LACTATION SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical ophthalmic ganciclovir administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Animal data indicate that ganciclovir is excreted in the milk of lactating rats. Caution should be exercised when ZIRGAN is administered to nursing mothers.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. ZIRGAN is an antiviral drug see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionZIRGAN contains ganciclovir, guanosine derivative that upon phosphorylation inhibits DNA replication by herpes simplex viruses (HSV). Ganciclovir is transformed by viral and cellular thymidine kinases (TK) to ganciclovir triphosphate, which works as an antiviral agent by inhibiting the synthesis of viral DNA in ways: competitive inhibition of viral DNA-polymerase and direct incorporation into viral primer strand DNA, resulting in DNA chain termination and prevention of replication.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions reported in patients were blurred vision (60%), eye irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).. Most common adverse reactions were blurred vision (60%), eye irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%). 6) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Lomb Incorporated, at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisGanciclovir was carcinogenic in the mouse at oral doses of 20 and 1,000 mg/kg/day (approximately 3,000 and 160,000 times the human ocular dose of 6.25 mcg/kg/day, assuming complete absorption). At the dose of 1,000 mg/kg/day there was significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland, and vagina) and liver in females. At the dose of 20 mg/kg/day, slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at mg/kg/day (160 times the human ocular dose). Except for histocytic sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered potential carcinogen in humans.MutagenesisGanciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitroat concentrations between 50 to 500 and 250 to 2,000 mcg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (IV) (24,000 to 80,000 times the human ocular dose) but not 50 mg/kg (8,000 times the human ocular dose). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5,000 mcg/mL.Impairment of FertilityGanciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 14,000 times the human ocular dose of 6.25 mcg/kg/day). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg (30 to 1,600 times the human ocular dose).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. ZIRGAN is an antiviral drug see Microbiology (12.4)] . 12.3 Pharmacokinetics. The estimated maximum daily dose of ganciclovir administered as drop, times per day is 0.375 mg. Compared to maintenance doses of systemically administered ganciclovir of 900 mg (oral valganciclovir) and mg/kg (IV ganciclovir), the ophthalmically administered daily dose is approximately 0.04% and 0.1% of the oral dose and IV doses, respectively, thus minimal systemic exposure is expected.. 12.4 Microbiology. Mechanism of ActionZIRGAN contains ganciclovir, guanosine derivative that upon phosphorylation inhibits DNA replication by herpes simplex viruses (HSV). Ganciclovir is transformed by viral and cellular thymidine kinases (TK) to ganciclovir triphosphate, which works as an antiviral agent by inhibiting the synthesis of viral DNA in ways: competitive inhibition of viral DNA-polymerase and direct incorporation into viral primer strand DNA, resulting in DNA chain termination and prevention of replication.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In one open-label, randomized, controlled, multicenter clinical trial which enrolled 164 patients with herpetic keratitis, ZIRGAN was non-inferior to acyclovir ophthalmic ointment, 3% in patients with dendritic ulcers. Clinical resolution (healed ulcers) at Day was achieved in 77% (55/71) for ZIRGAN versus 72% (48/67) for acyclovir, 3% (difference 5.8%, 95% CI 9.6%-18.3%). In three randomized, single-masked, controlled, multicenter clinical trials which enrolled 213 total patients, ZIRGAN was non-inferior to acyclovir ophthalmic ointment, 3% in patients with dendritic ulcers. Clinical resolution at Day was achieved in 72% (41/57) for ZIRGAN versus 69% (34/49) for acyclovir (difference 2.5%, 95% CI 15.6%-20.9%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. ZIRGAN (ganciclovir ophthalmic gel) 0.15% contains ganciclovir, nucleoside analog antiviral. ZIRGAN is sterile, preserved, clear, colorless, ophthalmic gel for topical ophthalmic use.The chemical name is 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (CAS number 82410-32-0). Ganciclovir is represented by the following structural formula:Ganciclovir has molecular weight of 255.23, and the empirical formula is 9H 13N 5O 4. Each gram of gel contains: ACTIVE: ganciclovir 1.5 mg (0.15%). INACTIVES: carbomer homopolymer, water for injection, sodium hydroxide (to adjust the pH to 7.2-7.6), mannitol. PRESERVATIVE: benzalkonium chloride 0.075 mg (0.0075%).. ChemStructure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage is drop in the affected eye times per day (approximately every hours while awake) until the corneal ulcer heals, and then drop times per day for days.. Apply drop in the affected eye times per day (approximately every hours while awake) until the corneal ulcer heals, and then drop times per day for days. 2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Ophthalmic gel: 0.15% ganciclovir.. Ophthalmic gel: 0.15% ganciclovir. 3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. InfertilityIt is not known whether topical ophthalmic ganciclovir administration could result in sufficient absorption to impair fertility in humans. Animal data indicate decreased fertility in female mice following intravenous doses at 90 mg/kg/day, approximately 1174 times the maximum RHOD (based on body surface area), and decreased fertility and hypospermatogenesis in male mice and dogs following intravenous doses at 10 mg/kg/day for mice, approximately 130 times the maximum RHOD (based on body surface area), and 3.6 mg/kg/day for dogs, approximately 240 times the maximum RHOD (based on body surface area).

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ZIRGAN (ganciclovir ophthalmic gel) 0.15% is supplied as grams of sterile, preserved, clear, colorless, topical ophthalmic gel containing 0.15% of ganciclovir in polycoated aluminum tube with white polyethylene tip and cap and protective band (NDC 24208-535-35).StorageStore at 15C to 25C (59F to 77F). Do not freeze.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ZIRGAN is indicated for the treatment of acute herpetic keratitis (dendritic ulcers) in adults and pediatric patients aged years and older.. ZIRGAN is nucleoside analog antiviral indicated for the treatment of acute herpetic keratitis (dendritic ulcers) in adults and pediatric patients aged years and older. 1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. When to Consult PhysicianAdvise patients to consult physician if pain develops, or if redness, itching, or inflammation becomes aggravated.Risk of ContaminationZIRGAN is sterile when packaged. Advise patients to not allow the dropper tip to touch any surface, as this may contaminate the gel.Avoidance of Contact LensesAdvise patients to not wear contact lenses when using ZIRGAN.Distributed by:Bausch Lomb Americas Inc.Bridgewater, NJ 08807 USAManufactured by: Bausch Lomb IncorporatedTampa, FL 33637 USAZirgan is trademark of Laboratoires Thea Corporation used under license.(C) 2026 Bausch Lomb Incorporated or its affiliates9224806 (Folded)9224706 (Flat).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisGanciclovir was carcinogenic in the mouse at oral doses of 20 and 1,000 mg/kg/day (approximately 3,000 and 160,000 times the human ocular dose of 6.25 mcg/kg/day, assuming complete absorption). At the dose of 1,000 mg/kg/day there was significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland, and vagina) and liver in females. At the dose of 20 mg/kg/day, slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at mg/kg/day (160 times the human ocular dose). Except for histocytic sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered potential carcinogen in humans.MutagenesisGanciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitroat concentrations between 50 to 500 and 250 to 2,000 mcg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (IV) (24,000 to 80,000 times the human ocular dose) but not 50 mg/kg (8,000 times the human ocular dose). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5,000 mcg/mL.Impairment of FertilityGanciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 14,000 times the human ocular dose of 6.25 mcg/kg/day). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg (30 to 1,600 times the human ocular dose).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL. NDC24208-535-35 BAUSCH LOMBZirgan(ganciclovirophthalmic gel)0.15%SterileFOR TOPICALOPHTHALMICUSE ONLYRx only5 gAB488359691901. Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ZIRGAN for the treatment of acute herpetic keratitis (dendritic ulcers) have been established in pediatric patients aged years and older. Use of ZIRGAN for this indication is supported by evidence from adequate and well-controlled studies.The safety and effectiveness of ZIRGAN have not been established in pediatric patients below the age of years.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The estimated maximum daily dose of ganciclovir administered as drop, times per day is 0.375 mg. Compared to maintenance doses of systemically administered ganciclovir of 900 mg (oral valganciclovir) and mg/kg (IV ganciclovir), the ophthalmically administered daily dose is approximately 0.04% and 0.1% of the oral dose and IV doses, respectively, thus minimal systemic exposure is expected.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available human data on use of ZIRGAN or ganciclovir during pregnancy to inform any drug-associated risk. Intravenous administration of ganciclovir to pregnant mice or rabbits during organogenesis or during the pre/postnatal period did not produce adverse embryofetal or offspring effects at clinically relevant doses see Data). The background risk in the U.S. general population of major birth defects is to 4% and the risk of miscarriage is 15 to 20% of clinically recognized pregnancies.DataAnimal DataDaily intravenous doses of ganciclovir were administered to pregnant mice [up to 108 mg/kg/day, approximately 1400 times the maximum recommended human ocular dose (RHOD) of 0.375 mg] and rabbits [up to 60 mg/kg/day, approximately 2400 times the maximum RHOD], and also to female mice [up to 90 mg/kg, approximately 1174 times the maximum RHOD] prior to mating, during gestation, and during lactation. Fetal resorptions were present in at least 85% of rabbits and mice. Additional effects observed in rabbits included fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. maternal no observed adverse effect level (NOAEL) was observed at 36 mg/kg/day (approximately 470 times higher than the maximum RHOD, based on body surface area) in mice and at mg/kg/day (approximately 240 times higher than the maximum RHOD, based on body surface area) in rabbits.In pre/postnatal development studies in mice, there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. maternal no observed adverse effect level (NOAEL) was observed at 20 mg/kg/day (approximately 261 times higher than the maximum RHOD, based on body surface area).

RISKS.

5.3 Risk of Contamination. Do not allow the tip of the container to touch any surface, as this may contaminate the ointment. If pain develops, or if redness, itching, or inflammation becomes aggravated, the patient should be advised to consult physician.

SPL UNCLASSIFIED SECTION.

5.1 Topical Ophthalmic Use Only. ZIRGAN is indicated for topical ophthalmic use only.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available human data on use of ZIRGAN or ganciclovir during pregnancy to inform any drug-associated risk. Intravenous administration of ganciclovir to pregnant mice or rabbits during organogenesis or during the pre/postnatal period did not produce adverse embryofetal or offspring effects at clinically relevant doses see Data). The background risk in the U.S. general population of major birth defects is to 4% and the risk of miscarriage is 15 to 20% of clinically recognized pregnancies.DataAnimal DataDaily intravenous doses of ganciclovir were administered to pregnant mice [up to 108 mg/kg/day, approximately 1400 times the maximum recommended human ocular dose (RHOD) of 0.375 mg] and rabbits [up to 60 mg/kg/day, approximately 2400 times the maximum RHOD], and also to female mice [up to 90 mg/kg, approximately 1174 times the maximum RHOD] prior to mating, during gestation, and during lactation. Fetal resorptions were present in at least 85% of rabbits and mice. Additional effects observed in rabbits included fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. maternal no observed adverse effect level (NOAEL) was observed at 36 mg/kg/day (approximately 470 times higher than the maximum RHOD, based on body surface area) in mice and at mg/kg/day (approximately 240 times higher than the maximum RHOD, based on body surface area) in rabbits.In pre/postnatal development studies in mice, there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. maternal no observed adverse effect level (NOAEL) was observed at 20 mg/kg/day (approximately 261 times higher than the maximum RHOD, based on body surface area).. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical ophthalmic ganciclovir administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Animal data indicate that ganciclovir is excreted in the milk of lactating rats. Caution should be exercised when ZIRGAN is administered to nursing mothers.. 8.3 Females and Males of Reproductive Potential. InfertilityIt is not known whether topical ophthalmic ganciclovir administration could result in sufficient absorption to impair fertility in humans. Animal data indicate decreased fertility in female mice following intravenous doses at 90 mg/kg/day, approximately 1174 times the maximum RHOD (based on body surface area), and decreased fertility and hypospermatogenesis in male mice and dogs following intravenous doses at 10 mg/kg/day for mice, approximately 130 times the maximum RHOD (based on body surface area), and 3.6 mg/kg/day for dogs, approximately 240 times the maximum RHOD (based on body surface area).. 8.4 Pediatric Use. The safety and effectiveness of ZIRGAN for the treatment of acute herpetic keratitis (dendritic ulcers) have been established in pediatric patients aged years and older. Use of ZIRGAN for this indication is supported by evidence from adequate and well-controlled studies.The safety and effectiveness of ZIRGAN have not been established in pediatric patients below the age of years.. 8.5 Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. ZIRGAN is indicated for topical ophthalmic use only. 5.1) Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN. 5.2) ZIRGAN is indicated for topical ophthalmic use only. 5.1) Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN. 5.2) 5.1 Topical Ophthalmic Use Only. ZIRGAN is indicated for topical ophthalmic use only.. 5.2 Avoidance of Contact Lenses. Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN.. 5.3 Risk of Contamination. Do not allow the tip of the container to touch any surface, as this may contaminate the ointment. If pain develops, or if redness, itching, or inflammation becomes aggravated, the patient should be advised to consult physician.