1、RESTASIS- cyclosporine emulsion Allergan, Inc.-HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use RESTASIS 0.05% safely and effectively.See full prescribing information for RESTASIS .RESTASIS (cyclosporine ophthalmic emulsion) 0.05%Initial U.S. App
2、roval: 1983INDICATIONS AND USAGERESTASIS is a topical immunomodulator indicated to increase tear production in patients whose tear production ispresumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tearproduction was not seen in patients currently
3、 taking topical anti-inflammatory drugs or using punctal plugs. (1)DOSAGE AND ADMINISTRATIONInstill one drop of RESTASIS ophthalmic emulsion twice a day in each eye approximately 12 hours apart. (2)DOSAGE FORMS AND STRENGTHSOphthalmic emulsion containing cyclosporine 0.5 mg/mL (3)CONTRAINDICATIONSHy
4、persensitivity (4)WARNINGS AND PRECAUTIONSTo avoid the potential for eye injury and contamination, be careful not to touch the vial tip to your eye or other surfaces.(5.1)ADVERSE REACTIONSThe most common adverse reaction following the use of RESTASIS was ocular burning (17%). (6.1)To report SUSPECTE
5、D ADVERSE REACTIONS, contact Allergan, Inc. at 1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.See 17 for PATIENT COUNSELING INFORMATION. Revised: 6/2013FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICA
6、TIONS5 WARNINGS AND PRECAUTIONS5.1 Potential for Eye Injury and Contamination5.2 Use with Contact Lenses6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Post-marketing Experience8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use11 DESCRIPTION12 CLINIC
7、AL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Handling the Container17.2 Use with Contact Lenses17.3 Administra
8、tion*FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGERESTASIS ophthalmic emulsion is indicated to increase tear production in patients whose tearproduction is presumed to be suppressed due to ocular inflammation associated withkeratoconjunctivitis sicca. Increased tear production was not seen in
9、patients currently taking topicalanti-inflammatory drugs or using punctal plugs.2 DOSAGE AND ADMINISTRATIONInvert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instill onedrop of RESTASIS ophthalmic emulsion twice a day in each eye approximately 12 hours ap
10、art.RESTASIS can be used concomitantly with artificial tears, allowing a 15 minute interval betweenproducts. Discard vial immediately after use.3 DOSAGE FORMS AND STRENGTHSOphthalmic emulsion containing cyclosporine 0.5 mg/mL4 CONTRAINDICATIONSRESTASIS is contraindicated in patients with known or su
11、spected hypersensitivity to any of theingredients in the formulation.5 WARNINGS AND PRECAUTIONS5.1 Potential for Eye Injury and ContaminationTo avoid the potential for eye injury and contamination, be careful not to touch the vial tip to your eyeor other surfaces.5.2 Use with Contact LensesRESTASIS
12、should not be administered while wearing contact lenses. Patients with decreased tearproduction typically should not wear contact lenses. If contact lenses are worn, they should be removedprior to the administration of the emulsion. Lenses may be reinserted 15 minutes followingadministration of REST
13、ASIS ophthalmic emulsion.Sections or subsections omitted from the full prescribing information are not listed.6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot
14、 be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.In clinical trials, the most common adverse reaction following the use of RESTASIS was ocularburning (17%).Other reactions reported in 1% to 5% of patients included conjunctival hy
15、peremia, discharge, epiphora,eye pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring).6.2 Post-marketing ExperienceThe following adverse reactions have been identified during post approval use of RESTASIS .Because these reactions are reported voluntarily fro
16、m a population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish a causal relationship to drug exposure.Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases ofsevere angioedema, face swelling, tongue swelling, p
17、haryngeal edema, and dyspnea); and superficialinjury of the eye (from the vial tip touching the eye during administration).8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTeratogenic Effects: Pregnancy Category CAdverse effects were seen in reproduction studies in rats and rabbits only at dose levels toxi
18、c to dams.At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), cyclosporine oral solution, USP, wasembryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weighttogether with related skeletal retardations. These doses are 5,000 and 32,000 times g
19、reater (normalizedto body surface area), respectively, than the daily human dose of one drop (approximately 28 mcL) of0.05% RESTASIS twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that theentire dose is absorbed. No evidence of embryofetal toxicity was observed in rats or ra
20、bbits receivingcyclosporine at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively, during organogenesis.These doses in rats and rabbits are approximately 3,000 and 10,000 times greater (normalized to bodysurface area), respectively, than the daily human dose.Offspring of rats receiving a 45
21、 mg/kg/day oral dose of cyclosporine from Day 15 of pregnancy untilDay 21 postpartum, a maternally toxic level, exhibited an increase in postnatal mortality; this dose is7,000 times greater than the daily human topical dose (0.001 mg/kg/day) normalized to body surfacearea assuming that the entire do
22、se is absorbed. No adverse events were observed at oral doses up to 15mg/kg/day (2,000 times greater than the daily human dose).There are no adequate and well-controlled studies of RESTASIS in pregnant women. RESTASISshould be administered to a pregnant woman only if clearly needed.8.3 Nursing Mothe
23、rsCyclosporine is known to be excreted in human milk following systemic administration, but excretion inhuman milk after topical treatment has not been investigated. Although blood concentrations areundetectable after topical administration of RESTASIS ophthalmic emulsion, caution should beexercised
24、 when RESTASIS is administered to a nursing woman.8.4 Pediatric Use The safety and efficacy of RESTASIS ophthalmic emulsion have not been established in pediatricpatients below the age of 16.8.5 Geriatric UseNo overall difference in safety or effectiveness has been observed between elderly and young
25、erpatients.11 DESCRIPTIONRESTASIS (cyclosporine ophthalmic emulsion) 0.05% contains a topical immunomodulator with anti-inflammatory effects. Cyclosporines chemical name is Cyclo(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-m
26、ethyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl and it has thefollowing structure:Structural FormulaFormula: C H N O Mol. Wt.: 1202.6Cyclosporine is a fine white powder. RESTASIS appears as a white opaque to slightly translucenthomogeneous emulsion. It has an os
27、molality of 230 to 320 mOsmol/kg and a pH of 6.5-8.0. Each mL ofRESTASIS ophthalmic emulsion contains: Active: cyclosporine 0.05%. Inactives: glycerin; castoroil; polysorbate 80; carbomer copolymer type A; purified water; and sodium hydroxide to adjust pH.12 CLINICAL PHARMACOLOGY12.1 Mechanism of Ac
28、tionCyclosporine is an immunosuppressive agent when administered systemically.In patients whose tear production is presumed to be suppressed due to ocular inflammation associatedwith keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator.The exact mechanism
29、of action is not known.12.3 PharmacokineticsBlood cyclosporine A concentrations were measured using a specific high pressure liquidchromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the samplescollected, after topical administration of RESTASIS 0.05%, twice daily, i
30、n humans for up to 12months, were below the quantitation limit of 0.1 ng/mL. There was no detectable drug accumulation inblood during 12 months of treatment with RESTASIS ophthalmic emulsion.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: Systemic ca
31、rcinogenicity studies were carried out in male and female mice and rats. In62 111 11 12the 78-week oral (diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statisticallysignificant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellularcarcinomas i
32、n mid-dose males significantly exceeded the control value.In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomassignificantly exceeded the control rate in the low dose level. The hepatocellular carcinomas andpancreatic islet cell adenomas were not
33、 dose related. The low doses in mice and rats are approximately80 times greater (normalized to body surface area) than the daily human dose of one drop(approximately 28 mcL) of 0.05% RESTASIS twice daily into each eye of a 60 kg person (0.001mg/kg/day), assuming that the entire dose is absorbed.Muta
34、genesis: Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests inChinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm fromtreated mi
35、ce. A study analyzing sister chromatid exchange (SCE) induction by cyclosporine using humanlymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE).Impairment of Fertility: No impairment in fertility was demonstrated in studies in male and female ratsreceiving oral doses of
36、 cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human dailydose of 0.001 mg/kg/day normalized to body surface area) for 9 weeks (male) and 2 weeks (female)prior to mating.14 CLINICAL STUDIESFour multicenter, randomized, adequate and well-controlled clinical studies were performed ina
37、pproximately 1,200 patients with moderate to severe keratoconjunctivitis sicca. RESTASISdemonstrated statistically significant increases in Schirmer wetting of 10 mm versus vehicle at sixmonths in patients whose tear production was presumed to be suppressed due to ocular inflammation.This effect was
38、 seen in approximately 15% of RESTASIS ophthalmic emulsion-treated patientsversus approximately 5% of vehicle-treated patients. Increased tear production was not seen in patientscurrently taking topical anti-inflammatory drugs or using punctal plugs.No increase in bacterial or fungal ocular infectio
39、ns was reported following administration ofRESTASIS .16 HOW SUPPLIED/STORAGE AND HANDLINGRESTASIS ophthalmic emulsion is packaged in sterile, preservative-free single-use vials. Each vialcontains 0.4 mL fill in a 0.9 mL LDPE vial; 30 or 60 vials are packaged in a polypropylene tray with analuminum p
40、eelable lid. The entire contents of each tray (30 vials or 60 vials) must be dispensed intact.30 Vials 0.4 mL each - NDC 0023-9163-3060 Vials 0.4 mL each - NDC 0023-9163-60Storage: Store at 15-25C (59-77F).17 PATIENT COUNSELING INFORMATION17.1 Handling the ContainerAdvise patients to not allow the t
41、ip of the vial to touch the eye or any surface, as this may contaminatethe emulsion. To avoid the potential for injury to the eye, advise patients to not touch the vial tip to theireye see Warnings and Precautions (5.1).17.2 Use with Contact LensesRESTASIS should not be administered while wearing co
42、ntact lenses. Patients with decreased tearproduction typically should not wear contact lenses. Advise patients that if contact lenses are worn, theyshould be removed prior to the administration of the emulsion. Lenses may be reinserted 15 minutesfollowing administration of RESTASIS ophthalmic emulsi
43、on see Warnings and Precautions (5.2).17.3 AdministrationAdvise patients that the emulsion from one individual single-use vial is to be used immediately afteropening for administration to one or both eyes, and the remaining contents should be discardedimmediately after administration. 2014 Allergan,
44、 Inc.Irvine, CA 92612, U.S.A. marks owned by Allergan, Inc.Patented. See: in the U.S.A.71876US18NDC 0023-9163-60 No. 94529Restasis (Cyclosporine Ophthalmic Emulsion) 0.05%60 Single-Use Vials (0.4 mL each) One Month Supply Sterile, Preservative-FreeEach mL contains: Active: cyclosporine 0.05% Inacti
45、ves: glycerin; castor oil; polysorbate 80;carbomer copolymer type A; purified water; and sodium hydroxide to adjust pH. Usual Dosage: Twicedaily approximately 12 hours apart. Invert the vial before using. Use immediately after opening and thendiscard. Storage: Store at 15-25C (59-77F). Store vials i
46、n the thermoformed tray until use. Theentire contents of each package (60 vials) must be dispensed intact. 2013 Allergan, Inc.Irvine, CA 92612, U.S.A. marks owned by Allergan, Inc.Patented. See: in the U.S.A.ALLERGANLot:Exp.:Rx only55091US10RESTASIS cyclosporine emulsionProduct InformationProduct T
47、ype HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0023-9163Route of Administration OPHTHALMIC DEA Schedule Active Ingredient/Active MoietyIngredient Name Basis of Strength Strengthcyclosporine (UNII: 83HN0GTJ6D) (cyclosporine - UNII:83HN0GTJ6D) cyclosporine 0.5 mg in 1 mLInactive IngredientsIngredi
48、ent Name Strengthglycerin (UNII: PDC6A3C0OX) castor oil (UNII: D5340Y2I9G) polysorbate 80 (UNII: 6OZP39ZG8H) carbomer copolymer type A (UNII: 71DD5V995L) water (UNII: 059QF0KO0R) sodium hydroxide (UNII: 55X04QC32I) Packaging# Item Code Package Description Marketing StartDate Marketing EndDateAllerga
49、n, Inc.1 NDC:0023-9163-12 5 in 1 CARTON1 0.4 mL in 1 VIAL, SINGLE-USE; Type 0: Not a CombinationProduct2 NDC:0023-9163-30 30 in 1 TRAY2 0.4 mL in 1 VIAL, SINGLE-USE; Type 0: Not a CombinationProduct3 NDC:0023-9163-60 60 in 1 TRAY3 0.4 mL in 1 VIAL, SINGLE-USE; Type 0: Not a CombinationProductMarketing InformationMarketing Category Application Number or Monograph Citation Marketing Start Date Marketing End DateNDA NDA050790 04/01/2003Label
