HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. CYSTARAN (cysteamine ophthalmic solution) 0.44% is supplied in 15 mL, opaque, white, low-density polyethylene (LDPE) bottle with 15 mm white, LDPE controlled dropper tip and closed with white, polypropylene screw cap.. Storage: Store in freezer at -25C to -15C (-13F to 5F) in the original carton. Thaw for approximately 24 hours before use. Store thawed bottle at 2C to 25C (36F to 77F) for up to week. Do not refreeze the thawed medication. Discard after week of use.NDC 54482-020-01.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (incidence approximately 10% or greater) are sensitivity to light, redness, eye pain/irritation, headache and visual field defects. 6) To report SUSPECTED ADVERSE REACTIONS, contact Leadiant Biosciences, Inc. at 1-888-393-4584 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data described below reflect exposure in controlled clinical trials of six months to 19 years duration in approximately 300 patients.The most frequently reported ocular adverse reactions occurring in >=10% of patients were sensitivity to light, redness, and eye pain/irritation, headache and visual field defects.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCysteamine has not been tested for its carcinogenic potential in long-term animal studies.. MutagenesisCysteamine was not mutagenic in the Ames test. It produced negative response in an in vitro sister chromatid exchange assay in human lymphocytes but positive response in similar assay in hamster ovarian cells. Impairment of FertilityRepeat breeding reproduction studies were conducted in male and female rats. Cysteamine was found to have no effect on fertility and reproductive performance at an oral dose of 75 mg/kg/day (173 times the recommended human ophthalmic dose based on body surface area). At an oral dose of 375 mg/kg/day (864 times the recommended human ophthalmic dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cysteamine acts as cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation.. 12.3 Pharmacokinetics. The peak plasma concentration of cysteamine following ocular administration of cysteamine ophthalmic solution in humans is unknown, but it is expected to be substantially less than the peak plasma concentration following oral administration of cysteamine bitartrate.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Clinical efficacy was evaluated in controlled clinical trials in approximately 300 patients. The primary efficacy end point was the response rate of eyes that had reduction of at least unit in the photo-rated Corneal Cystine Crystal Score (CCCS) at some time point during the study when baseline CCCS >=1, or lack of an increase of more than unit in CCCS throughout the study when baseline CCCS <1.Study combined the data from three smaller studies. For eyes with lower baseline of CCCS <1, the response rate was 13% (4/30) [95% CI: (4, 32)]. For eyes with higher baseline of CCCS >=1, the response rate was 32% (94/291) [95% CI: (27, 38)].Study evaluated ocular cystinosis patients who had baseline of CCCS >=1. The response rate was 67% (10/15) [95% CI: (38, 88)].Study also evaluated ocular cystinosis patients; for eyes with baseline of CCCS >=1, the response rate was 33% (3/9) [95% CI: (8, 70)].Corneal crystals accumulate if CYSTARAN is discontinued.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data described below reflect exposure in controlled clinical trials of six months to 19 years duration in approximately 300 patients.The most frequently reported ocular adverse reactions occurring in >=10% of patients were sensitivity to light, redness, and eye pain/irritation, headache and visual field defects.

DESCRIPTION SECTION.

11 DESCRIPTION. CYSTARAN is sterile ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride, equivalent to 4.4 mg/mL of cysteamine (0.44%) as the active ingredient. Cysteamine is cystine-depleting agent which lowers the cystine content of cells in patients with cystinosis.Molecular Formula: 2H 7NS HCl Molecular Weight: 113.61 Each milliliter of CYSTARAN contains: Active: cysteamine 4.4 mg (equivalent to cysteamine hydrochloride 6.5 mg); Preservative: benzalkonium chloride 0.1 mg; Inactive Ingredients: sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH to 4.1-4.5), and purified water.. Chemical Structure.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Storage of BottlesPatients should be advised to store bottles in the freezer in the original carton.Each week, one new bottle should be removed from the freezer.Patients should be advised to allow the bottle to thaw completely (approximately 24 hours) prior to use.After the bottle is completely thawed, the patient should record the discard date on the bottle label. The discard date is seven (7) days from the day the bottle is thawed.Patients should be advised to store thawed bottle at 2C to 25C (36F to 77F) for up to week. The thawed bottles should not be refrozen.At the end of week (7 days), patients should discard the bottle. There may be medication left in the bottle; however, the bottle must be discarded by the patient because the medication is only stable for week after thawing.. Patients should be advised to store bottles in the freezer in the original carton.. Each week, one new bottle should be removed from the freezer.. Patients should be advised to allow the bottle to thaw completely (approximately 24 hours) prior to use.. After the bottle is completely thawed, the patient should record the discard date on the bottle label. The discard date is seven (7) days from the day the bottle is thawed.. Patients should be advised to store thawed bottle at 2C to 25C (36F to 77F) for up to week. The thawed bottles should not be refrozen.. At the end of week (7 days), patients should discard the bottle. There may be medication left in the bottle; however, the bottle must be discarded by the patient because the medication is only stable for week after thawing.. Risk of ContaminationPatients should be advised not to touch the eyelid or surrounding areas with the dropper tip of the bottle. The cap should remain on the bottle when not in use.. Use with Contact LensesPatients should be advised that contact lenses should be removed prior to application of CYSTARAN. Contact lenses may be reinserted 15 minutes following CYSTARAN administration.. Topical Ophthalmic Use Patients should be advised that CYSTARAN is for topical ophthalmic use.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of cysteamine in human milk, the effects on the breastfed infants, or the effects on milk production. Cysteamine administered orally is present in milk of lactating rats. It is not known whether measurable levels of cysteamine would be present in maternal milk following topical ocular administration of CYSTARAN.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCysteamine has not been tested for its carcinogenic potential in long-term animal studies.. MutagenesisCysteamine was not mutagenic in the Ames test. It produced negative response in an in vitro sister chromatid exchange assay in human lymphocytes but positive response in similar assay in hamster ovarian cells. Impairment of FertilityRepeat breeding reproduction studies were conducted in male and female rats. Cysteamine was found to have no effect on fertility and reproductive performance at an oral dose of 75 mg/kg/day (173 times the recommended human ophthalmic dose based on body surface area). At an oral dose of 375 mg/kg/day (864 times the recommended human ophthalmic dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel Carton. NDC 54482-020-01cystaran (R) (cysteamine ophthalmic solution) 0.44% For Ophthalmic Use OnlySterile15 mLRx onlyActive Ingredient: Each mL contains 6.5mg cysteamine hydrochloride, equivalent to 4.4mg cysteamine; Inactive Ingredients: Benzalkonium chloride (preservative); Sodium chloride; hydrochloric acid and/or sodium hydroxide (to adjust pH) and purified water. Dosage: See package insert for full prescribing information. Storage: Store in freezer at -25C to -15C (-13F to 5F). Thaw for approximately 24 hours before use. Store thawed bottle at 2C to 25C (36F to 77F) for up to week. Do not refreeze. Discard after week of use, even if there is remaining drug product. Avoid touching dropper tip to any surface. For Ophthalmic Use Only.cysc-11-ht 0717Leadiant Biosciences Manufactured by Hi-Tech Pharmacal Co. Inc., Amityville, NY 11701 for Leadiant Biosciences, Inc., Gaithersburg, MD 20878 Rev.915:04 07/17. Principal Display Panel Carton Label.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate and well controlled studies of ophthalmic cysteamine in pregnant women to inform any drug associated risks. Oral administration of cysteamine to pregnant rats throughout the period of organogenesis was teratogenic at doses 86 to 345 times the recommended human ophthalmic dose (based on body surface area) [see Data] CYSTARAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data. Animal DataTeratology studies have been performed in rats at oral doses in the range of 37.5 mg/kg/day to 150 mg/kg/day (86 to 345 times the recommended human ophthalmic dose based on body surface area) and have revealed cysteamine bitartrate to be teratogenic. Observed teratogenic findings were intrauterine death, cleft palate, kyphosis, heart ventricular septal defects, microcephaly, exencephaly, and growth deficits.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics of cysteamine following ophthalmic administration of cysteamine ophthalmic solution has not been evaluated because ophthalmic exposure compared to systemic exposure is negligible. The majority of the patients in the ophthalmic clinical studies are assumed to have had some degree of renal impairment due to their underlying systemic disease. The total daily ophthalmic dose is less than 2% of the recommended oral daily dose of cysteamine; thus, the systemic exposure following ophthalmic administration is expected to be negligible compared to oral administration.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no adequate and well controlled studies of ophthalmic cysteamine in pregnant women to inform any drug associated risks. Oral administration of cysteamine to pregnant rats throughout the period of organogenesis was teratogenic at doses 86 to 345 times the recommended human ophthalmic dose (based on body surface area) [see Data] CYSTARAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data. Animal DataTeratology studies have been performed in rats at oral doses in the range of 37.5 mg/kg/day to 150 mg/kg/day (86 to 345 times the recommended human ophthalmic dose based on body surface area) and have revealed cysteamine bitartrate to be teratogenic. Observed teratogenic findings were intrauterine death, cleft palate, kyphosis, heart ventricular septal defects, microcephaly, exencephaly, and growth deficits.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of cysteamine in human milk, the effects on the breastfed infants, or the effects on milk production. Cysteamine administered orally is present in milk of lactating rats. It is not known whether measurable levels of cysteamine would be present in maternal milk following topical ocular administration of CYSTARAN.. 8.4 Pediatric Use. The safety and effectiveness of CYSTARAN (cysteamine ophthalmic solution) 0.44% have been established in pediatric patients.. 8.5 Geriatric Use. When the clinical studies with CYSTARAN were conducted, the reduced life expectancy from cystinosis did not make it possible to include patients in the geriatric age range.. 8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics of cysteamine following ophthalmic administration of cysteamine ophthalmic solution has not been evaluated because ophthalmic exposure compared to systemic exposure is negligible. The majority of the patients in the ophthalmic clinical studies are assumed to have had some degree of renal impairment due to their underlying systemic disease. The total daily ophthalmic dose is less than 2% of the recommended oral daily dose of cysteamine; thus, the systemic exposure following ophthalmic administration is expected to be negligible compared to oral administration.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. To minimize the risk of contamination, do not touch the dropper tip to any surface. Keep bottle tightly closed when not in use. 5.1) 5.1 Contamination of Tip and Solution. To minimize contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use.. 5.2 Benign Intracranial Hypertension. There have been reports of benign intracranial hypertension (or pseudotumor cerebri) associated with oral cysteamine treatment that has resolved with the addition of diuretic therapy.There have also been reports associated with ophthalmic use of cysteamine; however, all of these patients were on concurrent oral cysteamine.. 5.3 Contact Lens Use. CYSTARAN contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes following its administration [see Patient Counseling Information (17)] . 5.4 Topical Ophthalmic Use. CYSTARAN is for topical ophthalmic use.