These Highlights Do Not Include All The Information Needed To Use Cystaran®

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.

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.

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:   C₂H₇NS 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.

The safety and effectiveness of CYSTARAN (cysteamine ophthalmic solution) 0.44% have been established in pediatric patients.

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.

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.

None.

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.

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)].

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.

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.

CYSTARAN^® is a cystine-depleting agent indicated for the treatment of corneal cystine crystal accumulation in patients with cystinosis.

Cysteamine acts as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation.

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)

CYSTARAN is for topical ophthalmic use.

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.

Ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride equivalent to 4.4 mg/mL of cysteamine (0.44%).

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.

NDC 54482-035-02

cystaran^®

(cysteamine ophthalmic

solution) 0.44%

For Topical Ophthalmic Use

Sterile

NEW STORAGE

Rx only

15 mL

Active Ingredient: Each mL

contains 6.5 mg cysteamine

hydrochloride, equivalent to

4.4 mg cysteamine.

Inactive Ingredients: Benzalko-

nium chloride (preservative);

Sodium chloride; hydrochloric

acid and/or sodium hydroxide (to

adjust pH) and purified water.

Dosage: See Prescribing

Information.

Storage:

Before Opening: Store in

refrigerator in original packaging,

including unopened foil, at 2°C to

8°C (36°F to 46°F).

After Opening: After opening the

foil, store bottle at room

temperature 20°C to 25°C (68°F

to 77°F) during week of use.

Discard the bottle 1 week after

opening the foil and bottle, even

if there is remaining medication

in the bottle. Avoid touching

dropper tip to any surface.

cysc-7-m

Distributed by:

Leadiant Biosciences, Inc.,

Rockville, MD 20850

Made in Switzerland

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.

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.

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.

NDC 54482-020-02

cystaran^®

(cysteamine ophthalmic

solution) 0.44%

For Topical Ophthalmic Use

Sterile

15 mL

Rx only

Active Ingredient: Each mL

contains 6.5 mg cysteamine

hydrochloride, equivalent to

4.4 mg cysteamine. Inactive

Ingredients: Benzalkonium

chloride (preservative); Sodium

chloride; hydrochloric acid

and/or sodium hydroxide (to

adjust pH) and purified water.

Dosage: See Prescribing

Information.

Storage: Store in freezer in

original carton at -25°C to -15°C

(-13°F to 5°F). Thaw in original

carton for approximately 24

hours before use. Store thawed

bottle at 2°C to 25°C (36°F to

77°F) for up to 1 week. Do not

refreeze thawed medication.

Discard after 1 week of use,

even if there is remaining drug

product. Avoid touching dropper

tip to any surface.

For Topical Ophthalmic Use

cysc-6-m

Distributed by:

Leadiant Biosciences Inc.,

Rockville, MD 20850

Made in Switzerland

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.

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.

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:   C₂H₇NS 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.

The safety and effectiveness of CYSTARAN (cysteamine ophthalmic solution) 0.44% have been established in pediatric patients.

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.

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.

None.

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.

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)].

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.

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.

CYSTARAN^® is a cystine-depleting agent indicated for the treatment of corneal cystine crystal accumulation in patients with cystinosis.

Cysteamine acts as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation.

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)

CYSTARAN is for topical ophthalmic use.

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.

Ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride equivalent to 4.4 mg/mL of cysteamine (0.44%).

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.

NDC 54482-035-02

cystaran^®

(cysteamine ophthalmic

solution) 0.44%

For Topical Ophthalmic Use

Sterile

NEW STORAGE

Rx only

15 mL

Active Ingredient: Each mL

contains 6.5 mg cysteamine

hydrochloride, equivalent to

4.4 mg cysteamine.

Inactive Ingredients: Benzalko-

nium chloride (preservative);

Sodium chloride; hydrochloric

acid and/or sodium hydroxide (to

adjust pH) and purified water.

Dosage: See Prescribing

Information.

Storage:

Before Opening: Store in

refrigerator in original packaging,

including unopened foil, at 2°C to

8°C (36°F to 46°F).

After Opening: After opening the

foil, store bottle at room

temperature 20°C to 25°C (68°F

to 77°F) during week of use.

Discard the bottle 1 week after

opening the foil and bottle, even

if there is remaining medication

in the bottle. Avoid touching

dropper tip to any surface.

cysc-7-m

Distributed by:

Leadiant Biosciences, Inc.,

Rockville, MD 20850

Made in Switzerland

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.

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.

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.

NDC 54482-020-02

cystaran^®

(cysteamine ophthalmic

solution) 0.44%

For Topical Ophthalmic Use

Sterile

15 mL

Rx only

Active Ingredient: Each mL

contains 6.5 mg cysteamine

hydrochloride, equivalent to

4.4 mg cysteamine. Inactive

Ingredients: Benzalkonium

chloride (preservative); Sodium

chloride; hydrochloric acid

and/or sodium hydroxide (to

adjust pH) and purified water.

Dosage: See Prescribing

Information.

Storage: Store in freezer in

original carton at -25°C to -15°C

(-13°F to 5°F). Thaw in original

carton for approximately 24

hours before use. Store thawed

bottle at 2°C to 25°C (36°F to

77°F) for up to 1 week. Do not

refreeze thawed medication.

Discard after 1 week of use,

even if there is remaining drug

product. Avoid touching dropper

tip to any surface.

For Topical Ophthalmic Use

cysc-6-m

Distributed by:

Leadiant Biosciences Inc.,

Rockville, MD 20850

Made in Switzerland