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 reported in patients 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 1-800-321-4576 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. Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1,000 mg/kg/day (approximately 3,000x and 160,000x 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 (160x 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. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at 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) (24,000x to 80,000x human ocular dose) but not 50 mg/kg (8,000x human ocular dose). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5,000 mcg/mL. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 14,000x 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 (30x to 1,600x the human ocular dose).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. ZIRGAN contains the active ingredient, ganciclovir, which is 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.. 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.

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 noninferior 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%).

DESCRIPTION SECTION.

11 DESCRIPTION. ZIRGAN (ganciclovir ophthalmic gel) 0.15% contains sterile, topical antiviral for 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 C9H13N5O4. 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%).. Ganciclovir (structural formula).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosing regimen for ZIRGAN 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. The recommended dosing regimen for ZIRGAN 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. (2).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ZIRGAN 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 15 to 25C (59 to 77F). Do not freeze.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. This product is sterile when packaged. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the gel. If pain develops, or if redness, itching, or inflammation becomes aggravated, the patient should be advised to consult physician. Patients should be advised not to wear contact lenses when using ZIRGAN.Zirgan is trademark of Laboratoires Thea Corporation used under license.Distributed by: Bausch Lomb, division of Bausch Health US, LLC Bridgewater, NJ 08807 USA(C) 2019 Bausch Lomb Incorporated or its affiliates9224704 (flat)9224804 (folded).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. ZIRGAN contains the active ingredient, ganciclovir, which is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1,000 mg/kg/day (approximately 3,000x and 160,000x 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 (160x 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. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at 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) (24,000x to 80,000x human ocular dose) but not 50 mg/kg (8,000x human ocular dose). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5,000 mcg/mL. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 14,000x 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 (30x to 1,600x the human ocular dose).

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. Teratogenic EffectsGanciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (approximately 10,000x and 17,000x the human ocular dose of 6.25 mcg/kg/day), respectively, assuming complete absorption. 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. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses of 90 mg/kg/day (14,000x the human ocular dose) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)]. There are no adequate and well-controlled studies in pregnant women. ZIRGAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Teratogenic EffectsGanciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (approximately 10,000x and 17,000x the human ocular dose of 6.25 mcg/kg/day), respectively, assuming complete absorption. 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. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses of 90 mg/kg/day (14,000x the human ocular dose) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)]. There are no adequate and well-controlled studies in pregnant women. ZIRGAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. 8.3 Nursing Mothers. It is not known whether topical ophthalmic ganciclovir administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Caution should be exercised when ZIRGAN is administered to nursing mothers.. 8.4 Pediatric Use. Safety and efficacy in pediatric patients below the age of years have not been established.. 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. oZIRGAN is indicated for topical ophthalmic use only. (5.1) oPatients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN. (5.2). oZIRGAN is indicated for topical ophthalmic use only. (5.1) oPatients 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.