CYSTADROPS (Page 2 of 3)

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. Clearance of cysteamine from the conjunctival sac of the eye is not dependent on renal function and the total systemic dose is negligible, so impaired renal function is unlikely to affect total body clearance.

The total daily ophthalmic dose is less than 4% of the recommended oral daily dose of cysteamine; thus, the systemic exposure following ophthalmic administration is expected to be negligible compared to oral administration.

11 DESCRIPTION

CYSTADROPS is a sterile, viscous, ophthalmic solution containing 3.8 mg/mL of cysteamine (0.37%) equivalent to 5.6 mg/mL of cysteamine hydrochloride (0.55%). Cysteamine is a cystine- depleting agent which lowers the cystine content of cells in patients with cystinosis.
Structural Formula

Molecular Formula: C2 H7 NS HCl

Molecular Weight: 113.61

Each milliliter of CYSTADROPS contains: Active: cysteamine 3.8 mg (equivalent to cysteamine hydrochloride 5.6 mg); Preservative: benzalkonium chloride 0.1 mg; Inactive Ingredients: carmellose sodium, citric acid monohydrate, disodium edetate dihydrate, hydrochloric acid and sodium hydroxide (to adjust pH to 4.6-5.4), and water for injection.

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, because all patients concomitantly received oral cysteamine and the total daily ophthalmic dose is less than 4% of the recommended oral daily dose of cysteamine.

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 (480 times the recommended human ophthalmic dose based on body surface area). At an oral dose of 375 mg/kg/day (2,400 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 safety and efficacy of CYSTADROPS were assessed in two studies: a single-arm study conducted for 5 years (OCT-1) and a randomized controlled study conducted for 90 days (CHOC).

In the OCT-1 study, 8 patients with cystinosis (2 males and 6 females) with a mean age of 12.1 ± 4.6 (range: 7.0 – 21.0) were enrolled and received a median of 4 drops/eye/day of CYSTADROPS. In CHOC study, 32 patients with cystinosis (15 males and 17 females) with a mean age of 17.1 ± 13.0 (range: 2.9 – 62.6) were enrolled and received a median of 4 drops/eye/day. Fifteen patients were exposed to CYSTADROPS and 16 were exposed to cysteamine hydrochloride 0.1% (control arm).

Efficacy was assessed with In-Vivo Confocal Microscopy total score (IVCM score) by quantifying the cystine crystals in the cornea. A decrease in IVCM total score from baseline indicated a reduction in corneal crystals.

In the CHOC study, after 30 and 90 days of treatment with CYSTADROPS, 12% and 40% reduction in the total IVCM total score across all corneal layers was observed from baseline, respectively. CYSTADROPS demonstrated greater reduction compared to the control arm at 90 days. The average reduction in IVCM total score was 4.6 in the CYSTADROPS arm and 0.5 in the control arm, mean difference 3.8 (95% CI: (2.1, 5.6)).

In the OCT-1 study, a mean decrease in corneal cystine crystal deposits of 30%, in comparison with baseline, was maintained over the 60 month period of the study.

16 HOW SUPPLIED/STORAGE AND HANDLING

CYSTADROPS (cysteamine ophthalmic solution) 0.37% is supplied as a 5 mL sterile viscous solution in a 10 mL amber glass bottle closed by a bromobutyl stopper and sealed with an aluminum tear-off cap. A PVC dropper applicator with HDPE closure is packed separately and included in each carton box.

Each carton box (NDC 55292-410-05) contains 1 bottle (NDC 55292-410-05) and 1 dropper applicator individually wrapped.

Before First Opening: Before opening, store new, unopened CYSTADROPS in the refrigerator between 36°F to 46°F (2°C to 8°C). Keep the bottle in the outer carton in order to protect from light.

After First Opening: After opening, store opened CYSTADROPS at room temperature between 68°F to 77°F (20°C to 25°C). Do not refrigerate after opening. Keep the dropper bottle tightly closed in the outer carton in order to protect from light. Discard 7 days after first opening.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Preparation for Administration and Storage of Bottles

  1. Advise patients to store new unopened bottles in the refrigerator in the original carton.
  2. Each week, one new bottle should be removed from the refrigerator. Advise patients to write the date the bottle was opened in the space on the carton. After first opening, keep the bottle tightly closed and store at room temperature in the original carton.
  3. Patients are to wash their hands carefully in order to avoid microbiological contamination of the content in the bottle.
  4. Remove the green protective cap (see Figure A).
  5. Remove the metal seal (see Figure B).
  6. Remove the gray stopper (see Figure C) from the bottle.
  7. Do not touch the opening of the bottle after removing the gray stopper.
Figures A, B, C
(click image for full-size original)
  1. Take the dropper out of its packaging, without touching the end intended to be attached to the bottle, attach it (see Figure D) to the bottle and do not remove it.
  2. Patients should be advised not to lose the small white cap (see Figure E) that comes on the top of the dropper. Keep the small white cap tightly closed when not in use.
    Figures D, E
    (click image for full-size original)
  3. Instill one drop of CYSTADROPS in each eye, 4 times a day during waking hours.
  4. Instruct patients to discard the bottle at the end of 7 days. There may be medication left in the bottle; however, the bottle must be discarded by the patient because the medication is only stable for 7 days after first opening.

Risk of Contamination

Advise patients 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.

Contact Lens Use

Advise patients that contact lenses should be removed prior to application of CYSTADROPS. Contact lenses may be reinserted 15 minutes following CYSTADROPS administration [see Warnings and Precautions ( 5.3)].

Topical Ophthalmic Use

Advise patients that CYSTADROPS is for topical ophthalmic use.

Missed Dose

If the patient misses an instillation, instruct the patient to administer a dose as soon as feasible and then to continue the treatment with the next scheduled instillation.

Manufactured by: Baccinex SA, 2822 Courroux, Switzerland

Manufactured for: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.

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This product label may have been updated. For the most recent prescribing information, please visit www.recordatirarediseases.com/us.

INSTRUCTIONS FOR USE CYSTADROPS® (sys-tah-drops) (cysteamine ophthalmic solution) for topical ophthalmic use
Read this Instructions for Use carefully before you start using CYSTADROPS and each time you get a refill; there may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.
Important information:
Use CYSTADROPS exactly as your healthcare provider tells you to use it.
CYSTADROPS is for use in the eyes.
Wash your hands before each use.
If you use CYSTADROPS with other eye medicines, you should wait at least 10 minutes between using CYSTADROPS and your other eye medicines.
If you wear contact lenses, remove them before using CYSTADROPS. You should wait at least 15 minutes after using CYSTADROPS, before placing your contact lenses back in your eyes.
Do not let the CYSTADROPS dropper touch your eyelids or any other surfaces.
Storing CYSTADROPS:
Before opening, store new, unopened CYSTADROPS in the refrigerator between 36°F to 46°F (2°C to 8°C).
After first opening, store opened CYSTADROPS at room temperature between 68°F to 77°F (20°C to 25°C). Do not refrigerate after opening.
Keep CYSTADROPS in the original carton to protect from light.
Keep the CYSTADROPS dropper bottle tightly closed when not in use.
Throw away any unused CYSTADROPS 7 days after opening.
Keep CYSTADROPS and all medicines out of the reach of children.
Supplies needed:
CYSTADROPS bottle and dropper
mirror
tissue
Using CYSTADROPS:
Use 1 drop in each eye, four times a day.
If you miss a dose, administer the missed dose as soon as possible and then use the drops at your next regular scheduled time.
Step 1: Before using a CYSTADROPS bottle for the first time
Check the expiration date on the CYSTADROPS bottle before use. Do not use CYSTADROPS if the expiration date has passed.
After opening a CYSTADROPS bottle, allow it to reach room temperature before using it for the first time.
After opening a CYSTADROPS bottle for the first time, write the date of opening in the space provided on the carton.
Wash your hands carefully in order to avoid contamination of the contents in the bottle.
Remove the green protective cap (Figure A).
Remove the metal seal (Figure B).
Remove the gray stopper (Figure C).
Do not touch the opening of the bottle after removing the gray stopper.
Place the opened bottle on a flat surface.
Figures A, B, C
(click image for full-size original)
Take the dropper out of its packaging. Do not touch the end of the dropper that will be attached to the bottle. Attach the dropper (Figure D) to the bottle. After attaching the dropper to the bottle, do not remove the dropper from the bottle (Figure E).
Figures D, E
(click image for full-size original)
Make sure that you do not lose the small white cap (Figure E) that comes on the top of the dropper.
Step 2: Before using CYSTADROPS
Check the opening date that you wrote down on the carton. Do not use CYSTADROPS if more than 7 days have passed since the opening date.
Get the CYSTADROPS dropper bottle, mirror, and tissue.
Wash your hands.
Step 3: Using the CYSTADROPS dropper bottle
Twist the small white cap to remove it from the dropper. Do not throw the small white cap away.
Hold the CYSTADROPS dropper bottle with the dropper pointing down, between your thumb and fingers. If no medicine fills the dropper, move the CYSTADROPS dropper bottle up and down until medicine fills the dropper.
Tilt your head back. Pull down your lower eyelid with a clean finger and look up (Figure F). The medicine will go into the space between your lower eyelid and your eye.
figure F
Use the mirror to help you bring the dropper bottle tip close to the eye.
Do not let the CYSTADROPS dropper touch your eyelids or any other surfaces.
Gently squeeze the dropper to release 1 drop of CYSTADROPS.
If a drop misses your eye, try again.
After using CYSTADROPS, close your eye and press a finger into the corner of your eye by the nose (Figure G), then gently massage your upper eyelid to spread the CYSTADROPS over the eye.
Figure G
Remove any medicine around the eye with a tissue (Figure H).
Repeat Step 3 for the other eye.
Replace the small white cap on the dropper immediately after use.
Figure H
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Manufactured by: Baccinex SA, 2822 Courroux, Switzerland
Manufactured for: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.
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Approved: 08/2020

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