NDA 22-211

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HIGHLIGHTS OF PRESCRIBING -------------CO NTRAIND I CA TI 0 NS---------------­

INFORMATION None.

These highlights do not include all of the ------WARNINGS AND PRECAUTIONS---------­

information needed to use ZIRGAN safely and . ZIRGAN is indicated for topical ophthalmic use
effectively. See full prescribing information for only. (5.1)
ZIRGAN. . Patients should not wear contact lenses if they
have signs or symptoms of herpetic keratitis or
ZIRGAN (gancic1ovir ophthalmic gel) 0.15% during the course of therapy with ZIRGAN. (5.2)
Initial US approval: 1989
-------------ADVERSE REA CTI 0 NS----------------­
-----------INDICA TIONS AND USAGE--------~---~­ Most common adverse reactions reported in patients
ZIRGAN is a topical ophthalmic antiviral that is were blurred vision (60%), eye irritation (20%),
indicated for the treatment of acute herpetic keratitis punctate keratitis (5%), and conjunctival hyperemia
(dendritic ulcers). (1) (5%). (6)

------DOSAGE AND ADMINISTRA TION---------­ To report SUSPECTED ADVERSE REACTIONS,

The recommended dosing regimen for ZIRGAN is 1 contact Sirion Therapeutics at 1-866-4SIRION (1­
drop in the affected eye 5 times per day 866-474-7466) or FDA at 1-800-FDA-I088 or
(approximately every 3 hours while awake) unti the www.fda.gov/medwatch.
corneal ulcer heals, and then 1 drop 3 times per day
for 7 days. (2) See 17 for PATIENT COUNSELING
INFORMATION
------DOSAGE FORMS AND STRENGTHS-------­
ZIRGAN contains 0.15% of gancic10vir in a sterile Revised: September 2009
preserved topical ophthalmic gel. (3)

FULL PRESCRIBING INFORMATION: 8.5 Geriatric Use

CONTENTS* 11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
1 INDICATIONS AND USAGE 12.1 Mechanism of Action
2 DOSAGE AND ADMINISTRATION 12.3 Pharmacokinetics
3 DOSAGE FORMS AND STRENGTHS 13 NONCLINICAL TOXICOLOGY
4 CONTRAINDICATIONS 13.1 Carcinogenesis, Mutagenesis, and Impairment
5 WARNINGS AND PRECAUTIONS of Fertilty
5. i Topical Ophthalmic Use Only 14 CLINICAL STUDIES
5.2 Avoidance of Contact Lenses 16 HOW SUPPLIED/STORAGE AND HANDLING
6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION
8 USE IN SPECIFIC POPULATIONS
8. i Pregnancy *Sections or subsections omitted from the full
8.3 Nursing Mothers prescribing information are not listed.
8.4 Pediatric Use
NDA 22-211
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FULL PRESCRIBING INORMTION administered 60 mg/kg/day and 108

mg/g/day (approximately 10,000x and
1 INDICATIONS AN USAGE 17,000x the human ocular dose of 6.25
ZIRGAN (ganciclovir ophthalmic gel) 0.15% mcg/kg/day), respectively, assuming complete
is indicated for the treatment of acute herpetic absorption. Effects observed in rabbits
keratitis (dendritic ulcers). included: fetal growth retardation,
embryo lethality, teratogenicity, and/or
2 DOSAGE AND ADMIISTRATION maternal toxicity. Teratogenic changes
The recommended dosing regimen for included cleft palate,
ZIRGAN is 1 drop in the affected eye 5 times anophthalmia/microphthalmia, aplastic organs
per day (approximately every 3 hours while (kidney and pancreas), hydrocephaly, and
awake) until the corneal ulcer heals, and then brachygnathia. In mice, effects observed
1 drop 3 times per day for 7 days. were maternal/fetal toxicity and
embryo lethality. Daily intravenous doses of
3 DOSAGE FORMS AND STRENGTHS 90 mg/kg/day (14,000x the human ocular
ZIRGAN contains 0.15% of ganciclovir in a dose) administered to female mice prior to
sterile preserved topical ophthalmic gel. mating, during gestation, and during lactation
caused hypoplasia ofthe testes and seminal
4 CONTRAINDICATIONS vesicles in the month-old male offspring, as
None. well as pathologic changes in the
nonglandular region of the stomach (see
5 WARINGS AN PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment of
5.1 Topical Ophthalmic Use Only Fertilty).
ZIRGAN is indicated for topical ophthalmic
use only. There are no adequate and well-controlled
studies in pregnant women. ZIRGAN should
5.2 Avoidance Of Contact Lenses be used during pregnancy only if the potential
Patients should not wear contact lenses if they benefit justifies the potential risk to the fetus.
have signs or symptoms of herpetic keratitis
or during the course of therapy with 8.3 Nursing Mothers
ZIRGAN. It is not known whether topical ophthalmic
ganciclovir administration could result in
6 ADVERSE REACTIONS sufficient systemic absorption to produce
Most common adverse reactions reported in detectable quantities in breast milk. Caution
patients were blurred vision (60%), eye should be exercised when ZIRGAN is
irritation (20%), punctate keratitis (5%), and administered to nursing mothers.
conjunctival hyperemia (5%).
8.4 Pediatric Use
8 USE IN SPECIFIC POPULATIONS Safety and efficacy in pediatric patients below
8.1 Pregnancy: Teratogenic Effects the age of2 years have not been established.
Pregnancy Category C: Ganciclovir has been
shown to be embryotoxic in rabbits and mice 8.5 Geriatric Use
following intravenous administration and No overall differences in safety or
teratogenic in rabbits. Fetal resorptions were effectiveness have been observed between
present in at least 85% of rabbits and mice elderly and younger patients.
NDA 22-211
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12.3 Pharmacokinetics
11 DESCRIPTION The estimated maximum daily dose of
ZIRGAN (ganciclovir ophthalmic gel) 0.15% ganciclovir administered as 1 drop, 5 times
contains a sterile, topical antiviral for per day is 0.375 mg. Compared to
ophthalmic use. The chemical name is 9-(((2­ maintenance doses of systemically
hydroxy-l-(hydroxymethyl)ethoxy)methyl) administered ganciclovir of 900 mg (oral
guanine (CAS number 82410-32-0). valganciclovir) and 5 mglkg (IV gancic1ovir),
Ganciclovir is represented by the following the ophthalmically administered daily dose is
structural formula: approximately 0.04% and 0.1 % ofthe oral
dose and IV doses, respectively, thus minimal
o systemic exposure is expected.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and

~J:Jo OH
N lo~OH Impairment of Fertilty
Ganciclovir was carcinogenic in the mouse at
oral doses of20 and 1,000 mg/kg/day
(approximately 3,000x and 160,000x the
humàn ocular dose of 6.25 mcg/g/day,
assuming complete absorption). At the dose
Gancic10vir has a molecular weight of255.23, of 1,000 mg/g/day there was a significant
and the empirical formula is C9H13Nsû4. increase in the incidence of tumors of the
Each gram of gel contains: preputial gland in males, forestomach
ACTIVE: ganciclovir 1.5 mg (0.15%). (nonglandular mucosa) in males and females,
INACTIVES: carbopol, water for injection, and reproductive tissues (ovaries, uterus,
sodium hydroxide (to adjust the pH to 7.4), mammary gland, clitoral gland, and vagina)
mannitoL. PRESERVATIVE: benzalkonium and liver in females. At the dose of20
chloride 0.075 mg. mg/kg/day, a slightly increased incidence of
tumors was noted in the preputial and
12 CLINCAL PHAMACOLOGY harderian glands in males, forestomach in
12.1 Mechanism of Action males and females, and liver in females. No
ZIRGAN (ganciclovir ophthalmic gel) 0.15% carcinogenic effect was observed in mice
contains the active ingredient, ganciclovir, administered gancic10vir at 1 mg/g/day
which is a guanosine derivative that, upon (l60x the human ocular dose). Except for
phosphorylation, inhibits DNA replication by histocytic sarcoma of the liver, ganciclovir­
herpes simplex viruses (HSV). Ganciclovir is induced tumors were generally of epithelial or
transformed by viral and cellular thymidine vascular origin. Although the preputial and
kinases (TK) to ganciclovir triphosphate, clitoral glands, forestomach and harderian
which works as an antiviral agent by glands of mice do not have human
inhibiting the synthesis of viral DNA in 2 counterparts, ganciclovir should be
ways: competitive inhibition of viral DNA- considered a potential carcinogen in humans.
polymerase and direct incorporation into viral Gancic10vir increased mutations in mouse
primer strand DNA, resulting in DNA chain lymphoma cells and DNA damage in human
termination and prevention of replication. lymphocytes in vitro at concentrations
between 50 to 500 and 250 to 2,000 mcg/mL,
respectively. In thè mouse micronucleus
NDA 22-21 I
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assay, ganciclovir was clastogenic at doses of 16 HOW SUPPLIED/STORAGE AND

150 and 500 mg/kg (IV) (24,000x to 80,000x HANDLING
human ocular dose) but not 50 mg/kg (8,000x ZIRGAN is supplied as 5 grams of a sterile,
human ocular dose). Ganciclovir was not preserved, clear, colorless, topical ophthalmic
mutagenic in the Ames Salmonella assay at gel containing O. i 5% of ganciclovir in a
concentrations of 500 to 5,000 mcg/mL. polycoated aluminum tube with a white
Gancic10vir caused decreased mating polyethylene tip and cap and protective band
behavior, decreased fertility, and an increased (NDC 42826-605-50).
incidence of embryolethality in female mice
following intravenous doses of 90 mg/kg/day Storage
(approximately 14,000x the human ocular Store at L5°C-25°C (59°F-7JOF). Do not
dose of 6.25 mcg/kg/day). Ganciclovir caused freeze.
decreased fertilty in male mice and
hypospermatogenesis in mice and dogs 17 PATIENT COUNSELING
following daily oral or intravenous INFORMATION
administration of doses ranging from 0.2 to This product is sterile when packaged.
10 mg/kg (30x to 1 ,600x the human ocular Patients should be advised not to allow the
dose). dropper tip to touch any surface, as this may
contaminate the gel. If pain develops, or if
14 CLINICAL STUDIES redness, itching, or inflammation becomes
In one open-label, randomized, controlled, aggravated, the patient should be advi~ed to
multicenter clinical trial which enrolled 164 consult a physician. Patients should be
patients with herpetic keratitis, ZIRGAN was advised not to wear contact lenses when using
non-inferior to acyclovir ophthalmic ZIRGAN.
ointment, 3% in patients with dendritic ulcers.
Clinical resolution (healed ulcers) at Day 7 Revised: September 2009
was achieved in 77% (55/71) for ZIRGAN
versus 72% (48/67) for acyclovir 3% SIRiON-, ")
(difference 5.8%, 95% CI -9.6%-18.3%). Therapeutics

In three randomized, single-masked, Manufactured for: Sirion Therapeutics, Inc.,

controlled, multicenter clinical trials which Tampa, FL 33619
enrolled 213 total patients, ZIRGAN was
non-inferior to acyclovir ophthalmic ointment By: Alliance Medical Products, Inc., Irvine,
3% in patients with dendritic ulcers. Clinical CA 92688
resolution at Day 7 was achieved in 72%
(41/57) for ZIRGAN versus 69% (34/49) for Zirgan™ is the trademark of Laboratoires
acyclovir (difference 2.5%, Thea S.A., and is distributed under license
95% CI -15.6%-20.9%). agreement by Sirion Therapeutics, Inc.

(Ç 2009, Sirion Therapeutics, Inc. All Rights

Reserved. PI605