeys, latanoprost has been shown to induce increased pigmentation of the iris. The
mechanism of increased pigmentation seems to be stimulation of melanin production in
melanocytes of the iris, with no proliferative changes observed. The change in iris color
may be permanent.
Ocular administration of latanoprost at a dose of 6 µg/eye/day (4 times the daily human
dose) to cynomolgus monkeys has also been shown to induce increased palpebral fissure.
This effect was reversible upon discontinuation of the drug.
INDICATIONS AND USAGE

XALATAN Sterile Ophthalmic Solution is indicated for the reduction of elevated
intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
CLINICAL STUDIES
Patients with mean baseline intraocular pressure of 24 - 25 mmHg who were treated for 6
months in multi-center, randomized, controlled trials demonstrated 6 -8 mmHg
reductions in intraocular pressure. This IOP reduction with XALATAN Sterile
Ophthalmic Solution 0.005% dosed once daily was equivalent to the effect of timolol
0.5% dosed twice daily.
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 five 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.
CONTRAINDICATIONS
Known hypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in
this product.
WARNINGS
XALATAN Sterile Ophthalmic Solution 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, and growth of
eyelashes. Pigmentation is expected to increase as long as XALATAN is administered.
After discontinuation of XALATAN, 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. The effects of increased pigmentation beyond 5
years are not known.
PRECAUTIONS
General: XALATAN Sterile Ophthalmic Solution may gradually increase the
pigmentation of the iris. The eye color change is due to increased melanin content in the
stromal melanocytes of the iris rather than to an increase in the number of melanocytes.
This change may not be noticeable for several months to years (see WARNINGS).
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.
During clinical trials, the increase in brown iris pigment has not been shown to progress
further upon discontinuation of treatment, but the resultant color change may be
permanent.
Eyelid skin darkening, which may be reversible, has been reported in association with the
use of XALATAN (see WARNINGS).
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.
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.

Macular edema, including cystoid macular edema, has been reported during treatment
with XALATAN. These reports have mainly occurred in aphakic patients, in
pseudophakic patients with a torn posterior lens capsule, or in patients with known risk
factors for macular edema. XALATAN should be used with caution in patients who do
not have an intact posterior capsule or who have known risk factors for macular edema.
There is limited experience with XALATAN in the treatment of angle closure,
inflammatory or neovascular glaucoma.
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 (see PRECAUTIONS, Information for
Patients).
Contact lenses should be removed prior to the administration of XALATAN, and may be
reinserted 15 minutes after administration (see PRECAUTIONS, Information for
Patients).
Information for Patients (see WARNINGS and PRECAUTIONS): Patients should
be advised about the potential for increased brown pigmentation of the iris, which may be
permanent. Patients should also be informed about the possibility of eyelid skin
darkening, which may be reversible after discontinuation of XALATAN.
Patients should also be informed of the possibility of eyelash and vellus hair changes in
the treated eye during treatment with XALATAN. 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.
Patients should be instructed to avoid allowing the tip of the dispensing container to
contact the eye or surrounding structures because this could cause the tip to become
contaminated by common bacteria known to cause ocular infections. Serious damage to
the eye and subsequent loss of vision may result from using contaminated solutions.
Patients also should be advised that if they develop an intercurrent ocular condition (e.g.,
trauma, or infection) or have ocular surgery, they should immediately seek their
physician's advice concerning the continued use of the multiple-dose container.
Patients should be advised that if they develop any ocular reactions, particularly
conjunctivitis and lid reactions, they should immediately seek their physician's advice.
Patients should also be advised that XALATAN contains benzalkonium chloride, which
may be absorbed by contact lenses. Contact lenses should be removed prior to
administration of the solution. Lenses may be reinserted 15 minutes following
administration of XALATAN.
If more than one topical ophthalmic drug is being used, the drugs should be administered
at least five (5) minutes apart.
Drug Interactions: In vitro studies have shown that precipitation occurs when eye
drops containing thimerosal are mixed with XALATAN. If such drugs are used they
should be administered at least five (5) minutes apart.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Latanoprost was not
mutagenic in bacteria, in mouse lymphoma or in mouse micronucleus tests.
Chromosome aberrations were observed in vitro with human lymphocytes.
Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage
at doses of up to 170 µg/kg/day (approximately 2,800 times the recommended maximum
human dose) for up to 20 and 24 months, respectively.
Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were
negative. Latanoprost has not been found to have any effect on male or female fertility in
animal studies.
Pregnancy: Teratogenic Effects: Pregnancy Category C.
Reproduction studies have been performed in rats and rabbits. In rabbits an incidence of 4
of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum
human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times
the maximum human dose. There are no adequate and well-controlled studies in pregnant
women. XALATAN should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers: 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.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: No overall differences in safety or effectiveness have been observed
between elderly and younger patients.
ADVERSE REACTIONS

Adverse events referred to in other sections of this insert:

Eyelash changes (increased length, thickness, pigmentation, and number of lashes);
eyelid skin darkening; intraocular inflammation (iritis/uveitis); iris pigmentation changes;
and macular edema, including cystoid macular edema (see WARNINGS and
PRECAUTIONS).
Controlled Clinical Trials:

The ocular adverse events and ocular signs and symptoms reported in 5 to 15% of the
patients on XALATAN Sterile Ophthalmic Solution in the three 6-month, multi-center,
double-masked, active-controlled trials were blurred vision, burning and stinging,
conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the
iris, and punctuate epithelial keratopathy.
Local conjunctival hyperemia was observed; however, less than 1% of the patients
treated with XALATAN required discontinuation of therapy because of intolerance to
conjunctival hyperemia.
In addition to the above listed ocular events/signs and symptoms, the following were
reported in 1 to 4% of the patients: dry eye, excessive tearing, eye pain, lid crusting, lid
discomfort/pain, lid edema, lid erythema, and photophobia.
The following events were reported in less than 1% of the patients: conjunctivitis,
diplopia and discharge from the eye.
During clinical studies, there were extremely rare reports of the following: retinal artery
embolus, retinal detachment, and vitreous hemorrhage from diabetic retinopathy.
The most common systemic adverse events seen with XALATAN were upper respiratory
tract infection/cold/flu, which occurred at a rate of approximately 4%. Chest pain/angina
pectoris, muscle/joint/back pain, and rash/allergic skin reaction each occurred at a rate of
1 to 2%.
Clinical Practice:
The following events have been identified during postmarketing use of XALATAN in
clinical practice. Because they are reported voluntarily from a population of unknown
size, estimates of frequency cannot be made. The events, 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: asthma and
exacerbation of asthma; corneal edema and erosions; dyspnea; eyelash and vellus hair
changes (increased length, thickness, pigmentation, and number); eyelid skin darkening;
herpes keratitis; intraocular inflammation (iritis/uveitis); keratitis; macular edema,
including cystoid macular edema; misdirected eyelashes sometimes resulting in eye
irritation; dizziness, headache, and toxic epidermal necrolysis.
OVERDOSAGE

Apart from ocular irritation and conjunctival or episcleral hyperemia, the ocular effects of
latanoprost administered at high doses are not known. Intravenous administration of large
doses of latanoprost in monkeys has been associated with transient bronchoconstriction;
however, in 11 patients with bronchial asthma treated with latanoprost,
bronchoconstriction was not induced. Intravenous infusion of up to 3 µg/kg in healthy
volunteers produced mean plasma concentrations 200 times higher than during clinical
treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 µg/kg
caused abdominal pain, dizziness, fatigue, hot flushes, nausea and sweating.
If overdosage with XALATAN Sterile Ophthalmic Solution occurs, treatment should be
symptomatic.
DOSAGE AND ADMINISTRATION

The recommended dosage is one drop (1.5 µg) 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 Sterile Ophthalmic Solution should not exceed once daily; the
combined use of two or more prostaglandins, or prostaglandin analogs including
XALATAN Sterile Ophthalmic Solution is not recommended. It has been shown that
administration of these prostaglandin drug products more than once daily may decrease
the intraocular pressure lowering effect or cause paradoxical elevations in IOP.
Reduction of the intraocular pressure 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 intraocular pressure. If more than one topical ophthalmic drug is being used, the
drugs should be administered at least five (5) minutes apart.
HOW SUPPLIED

XALATAN Sterile Ophthalmic Solution is a clear, isotonic, buffered, preserved colorless
solution of latanoprost 0.005% (50 µg/mL). It is supplied as a 2.5 mL solution in a 5 mL
clear low density polyethylene bottle with a clear low density polyethylene dropper tip, a
turquoise high density polyethylene screw cap, and a tamper-evident clear low density
polyethylene overcap.
2.5 mL fill, 0.005% (50 µg/mL)
Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks. Manufactured By: Cardinal Health Woodstock, IL 60098, USA LAB-0135-7.0 Revised

Source: http://www.xalatan.com/content/uspi-xalatan.pdf