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TEXT SIZE IS 6 POINT. N O H 2 N HN OH O OH N N 8/ 10.1 PROOF D BAUSCH & LOMB, 8500 HIDDEN RIVER P SPECIAL INSTRUCTIONS: DIELINE DOES NO Page Size: 8.25" x 11" Page Size, Non-Abbreviated Zirgan DESCRIPTION: COLORS: Black 9189101 AW #: FL 33637 - 813-866-2485 • F UCTIONS: DIELINE DOES NOT PRINT ge Size, 7" X 10" Image Size Brief Summary Non-Abbreviated COLORS: Black TEX 813-866-2525 T SIZE IS 6 POINT. INDICATIONS AND US ATIONS AND USAGE 1 FULL PRESCRIBING INFORMATION: C ORMATION: C ZIRGAN contains 0.15% of ganciclovir in a sterile pr --------------------------------------DOSAGE F every 3 hours while awake) until the corneal ulcer heals, and then 1 dr The recommended dosing regimen for ZIRGAN is 1 dr ---------------------------------------DOSAGE ulcers). (1) ZIRGAN is a topical ophthalmic antiviral that is indicated for the tr --------------------------------------------INDIC Initial U.S. approval: 1989 ZIRGAN (ganciclovir ophthalmic gel) 0.15% See full prescribing information for ZIRGAN. These highlights do not include all of the information needed t HIGHLIGHTS OF PRESCRIBING INFORMA ONTENTS* vir in a sterile preserved topical ophthalmic gel. (3) GE FORMS AND STRENGTHS-------------------------------------- e) until the corneal ulcer heals, and then 1 drop 3 times per day for 7 days. (2) AN is 1 drop in the a!ected eye 5 times per day (approximately GE AND ADMINISTRATION ATION --------------------------------------- al that is indicated for the treatment of acute herpetic keratitis (dendritic --------------------------------------------INDICATIONS ATIONS AND USAGE------------------------------------------- AN. safely and e!ec ® hese highlights do not include all of the information needed to use ZIRGAN ORMATION ORMATION DESCRIPTION 11 Geriatric Use 8.5 See 17 for PA See 17 for PATIENT C ATIENT COUNSELING INF at 1-800-FDA-1088 or www.fda.gov/ v/medw /medw To report SUSPECTED ADVERSE REA keratitis (5%), and conjunctival hyperemia (5 Most common adverse reactions reported in patients w ---------------------------------------------- AD course of therapy with ZIRGAN. (5.2) Patients should not wear contact lenses if they ha • ZIRGAN is indicated for topical ophthalmic use only • ---------------------------------------WARNING None. ---------------------------------------------C THS-------------------------------------- ximately --------------------------------------- atitis (dendritic GE------------------------------------------- ectively. Revised: June 20 OUNSELING INFORMATION. ORMATION. medwatch. ACTIONS, contact Bausch & Lomb at 1-800-323-0000 or FD emia (5%). (6) ted in patients were blurred vision (60%), eye irritation (20%), punct ---------------------------------------------- ADVERSE REACTIONS --------------------------------------------- .2) act lenses if they have signs or symptoms of herpetic keratitis or during the AN is indicated for topical ophthalmic use only. (5 AN is indicated for topical ophthalmic use only. (5.1) ARNINGS AND PRECAUTIONS---------------------------------------- ---------------------------------------------CONTRAINDICATIONS---------------------------------------------- ATIONS---------------------------------------------- vised: June 2010 -0000 or FDA ation (20%), punctate TIONS --------------------------------------------- atitis or during the UTIONS---------------------------------------- TIONS---------------------------------------------- ulcers). ZIRGAN (ganciclovir ophthalmic gel) 0.15% is indicated for the tr INDICATIONS AND US ATIONS AND USAGE 1 FULL PRESCRIBING INFORMATION ORMATION Pediatric Use 8.4 Nursing Mothers 8.3 Pregnancy 8.1 USE IN SPECIFIC POPULATIONS ATIONS 8 ADVERSE REACTIONS 6 Av Avoidance of Contact Lenses 5.2 Topical Ophthalmic Use Only Topical Ophthalmic Use Only 5.1 WARNINGS AND PRECAUTIONS 5 CONTRAINDICATIONS ATIONS 4 DOSAGE FORMS AND STRENGTHS 3 DOSAGE AND ADMINISTRATION ATION 2 INDICATIONS AND US ATIONS AND USAGE 1 % is indicated for the treatment of acute herpetic keratitis (dendritic THS TION derivative that, upon phosphorylation, inhibits DNA r ZIRGAN (ganciclovir ophthalmic gel) 0.15 Mechanism of Action 12.1 CLINICAL PHARMACOLOG 12 atitis (dendritic *Sections or subsections omitted from the full pr PA PATIENT C ATIENT COUNSELING INFORMA 17 HOW SUPPLIED/STORAGE AND HANDLING 16 CLINICAL STUDIES 14 Carcinogenesis, Mutagenesis, and Impairment of F 13.1 NONCLINICAL TOXICOLOGY 13 Pharmacokinetics 12.3 Mechanism of Action 12.1 CLINICAL PHARMACOLOG OLOGY 12 DESCRIPTION 11 ylation, inhibits DNA replication by herpes simplex viruses (HSV). Ganciclo 15% contains the active ingredient, ganciclovir, which is a guanosine vir, which is a guanosine OGY OGY om the full prescribing information are not listed. ORMATION ORMATION GE AND HANDLING agenesis, and Impairment of Fertility ). Ganciclovir , which is a guanosine of therapy with ZIRGAN. Patients should not wear contact lenses if they ha Av Avoidance of Contact Lenses 5.2 ZIRGAN is indicated for topical ophthalmic use only Topical Ophthalmic Use Only Topical Ophthalmic Use Only 5.1 WARNINGS AND PRECAUTIONS 5 None. CONTRAINDICATIONS ATIONS 4 ZIRGAN contains 0.15% of ganciclovir in a sterile pr DOSAGE FORMS AND STRENG 3 every 3 hours while awake) until the corneal ulcer heals, and then 1 dr The recommended dosing regimen for ZIRGAN is 1 dr DOSAGE AND ADMINISTRATION ATION 2 ulcers). act lenses if they have signs or symptoms of herpetic keratitis or during the cour AN is indicated for topical ophthalmic use only. UTIONS vir in a sterile preserved topical ophthalmic gel. TRENGTHS e) until the corneal ulcer heals, and then 1 drop 3 times per day for 7 days. AN is 1 drop in the a!ected eye 5 times per day (approximately TION gland, and vagina) and liver in females. At the dose of (nonglandular mucosa) in males and females, and r mg/kg/day ther g/day there was a significant increase in the incidence of t 160,000x the human ocular dose of 6.25 mcg/k and Ganciclovir was carcinogenic in the mouse at or Carcinogenesis, Mutagenesis, a 13.1 13.1 NONCLINICAL TOXICOLOG 13 dose and IV doses, respectively, thus minimal s ely, thus minimal s mg/kg (IV ganciclovir), the ophthalmically administer Compared to maintenance doses of systemically administer The estimated maximum daily dose of ganciclo Pharmacokinetics 12.3 replication. and direct incorporation into viral primer str antiviral agent by inhibiting the synthesis of vir is transformed by viral and cellular thymidine kinases (TK) to ganciclo derivative that, upon phosphorylation, inhibits DNA r atitis or during the course ximately 20 mg/kg/day g/day day, a slightly increased incidence of t t the dose of (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitor ease in the incidence of tumors of the preputial gland in males, for 000x the human ocular dose of 6.25 mcg/kg/day g/day, as day, assuming complete absorption). At the dose of cinogenic in the mouse at oral doses of 20 and 1,000 mg/kg/day (appr g/day (approximately 3, agenesis, and Impairment of Fertilty OGY , thus minimal systemic exposure is expected. vir), the ophthalmically administered daily dose is approximately 0.04% and 0.1% of the or stemically administered ganciclovir of 900 mg (oral valganciclo The estimated maximum daily dose of ganciclovir administered as 1 drop, 5 times per day is 0.375 mg. al primer strand DNA, resulting in DNA chain termination and prev ynthesis of viral DNA in 2 ways: competitive inhibition of viral DNA-polymer al and cellular thymidine kinases (TK) to ganciclovir triphosphate, which works as an ylation, inhibits DNA replication by herpes simplex viruses (HSV). Ganciclo eased incidence of tumors y gland, clitoral tial gland in males, forestomach 1,000 t the dose of ximately 3,000x 1% of the oral alganciclovir) and 5 5 mg. vention of al DNA-polymerase orks as an ). Ganciclovir Impairment of Fertility). as pathologic changes in the nonglandular region of the stomach (see Car during lactation caused hypoplasia of the testes and seminal v kg/day (14, g/day (14,000x the human ocular dose) administer In mice, e!ects observed were maternal/fet e maternal/fetal to palate, anophthalmia/micr palate, anophthalmia/microphthalmia, aplastic or growth retardation, embryolethality, ter y, teratogenicit of 6.25 mcg/kg/day), r g/day), respectively, as ely, assuming complete absorption. E administered 60 mg/kg/day and 1 g/day and 108 mg/kg/day (appr g/day (appr administration and teratogenic in rabbits. Fetal r Pregnancy Category C: Ganciclovir has been sho Pregnancy: Ter ncy: Teratogenic E!ects 8.1 8.1 USE IN SPECIFIC POPULATIONS ATIONS 8 keratitis (5%), and conjunctival hyperemia (5%). Most common adverse reactions reported in patients w ADVERSE REACTIONS 6 of therapy with ZIRGAN. egion of the stomach (see Carcinogenesis, Mutagenesis, and ation caused hypoplasia of the testes and seminal vesicles in the month-old male o!spring, as w 000x the human ocular dose) administered to female mice prior to mating, during gestation, and al toxicity and embryolethality. Daily intravenous doses of 90 mg/ ophthalmia, aplastic organs (kidney and pancreas), hydrocephaly, and br ocephaly, and brachy atogenicity, and/ y, and/or maternal to , and/or maternal toxicity. T y. Ter . Teratogenic changes included clef suming complete absorption. E!ects observed in rabbits included: fet day (approximately 10,000x and 17, 000x and 17,000x the human ocular dose al resorptions were present in at least 85% of rabbits and mice vir has been shown to be embryotoxic in rabbits and mice following intr TIONS %). ted in patients were blurred vision (60%), eye irritation (20%), punct keratitis, ZIRGAN was non-inferior to acyclo In one open-label, randomized, controlled, multicenter clinical trial which enr CLINICAL STUDIES 14 human ocular dose). dogs following daily oral or intravenous administr 6.25 mcg/kg/day). Ganciclo g/day). Ganciclovir caused decr in female mice following intravenous doses of 90 mg/k Ganciclovir caused decreased mating beha the Ames Salmonella assay at concentrations of 500 to 5 80,000x human ocular dose) but not 50 mg/k In the mouse micronucleus assay, ganciclo say, ganciclovir w 50 to 500 and 250 to 2,000 mcg/mL, r 000 mcg/mL, respectiv mut human counterparts, ganciclovir should be consider vascular origin. Although the preputial and clitor dose). Except for histocytic sarcoma of the liv No carcinogenic e!ect was observed in mice administer was noted in the preputial and harderian glands in males, for gland, and vagina) and liver in females. At the dose of agenesis, and spring, as well ation, and enous doses of 90 mg/ achygnathia. atogenic changes included cleft abbits included: fetal 000x the human ocular dose abbits and mice wing intravenous ation (20%), punctate clovir ophthalmic ointment, 3% in patients with dendritic olled, multicenter clinical trial which enrolled 164 patients with herpetic enous administration of doses ranging from 0.2 to 10 mg/kg (30x to 1, vir caused decreased fertility in male mice and hypospermatogenesis in mice and enous doses of 90 mg/kg/day (appr g/day (approximately 14,000x the human ocular dose of eased mating behavior, decr vior, decreased fertility, and an incr y, and an increased incidence of embr ations of 500 to 5,000 mcg/mL. 000 mcg/mL. t not 50 mg/kg (8,000x human ocular dose). Ganciclovir was not mu vir was clastogenic at doses of 150 and 500 mg/kg (IV) (2 espectively. ely. tes in vitro at concentrations betw vir should be considered a potential carcinogen in humans. Ganciclo tial and clitoral glands, forestomach and harderian glands of mice do not ha coma of the liver, ganciclo er, ganciclovir-induced tumors were generally of epithelial or ed in mice administered ganciclovir at 1 mg/kg/day (160x the human ocular g/day (160x the human ocular derian glands in males, forestomach in males and females, and liv 20 mg/kg/day g/day, a slightly incr day, a slightly increased incidence of t t the dose of ulcers. Clinical olled 164 patients with herpetic g (30x to 1,600x the y in male mice and hypospermatogenesis in mice and 000x the human ocular dose of eased incidence of embryolethality as not mutagenic in ) (24,000x to ations between cinogen in humans. Ganciclovir increased derian glands of mice do not have ally of epithelial or day (160x the human ocular estomach in males and females, and liver in females. eased incidence of tumors represented by the following structural formula: 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine name is ZIRGAN (ganciclovir ophthalmic gel) 0.15% cont DESCRIPTION 11 No overall di!erences in safety or e!ectivenes Geriatric Use 8.5 Safety and efficacy in pediatric patients below the age of 2 y Pediatric Use 8.4 nursing mothers. to produce detectable quantities in breast milk. Cau It is not known whether topical ophthalmic ganciclo Nursing Mothers 8.3 pregnancy only if the potential benefit justifies the potential risk to the fet There are no adequate and well-controlled studies in pr Impairment of Fertility). O al formula: (CAS number 82410-32-0). Ganciclo xy]methyl]guanine % contains a sterile, topical antiviral for ophthalmic use. The chemical s have been observed between elderly and younger patients. w the age of 2 years have not been established. east milk. Caution should be exercised when ZIRGAN is administer wn whether topical ophthalmic ganciclovir administration could result in sufficient systemic absorption egnancy only if the potential benefit justifies the potential risk to the fetus. udies in pregnant women. ZIRGAN should be used during lenses when using ZIRGAN. aggravated, the patient should be advised to consult a phy surface, as this may contaminate the gel. If pain de This product is sterile when packaged. Patients should be advised not to allo PA PATIENT C ATIENT COUNSELING INF 17 Store at 15°C-25°C (59°F-77°F). Do not fr Storage 24208-535-35). of ganciclovir in a polycoated aluminum tube with a white poly ZIRGAN is supplied as 5 grams of a sterile, pr HOW SUPPLIED/S W SUPPLIED/STORAGE AND HANDLING 16 for acyclovir (di!erence 2.5%, 95% CI - 15 with dendritic ulcers. Clinical resolution at D trials which enrolled 213 total patients, ZIR 3% (di!erence 5.8%, 95% CI - 9.6%-18.3%). resolution (healed ulcers) at Day 7 was achie keratitis, ZIRGAN was non-inferior to acyclo 32-0). Ganciclovir is al for ophthalmic use. The chemical ounger patients. AN is administered to stemic absorption AN should be used during ated, the patient should be advised to consult a physician. Patients should be advised not to w aminate the gel. If pain develops, or if redness, itching, or inflammation becomes atients should be advised not to allow the dropper tip to touch any OUNSELING INFORMATION ORMATION o not freeze. ube with a white polyethylene tip and cap and protective band (NDC ams of a sterile, preserved, clear, colorles ed, clear, colorless, topical ophthalmic gel cont GE AND HANDLING % CI - 15.6%-20.9%). tion at Day 7 was achieved in 72% (41/57) for ZIRGAN versus 6 al patients, ZIRGAN was non-inferior to acyclovir ophthalmic ointment 3% in patients 18.3%). In three randomized, single-masked, controlled, multicenter as achieved in 77% (55/71) for ZIRGAN versus 72% (48/67 clovir ophthalmic ointment, 3% in patients with dendritic atients should be advised not to wear contact s, itching, or inflammation becomes opper tip to touch any e band (NDC s, topical ophthalmic gel containing O.15% sus 69% (34/4 4/49) vir ophthalmic ointment 3% in patients multicenter clinical ) for acyclovir ulcers. Clinical PRESERVATIVE: benzalk ATIVE: benzalkonium chloride 0.07 carbopol, water for injection, sodium hydroxide (to adjust the pH to 7 Each gram of gel contains: ACTIVE: ganciclovir 1.5 mg (0 . 4 O 5 N 13 H 9 C Ganciclovir has a molecular weight of 255.23, and the empirical formula is N N O HN N 2 H N 5 mg. xide (to adjust the pH to 7. xide (to adjust the pH to 7.4), mannitol. vir 1.5 mg (0.15%). INACTIVES: .23, and the empirical formula is OH OH © Bausch & Lomb Incorporated Bausch & Lomb Incorporated, Tampa, FL 3 ated, Tampa, FL 3 ZIRGAN is a trademark of Laboratoires Théa C Revised: June 2010 lenses when using ZIRGAN. ampa, FL 33637 es Théa Corporation licensed by Bausch & Lomb Incorporated. 9189101 ated.

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