RESTASIS- cyclosporine emulsion

United States - English - NLM (National Library of Medicine)

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Active ingredient:
CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D)
Available from:
A-S Medication Solutions
Administration route:
OPHTHALMIC
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
RESTASIS ® ophthalmic emulsion is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. RESTASIS ® is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in the formulation. Risk Summary Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following topical ocular administration [see Clinical Pharmacology ( 12.3 ) ], and maternal use is not expected to result in fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see  Data ]. Data Animal Data At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution (USP) was teratogenic as indicated by i
Product summary:
Product: 50090-4476 NDC: 50090-4476-0 .4 mL in a VIAL, SINGLE-USE / 30 in a TRAY
Authorization status:
New Drug Application
Authorization number:
50090-4476-0

RESTASIS- cyclosporine emulsion

A-S Medication Solutions

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These 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%

For topical ophthalmic use

Initial U.S. Approval: 1983

INDICATIONS AND USAGE

RESTASIS

is a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients whose tear

production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased

tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. (1)

DOSAGE AND ADMINISTRATION

Instill one drop of RESTASIS

ophthalmic emulsion twice a day in each eye approximately 12 hours apart. (2)

DOSAGE FORMS AND STRENGTHS

Cyclosporine ophthalmic emulsion 0.5 mg/mL (3)

CONTRAINDICATIONS

Hypersensitivity (4)

WARNINGS AND PRECAUTIONS

To 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 REACTIONS

The most common adverse reaction following the use of RESTASIS

was ocular burning (17%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Potential for Eye Injury and Contamination

5.2 Use with Contact Lenses

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-marketing Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

RESTASIS ophthalmic emulsion is indicated to increase tear production in patients whose tear

production is presumed to be suppressed due to ocular inflammation associated with

keratoconjunctivitis sicca. Increased tear production was not seen in patients currently taking topical

anti-inflammatory drugs or using punctal plugs.

2 DOSAGE AND ADMINISTRATION

Invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instill one

drop of RESTASIS ophthalmic emulsion twice a day in each eye approximately 12 hours apart.

RESTASIS can be used concomitantly with lubricant eye drops, allowing a 15-minute interval

between products. Discard vial immediately after use.

3 DOSAGE FORMS AND STRENGTHS

Ophthalmic emulsion containing cyclosporine 0.5 mg/mL

4 CONTRAINDICATIONS

RESTASIS is contraindicated in patients with known or suspected hypersensitivity to any of the

ingredients in the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 Potential for Eye Injury and Contamination

Be careful not to touch the vial tip to your eye or other surfaces to avoid potential for eye injury and

contamination.

5.2 Use with Contact Lenses

RESTASIS should not be administered while wearing contact lenses. Patients with decreased tear

production typically should not wear contact lenses. If contact lenses are worn, they should be removed

prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following

administration of RESTASIS ophthalmic emulsion.

6 ADVERSE REACTIONS

Sections or subsections omitted from the full prescribing information are not listed.

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The following serious adverse reactions are described elsewhere in the labeling:

Potential for Eye Injury and Contamination [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

In clinical trials, the most common adverse reaction following the use of RESTASIS was ocular

burning (17%).

Other reactions reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora,

eye pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring).

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of RESTASIS .

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of

severe angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial

injury of the eye (from the vial tip touching the eye during administration).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically

following topical ocular administration [see Clinical Pharmacology (12.3)], and maternal use is not

expected to result in fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or

rabbits did not produce teratogenicity at clinically relevant doses [see Data].

Data

Animal Data

At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral

solution (USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal

weight and skeletal retardations. These doses (normalized to body surface area) are 5,000 and 32,000

times greater, respectively, than the daily recommended human dose of one drop (approximately 28

mcL) of cyclosporine ophthalmic emulsion 0.05% twice daily into each eye of a 60 kg person (0.001

mg/kg/day), assuming that the entire dose is absorbed. No evidence of embryofetal toxicity was

observed in rats or rabbits receiving cyclosporine during organogenesis at oral doses up to 17

mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits are approximately 3,000 and

10,000 times greater, respectively, than the daily recommended human dose.

An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21

postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is

7,000 times greater than the daily recommended human dose. No adverse effects in dams or offspring

were observed at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human

dose).

8.2 Lactation

Risk Summary

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Cyclosporine is known to appear in human milk following systemic administration, but its presence in

human milk following topical treatment has not been investigated. Although blood concentrations are

undetectable following topical administration of RESTASIS ophthalmic emulsion [see Clinical

Pharmacology (12.3)], caution should be exercised when RESTASIS is administered to a nursing

woman. The developmental and health benefits of breastfeeding should be considered along with the

mother’s clinical need for RESTASIS and any potential adverse effects on the breast-fed child from

cyclosporine.

8.4 Pediatric Use

Safety and efficacy have not been established in pediatric patients below the age of 16.

8.5 Geriatric Use

No overall difference in safety or effectiveness has been observed between elderly and younger

patients.

11 DESCRIPTION

RESTASIS (cyclosporine ophthalmic emulsion) 0.05% contains a topical calcineurin inhibitor

immunosuppressant with anti-inflammatory effects. Cyclosporine’s 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-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-

leucyl-N-methyl-L-valyl] and it has the following structure:

Structural Formula

Formula: C

Mol. Wt.: 1202.6

Cyclosporine is a fine white powder. RESTASIS appears as a white opaque to slightly translucent

homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a pH of 6.5-8.0. Each mL of

RESTASIS ophthalmic emulsion contains: Active: cyclosporine 0.05%. Inactives: glycerin; castor

oil; polysorbate 80; carbomer copolymer type A; purified water; and sodium hydroxide to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cyclosporine is an immunosuppressive agent when administered systemically.

In patients whose tear production is presumed to be suppressed due to ocular inflammation associated

with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator.

The exact mechanism of action is not known.

12.3 Pharmacokinetics

Blood cyclosporine A concentrations were measured using a specific high pressure

liquid chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the

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liquid chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the

samples collected, after topical administration of RESTASIS 0.05%, twice daily, in humans for up to

12 months, were below the quantitation limit of 0.1 ng/mL. There was no detectable drug accumulation

in blood during 12 months of treatment with RESTASIS ophthalmic emulsion.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Systemic carcinogenicity studies were conducted in male and female mice and rats. In the 78-week oral

(diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was

found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in 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 adenomas

significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and

pancreatic islet cell adenomas were not dose related. The low doses in mice and rats are approximately

80 times greater (normalized to body surface area) than the daily recommended human dose of one drop

(approximately 28 mcL) of 0.05% RESTASIS twice daily into each eye of a 60 kg person (0.001

mg/kg/day), assuming that the entire dose is absorbed.

Mutagenesis

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 in Chinese

hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated

mice. A study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human

lymphocytes 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 rats receiving oral doses of

cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human daily dose of 0.001 mg/kg/day

normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior to mating.

14 CLINICAL STUDIES

Four multicenter, randomized, adequate and well-controlled clinical studies were performed

in approximately 1,200 patients with moderate to severe keratoconjunctivitis

sicca. RESTASIS

demonstrated statistically significant increases in Schirmer wetting of 10 mm

versus vehicle at six months in patients whose tear production was presumed to be suppressed due to

ocular inflammation. This effect was seen in approximately 15% of RESTASIS ophthalmic emulsion-

treated patients versus approximately 5% of vehicle-treated patients. Increased tear production was not

seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.

No increase in bacterial or fungal ocular infections was reported following administration

of RESTASIS .

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-4476

NDC: 50090-4476-0 .4 mL in a VIAL, SINGLE-USE / 30 in a TRAY

17 PATIENT COUNSELING INFORMATION

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Handling the Container

Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may contaminate

the emulsion. Advise patients to not touch the vial tip to their eye to avoid the potential for injury to the

eye [see Warnings and Precautions (5.1)].

Use with Contact Lenses

RESTASIS should not be administered while wearing contact lenses. Patients with decreased tear

production typically should not wear contact lenses. Advise patients that if contact lenses are worn, they

should be removed prior to the administration of the emulsion. Lenses may be reinserted 15 minutes

following administration of RESTASIS ophthalmic emulsion [see Warnings and Precautions (5.2)].

Adminis tration

Advise patients that the emulsion from one individual single-use vial is to be used immediately after

opening for administration to one or both eyes, and the remaining contents should be discarded

immediately after administration.

© 2017 Allergan. All rights reserved.

All trademarks are the property of their respective owners.

Patented. See www.allergan.com/patents

Irvine, CA 92612

Made in the U.S.A.

71876US19

Storage: Store at 15°-25°C (59°-77°F).

cyclos porine

RESTASIS

cyclosporine emulsion

Product Information

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A-S Medication Solutions

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 0 9 0 -4476 (NDC:0 0 23-9 16 3)

Route of Administration

OPHTHALMIC

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CYCLO SPO RINE (UNII: 8 3HN0 GTJ6 D) (CYCLOSPORINE - UNII:8 3HN0 GTJ6 D)

CYCLOSPORINE

0 .5 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

GLYCERIN (UNII: PDC6 A3C0 OX)

CASTO R O IL (UNII: D5340 Y2I9 G)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

CARBO MER CO PO LYMER TYPE A ( ALLYL PENTAERYTHRITO L CRO SSLINKED) (UNII: 71DD5V9 9 5L)

WATER (UNII: 0 59 QF0 KO0 R)

SO DIUM HYDRO XIDE (UNII: 55X0 4QC32I)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:50 0 9 0 -4476 -

30 in 1 TRAY

0 8 /26 /20 19

1

.4 mL in 1 VIAL, SINGLE-USE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 50 79 0

0 4/0 1/20 0 3

Labeler -

A-S Medication Solutions (830016429)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

A-S Medicatio n So lutio ns

8 30 0 16 429

RELABEL(50 0 9 0 -4476 )

Revised: 8/2019

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