Cystaran drug information

2 DOSAGE AND ADMINISTRATION Instill one drop of CYSTARAN in each eye, every waking hour. Do not touch dropper tip to any surface, as this may contaminate the solution. Discard after 1 week of use. Instill one drop of CYSTARAN in each eye, every waking hour. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride equivalent to 4.4 mg/mL of cysteamine (0.44%). Ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride equivalent to 4.4 mg/mL of cysteamine (0.44%). ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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.

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 a 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There 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 Data Teratology 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 a 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 Summary There 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.

8.1 Pregnancy Risk Summary There 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 Data Teratology 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 a 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.

8.4 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.

11 DESCRIPTION CYSTARAN is a 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 a cystine-depleting agent which lowers the cystine content of cells in patients with cystinosis. Molecular Formula: C 2 H 7 NS 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

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cysteamine acts as a 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.

12.1 Mechanism of Action Cysteamine acts as a 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Cysteamine has not been tested for its carcinogenic potential in long-term animal studies. Mutagenesis Cysteamine was not mutagenic in the Ames test. It produced a negative response in an in vitro sister chromatid exchange assay in human lymphocytes but a positive response in a similar assay in hamster ovarian cells. Impairment of Fertility Repeat 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Cysteamine has not been tested for its carcinogenic potential in long-term animal studies. Mutagenesis Cysteamine was not mutagenic in the Ames test. It produced a negative response in an in vitro sister chromatid exchange assay in human lymphocytes but a positive response in a similar assay in hamster ovarian cells. Impairment of Fertility Repeat 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.

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 a reduction of at least 1 unit in the photo-rated Corneal Cystine Crystal Score (CCCS) at some time point during the study when baseline CCCS ≥1, or a lack of an increase of more than 1 unit in CCCS throughout the study when baseline CCCS <1. Study 1 combined the data from three smaller studies. For eyes with a lower baseline of CCCS <1, the response rate was 13% (4/30) [95% CI: (4, 32)]. For eyes with a higher baseline of CCCS ≥1, the response rate was 32% (94/291) [95% CI: (27, 38)]. Study 2 evaluated ocular cystinosis patients who had a baseline of CCCS ≥1. The response rate was 67% (10/15) [95% CI: (38, 88)]. Study 3 also evaluated ocular cystinosis patients; for eyes with a baseline of CCCS ≥1, the response rate was 33% (3/9) [95% CI: (8, 70)]. Corneal crystals accumulate if CYSTARAN is discontinued.

16 HOW SUPPLIED/STORAGE AND HANDLING Fifteen (15) mL of CYSTARAN (cysteamine ophthalmic solution) 0.44% is supplied in an opaque, white, low-density polyethylene (LDPE) 88 mm tall bottle with a 1.6 mm blue, silicone rubber flow-controlled dropper tip and closed with a white, high-density polyethylene (HDPE) screw cap. The bottle is foil-wrapped and stored in a carton. CYSTARAN bottles must be stored in the following conditions: NDC 54482- 020 -02 Before Opening: Store unopened bottle in freezer at -25°C to -15°C (-13°F to 5°F) in the original packaging including unopened foil. Thaw for approximately 24 hours before use. Open the carton and the foil only when starting a new bottle. After Opening: Record discard date on the bottle, which is 1 week from the day the foil and bottle were opened. Store thawed bottle at 2°C to 25°C (36°F to 77°F) for up to 1 week. The thawed bottle does not require refrigeration between use. Do not refreeze the thawed medication. Discard 1 week after the foil and bottle were opened even if there is medication left in the bottle. NDC 54482- 035 -02 Before Opening: Store unopened bottle in refrigerator at 2°C to 8°C (36°F to 46°F) in the original packaging including unopened foil. Open the carton and the foil only when starting a new bottle. After Opening: Record discard date on the bottle, which is 1 week from the day the foil and bottle were opened. During the week of use, store bottle at room temperature, 20°C to 25°C (68°F to 77°F). Discard 1 week after the foil and bottle were opened even if there is medication left in the bottle.

CYSTARAN bottles must be stored in the following conditions: NDC 54482- 020 -02 Before Opening: Store unopened bottle in freezer at -25°C to -15°C (-13°F to 5°F) in the original packaging including unopened foil. Thaw for approximately 24 hours before use. Open the carton and the foil only when starting a new bottle. After Opening: Record discard date on the bottle, which is 1 week from the day the foil and bottle were opened. Store thawed bottle at 2°C to 25°C (36°F to 77°F) for up to 1 week. The thawed bottle does not require refrigeration between use. Do not refreeze the thawed medication. Discard 1 week after the foil and bottle were opened even if there is medication left in the bottle.

17 PATIENT COUNSELING INFORMATION Storage of Cystaran Bottles NDC 54482- 020 -02 Patients should be advised to store unopened bottles in the freezer in the intact foil pouch and 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 be advised to open the packaging (carton and foil) and record the discard date on the bottle label. The discard date is seven (7) days from the day the foil and bottle were opened. During the week of use, patients should be advised to store thawed bottle at 2°C to 25°C (36°F to 77°F) for up to 1 week. The thawed bottle does not require refrigeration between use and should not be refrozen. At the end of 1 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 1 week after the foil and bottle were opened. Storage of Cystaran Bottles NDC 54482- 035 -02 Patients should be advised to store unopened bottles in the refrigerator in the intact foil pouch and original carton. When starting a new bottle, patients should be advised to open the packaging (carton and foil) and record the discard date on the bottle label. The discard date is seven (7) days from the day the foil and bottle were opened. During the week of use, patients should be advised to store the bottle at room temperature 20°C to 25°C (68°F to 77°F) for up to 1 week. At the end of 1 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 1 week after the foil and bottle were opened. Risk of Contamination Patients 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 Lenses Patients 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.

CYSTARAN (cysteamine ophthalmic solution) 0.44% is distributed by Leadiant Biosciences, Inc., Rockville, MD 20850. cyspi-6-m Logo