Cysteamine (ophthalmic)

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# Overview
Cysteamine (ophthalmic) is an ophthalmic agent that is FDA approved for the treatment of corneal cystine crystal accumulation in patients with cystinosis.   Common adverse reactions include headache, eye irritation, pain in eye, photophobia, red eye, and visual field defect.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- CYSTARAN is a cystine-depleting agent indicated for the treatment of corneal cystine crystal accumulation in patients with cystinosis.

### Dosing Information
- 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cysteamine (ophthalmic) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Cysteamine (ophthalmic) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cysteamine (ophthalmic) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cysteamine (ophthalmic) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Cysteamine (ophthalmic) in pediatric patients.

# Contraindications
There is limited information regarding Cysteamine (ophthalmic) Contraindications in the drug label.

# Warnings
- 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.
- 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.
- 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.
- CYSTARAN is for topical ophthalmic use only.

# Adverse Reactions

## 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 occuring in 10% of patients were sensitivity to light, redness, and eye pain/irritation, headache and visual field defects.

## Postmarketing Experience
There is limited information regarding Cysteamine (ophthalmic) Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Cysteamine (ophthalmic) Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of ophthalmic cysteamine in pregnant women. CYSTARAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Teratology studies have been performed in rats at oral doses in a range of 37.5 mg/kg/day to 150 mg/kg/day (about 0.2 to 0.7 times the recommended human maintenance dose on a body surface basis) and have revealed cysteamine bitartrate to be teratogenic. Observed teratogenic findings were cleft palate, kyphosis, heart ventricular septal defects, microcephaly, and exencephaly.
- Nonteratogenic Effects: Cysteamine was fetotoxic, resulting in intrauterine death and growth retardation in rats at oral doses of 0.2 to 0.7 times the recommended human maintenance dose on a body surface basis.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cysteamine (ophthalmic) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Cysteamine (ophthalmic) during labor and delivery.

### Nursing Mothers
- It is not known whether oral cysteamine is excreted in human milk. Because many drugs are excreted in human milk and because of the manifested potential of cysteamine for developmental toxicity in suckling rat pups when it was administered to their lactating mothers at an oral dose of 375 mg/kg/day (2,250 mg/m2/day, 1.7 times the recommended human dose based on body surface area), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The incremental increase in systemic cysteamine levels derived from drug applied topically to the eye in patients treated with oral cysteamine is negligible.

### Pediatric Use
- The safety and effectiveness of CYSTARAN (cysteamine ophthalmic solution) 0.44% have been established.

### Geriatic 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.

### Gender
There is no FDA guidance on the use of Cysteamine (ophthalmic) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Cysteamine (ophthalmic) with respect to specific racial populations.

### 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.

### Hepatic Impairment
There is no FDA guidance on the use of Cysteamine (ophthalmic) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cysteamine (ophthalmic) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Cysteamine (ophthalmic) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Ophthalmic

### Monitoring
There is limited information regarding Cysteamine (ophthalmic) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Cysteamine (ophthalmic) and IV administrations.

# Overdosage
There is limited information regarding Cysteamine (ophthalmic) overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## 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.

## Structure
- 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.

## Pharmacodynamics
There is limited information regarding Cysteamine (ophthalmic) Pharmacodynamics in the drug label.

## 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.

## Nonclinical Toxicology
- Cysteamine has not been tested for its carcinogenic potential in long-term animal studies. 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.
- 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 (450 mg/m2/day, 0.4 times the recommended human dose based on body surface area). At an oral dose of 375 mg/kg/day (2,250 mg/m2/day, 1.7 times the recommended human dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.

# 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) . For eyes with a higher baseline of CCCS 1, the response rate was 32% (94/291) .
- Study 2 evaluated ocular cystinosis patients who had a baseline of CCCS 1. The response rate was 67% (10/15) .
- Study 3 also evaluated ocular cystinosis patients; for eyes with a baseline of CCCS 1, the response rate was 33% (3/9) .
- Corneal crystals accumulate if CYSTARAN is discontinued.

# How Supplied
CYSTARAN (cysteamine ophthalmic solution) 0.44% is supplied in a 15 mL, opaque, white, low-density polyethylene (LDPE) bottle with a 15 mm white, LDPE controlled dropper tip and closed with a white, polypropylene screw cap.
NDC 54482-020-01

## 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 1 week.
- Do not refreeze.
- Discard after 1 week of use.

# Images

## Drug Images

## Package and Label Display Panel
Vial Label
Vial Label
NDC 54482-020-01          15 mL
cystaranTM
(cysteamine 
-phthalmic solution) 0.44% 
For Ophthalmic Use Only
Sterile
Rx only
Dosage: See package insert.
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 1 week. Do 
not refreeze. Discard after 1 week of use. 
Each mL contains 6.5mg cysteamine hydrochloride, 
equivalent to 4.4mg cysteamine.
Mfd. by Hi-Tech Pharmacal, Co., Inc. for
Sigma-Tau Pharmaceuticals, Inc.
cysl-9-ht 1012
LOT
EXP.

# Patient Counseling Information
- 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 1 week. The thawed bottles 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 thawing.
- 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.
- 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.
- Patients should be advised that CYSTARAN is for topical ophthalmic use only.

# Precautions with Alcohol
Alcohol-Cysteamine (ophthalmic) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Cystaran

# Look-Alike Drug Names
There is limited information regarding Cysteamine (ophthalmic) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price