Cysteamine (Monograph)

Brand names: Cystagon, Procysbi
Drug class: Other Miscellaneous Therapeutic Agents
- Cystine-depleting Agents
- Anticystine Agents
Chemical name: Ethanethiol, 2-amino, (2R,3R)-2,3-dihydroxybutanedioate
Molecular formula: C₄H₆O₆•C₂H₇NS
CAS number: 27761-19-9

Introduction

Cystine-depleting agent.

Uses for Cysteamine

Cystinosis

Treatment of nephropathic cystinosis (designated an orphan drug by FDA for this use).

Immediate-release cysteamine bitartrate capsules (Cystagon) are indicated for use in children and adults. Delayed-release capsules and oral granules (Procysbi) are indicated for use in adults and pediatric patients ≥1 year of age.

Early and long-term oral cysteamine therapy has been shown to preserve renal glomerular function and reduce or prevent extra-renal complications such as growth retardation and hypothyroidism.

Cysteamine therapy should be considered for all patients with nephropathic cystinosis regardless of age and transplantation status, and such therapy should be continued lifelong.

Cysteamine Dosage and Administration

General

Patient Monitoring

• Monitor WBC cystine concentrations to guide dosing and monitor patient compliance. The goal of therapy is to maintain cystine levels below 1 nmol ½ cystine/mg protein. Some patients with poorer tolerability may still derive benefit with a WBC cystine level less than 2 nmol ½ cystine/mg protein.

• Monitor blood counts and liver function tests.

• Monitor patients for signs and symptoms of benign intracranial hypertension (e.g., headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye or pain with eye movement).

• Routinely monitor patient's skin and bones.

Administration

Oral Administration

Cysteamine bitartrate is administered orally. The drug is commercially available as immediate-release capsules or delayed-release capsules or oral granules.

Immediate-release Cysteamine

Immediate-release capsules (Cystagon) are administered every 6 hours; the capsules may be swallowed whole or the entire contents of the capsule(s) may be sprinkled on food. The manufacturer recommends that intact cysteamine capsules should not be administered to children under the age of approximately 6 years because of the risk of aspiration; in these patients, the capsules may be administered by sprinkling the capsule contents over food.

Delayed-release Cysteamine

Delayed-release cysteamine bitartrate capsules (Procysbi) are administered every 12 hours. The capsules should be swallowed whole with fruit juice (except grapefruit juice) or water; do not crush or chew the capsules or contents. For patients who cannot swallow the capsules, the capsules can be opened and the capsule contents sprinkled on and mixed in applesauce, berry jelly, or fruit juice (except grapefruit juice) and administered orally. For patients with a gastrostomy tube, the capsules can be opened and the capsule contents mixed in applesauce and administered.

Cysteamine bitartrate delayed-release oral granules should be sprinkled and mixed in applesauce, berry jelly, or fruit juice (except grapefruit juice) and administered orally; do not crush or chew the oral granules. For patients with a gastrostomy tube, the oral granules can be mixed in applesauce and administered.

Do not eat for at least 2 hours before taking delayed-release cysteamine and for at least 30 minutes after to maximize absorption. If patients are unable to take the drug without eating, take with food but limit the amount to approximately 4 ounces (½ cup) within 1 hour before to 1 hour after taking cysteamine. Administer the drug in a consistent manner with regard to food and avoid consumption of high fat foods close to dosing. Administer cysteamine at least 1 hour before or 1 hour after drugs containing bicarbonate or carbonate, and avoid alcohol while taking cysteamine.

Dosage

Available as cysteamine bitartrate; dosage is expressed in terms of cysteamine.

Initiate cysteamine therapy promptly once the diagnosis of nephropathic cystinosis is confirmed.

Pediatric Patients

Nephropathic Cystinosis (Immediate-release Cysteamine Capsules)

Oral

Initial dosage in treatment-naive patients should be (1/6)–¼ of the maintenance dosage; increase dosage gradually to minimize adverse effects. The maintenance dosage should be reached after 4 to 6 weeks of incremental dosage increases.

Patients who are currently taking cysteamine hydrochloride or phosphocysteamine may be transitioned to equimolar doses of immediate-release cysteamine bitartrate.

If patient is unable to tolerate cysteamine initially due to adverse effects, temporarily withhold therapy, then re-institute at a lower dosage and gradually increase to appropriate dosage.

The recommended maintenance dosage of immediate-release cysteamine in treatment-naive pediatric patients ≤12 years of age is 1.3 g/m² daily administered in 4 divided doses given every 6 hours. (See Table 1.)

The recommended maintenance dosage of immediate-release cysteamine in treatment-naive pediatric patients >12 years of age weighing >110 pounds is 2 g daily administered in 4 divided doses.

After maintenance dosage is achieved, obtain leukocyte cystine measurements 5 to 6 hours after dose administration in treatment-naive patients. Patients being transferred from cysteamine hydrochloride or phosphocysteamine to immediate-release cysteamine bitartrate should have their WBC cystine levels measured in 2 weeks, and every 3 months thereafter to assess optimal dosage.

Titrate dosage to achieve WBC cystine goal <1 nmol ½ cystine/mg protein. Determine WBC cystine concentration and increase dosage if WBC cystine >2 nmol ½ cystine/mg protein. May increase dosage to a maximum of 1.95 g/m² daily to achieve this level; however, some patients may not tolerate this dosage.

If a dose is missed, take the dose as soon as possible, unless it is within 2 hours of the next dose in which case the dose should be skipped and the regular dosing schedule resumed. Do not double a dose to make up for a missed dose.

Nephropathic Cystinosis (Delayed-release Cysteamine Capsules or Oral Granules)

Oral

Treatment-naive pediatric patients ≥1 year of age: recommended initial dosage should be (1/6)–¼ of the maintenance dosage; increase dosage gradually to a maintenance dosage of 1.3 g/m² daily administered in 2 divided doses every 12 hours. (See Table 2.)

In patients 1 year to <6 years of age, increase dosage in 10% increments to maintenance dosage while monitoring WBC cystine concentrations; allow a minimum of 2 weeks between dosage adjustments.

In patients ≥6 years of age, gradually increase dosage over 4–6 weeks until maintenance dosage is achieved.

If patient is unable to tolerate cysteamine initially because of adverse effects, decrease dosage and then gradually increase back to the maintenance dosage.

Determine WBC cystine concentrations and adjust dosage accordingly; consider other factors such as medication adherence, dosing interval, timing between the last dose and blood draw for laboratory measurement, and other administration factors before adjusting the dosage. In treatment-naive patients 1 year to less than 6 years of age, obtain a measurement 2 weeks after initiation of cysteamine treatment and continue monitoring during the dosage titration period until the therapeutic target WBC cystine concentration is achieved. Once this is achieved, continue monitoring monthly for 3 months, then quarterly for 1 year, and then twice-yearly, at a minimum. In treatment-naive patients ≥6 years of age, obtain a measurement after reaching the maintenance cysteamine dosage, then monitor monthly for 3 months, quarterly for 1 year, and then twice-yearly, at a minimum.

After maintenance dosage is achieved, further titrate dosage to achieve a WBC cystine <1 nmol ½ cystine/mg protein. If a dosage adjustment is required, increase dosage by 10%, rounded to nearest dosage that can be administered using the available strengths of capsules or packets of oral granules, up to a maximum dosage of 1.95 g/m² daily. For patients 1 year to less than 6 years of age, allow a minimum of 2 weeks between dosage increments.

If a dose is missed, take the dose as soon as possible up to 8 hours after the scheduled time. If the next scheduled dose is due in less than 4 hours, skip the missed dose and take the next dose at the usual scheduled time. Do not take a double dose to make up for a missed dose.

Adults

Nephropathic Cystinosis (Immediate-release Cysteamine Capsules)

Oral

Initial dosage in treatment-naive patients should be (1/6)–¼ of the maintenance dosage; increase dosage gradually to minimize adverse effects. The maintenance dosage should be reached after 4 to 6 weeks of incremental dosage increases.

Patients who are currently taking cysteamine hydrochloride or phosphocysteamine may be transitioned to equimolar doses of immediate-release cysteamine bitartrate.

If patient is unable to tolerate cysteamine initially due to adverse effects, temporarily withhold therapy, then re-institute at a lower dosage and gradually increase to appropriate dosage.

The recommended maintenance dosage of immediate-release cysteamine in treatment-naive adults weighing >110 pounds is 2 g daily administered in 4 divided doses.

After maintenance dosage is achieved, obtain leukocyte cystine measurements 5 to 6 hours after dose administration in treatment-naive patients. Patients being transferred from cysteamine hydrochloride or phosphocysteamine to immediate-release cysteamine bitartrate should have their WBC cystine levels measured in 2 weeks, and every 3 months thereafter to assess optimal dosage.

Titrate dosage to achieve WBC cystine goal <1 nmol ½ cystine/mg protein. Determine WBC cystine concentration and increase dosage if WBC cystine >2 nmol ½ cystine/mg protein. May increase dosage to a maximum of 1.95 g/m² daily to achieve this level; however, some patients may not tolerate this dosage.

If a dose is missed, take the dose as soon as possible, unless it is within 2 hours of the next dose in which case the dose should be skipped and the regular dosing schedule resumed. Do not double a dose to make up for a missed dose.

Nephropathic Cystinosis (Delayed-release Cysteamine Capsules or Oral Granules)

Oral

Treatment-naive patients: recommended initial dosage should be (1/6)–¼ of the maintenance dosage; increase dosage gradually to a maintenance dosage of 1.3 g/m² daily administered in 2 divided doses every 12 hours. (See Table 2.)

Gradually increase dosage over 4–6 weeks until maintenance dosage is achieved.

If patient is unable to tolerate cysteamine initially because of adverse effects, decrease dosage and then gradually increase back to the maintenance dosage.

Determine WBC cystine concentrations and adjust dosage accordingly; consider other factors such as medication adherence, dosing interval, timing between the last dose and blood draw for laboratory measurement, and other administration factors before adjusting the dosage. In treatment-naive patients, obtain a measurement after reaching the maintenance cysteamine dosage, then monitor monthly for 3 months, quarterly for 1 year, and then twice-yearly, at a minimum.

After maintenance dosage is achieved, further titrate dosage to achieve a WBC cystine <1 nmol ½ cystine/mg protein. If a dosage adjustment is required, increase dosage by 10%, rounded to nearest dosage that can be administered using the available strengths of capsules or packets of oral granules, up to a maximum dosage of 1.95 g/m² daily.

If a dose is missed, take the dose as soon as possible up to 8 hours after the scheduled time. If the next scheduled dose is due in less than 4 hours, skip the missed dose and take the next dose at the usual scheduled time. Do not take a double dose to make up for a missed dose.

Prescribing Limits

Pediatric Patients

Nephropathic Cystinosis

Oral

1.95 g/m² daily.

Adults

Nephropathic Cystinosis

Oral

1.95 g/m² daily.

Special Populations

Hepatic Impairment

No special population dosage recommendations at this time.

Renal Impairment

No special population dosage recommendations at this time.

Geriatric Patients

No special population dosage recommendations at this time.

Cautions for Cysteamine

Contraindications

• Hypersensitivity to cysteamine or penicillamine.

Warnings/Precautions

General Precautions

Ehlers-Danlos-like Syndrome

Skin and bone lesions that resemble Ehlers-Danlos-like syndrome reported in patients taking high doses of cysteamine. Clinical findings included molluscoid pseudotumors (purplish hemorrhagic lesions), skin striae, bone lesions (e.g., osteopenia, compression fractures, scoliosis, and genu valgum), leg pain, and joint hyperextension.

Monitor for skin and bone abnormalities: if any abnormalities occur, reduce dosage of cysteamine.

Dermatologic Reactions

Severe skin reactions such as erythema multiforme bullosa and toxic epidermal necrolysis reported.

Routinely monitor the skin and bones of patients. If skin rash develops, discontinue cysteamine until rash resolves; may reinitiate drug at a lower dosage under close supervision and slowly titrate to the therapeutic dosage. Permanently discontinue therapy in patients who develop severe skin rash (e.g., erythema multiforme bullosa and toxic epidermal necrolysis).

GI Ulcers and Bleeding

GI symptoms (e.g., nausea, vomiting, diarrhea) are common adverse effects of cysteamine. GI bleeding and ulcers also reported.

Consider dosage reduction if severe GI symptoms occur.

Fibrosing Colonopathy

Fibrosing colonopathy, including colonic stricture formation, reported during postmarketing experience with delayed-release cysteamine bitartrate (Procysbi). Reported symptoms includes abdominal pain, vomiting, bloody or persistent diarrhea, and fecal incontinence.

Evaluate patients with severe, persistent, and/or worsening abdominal symptoms for fibrosing colonopathy. If a diagnosis is confirmed, permanently discontinue delayed-release cysteamine and switch to immediate-release capsules. An association between methacrylic acid-ethyl acrylate copolymer (an inactive ingredient in delayed-release cysteamine) and fibrosing colonopathy cannot be ruled out.

CNS Effects

CNS symptoms (e.g., seizures, lethargy, somnolence, depression, encephalopathy) reported. Neurological complications have also been described in some patients with cystinosis not receiving cysteamine therapy.

Monitor patients for CNS symptoms; reduce dosage if severe or persistent CNS symptoms occur.

Patients should not drive, operate machinery, or engage in other dangerous activities until they know how the drug will affect them.

Leukopenia

Reversible leukopenia and elevated alkaline phosphatase levels reported occasionally; monitor blood counts during cysteamine therapy.

Monitor WBC counts and alkaline phosphatase levels. If test values remain elevated, consider decreasing the dosage or discontinuing the drug until values return to normal.

Benign Intracranial Hypertension

Benign intracranial hypertension (or pseudotumor cerebri [PTC]) and/or papilledema reported. A causal relationship to the drug has not been established.

Monitor for symptoms of PTC including headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye, or pain with eye movement. Perform periodic eye examinations; initiate treatment promptly to prevent vision loss in patients who develop PTC.

Specific Populations

Pregnancy

No available data on cysteamine use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Cysteamine (administered as cysteamine bitartrate) was teratogenic and fetotoxic in rats at doses less than the recommended human maintenance dose.

Lactation

Not known whether oral cysteamine is distributed into human milk or whether the drug has any effects on the breast-fed infant or on milk production. Breastfeeding is not recommended.

Pediatric Use

Safety and efficacy established in pediatric patients; the drug is approved for use in such patients.

Safety and effectiveness of delayed-release cysteamine not established in patients <1 year of age.

Geriatric Use

No studies conducted in geriatric patients.

Common Adverse Effects

Common adverse effects with immediate-release cysteamine (>5%): vomiting, anorexia, fever, diarrhea, lethargy, rash.

Common adverse effects with delayed-release cysteamine in previously-treated patients ≥6 years of age (≥5%): vomiting, nausea, abdominal pain, breath odor, diarrhea, skin odor, fatigue, rash, headache.

Common adverse effects with delayed-release cysteamine in treatment-naive patients 1 year to <6 years of age (>10%): vomiting, gastroenteritis/viral gastroenteritis, diarrhea, breath odor, nausea, electrolyte imbalance, headache.

Drug Interactions

Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.

Drugs that Increase Gastric pH

Drugs that increase gastric pH (e.g., medications containing bicarbonate or carbonate) may alter pharmacokinetics of cysteamine due to the premature release of cysteamine from the delayed-release preparations and increase WBC cystine concentration.

Monitor WBC cystine concentration when drugs that increase the gastric pH are used concomitantly with delayed-release cysteamine.

Alcohol

Consumption of alcohol with delayed-release cysteamine may increase the rate of cysteamine release and/or adversely alter the pharmacokinetics, effectiveness, and safety of cysteamine.

Avoid consumption of alcoholic beverages during treatment with cysteamine.

Other Medications Used in Fanconi Syndrome

Cysteamine may be administered with electrolyte and mineral replacements necessary for management of Fanconi Syndrome, vitamin D, and thyroid agents.

Cysteamine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations occurred in about 73 minutes after oral administration of conventional capsules. Following oral administration of delayed-release capsules, peak plasma concentrations occurred in about 188 minutes.

Onset

Maximum reduction of WBC cystine of about 0.46 nmol ½ cystine/mg protein occurs approximately 1.8 hours after oral administration of conventional capsules.

Duration

WBC cystine levels return to baseline 6 hours after oral administration of conventional capsules.

Food

Food may reduce systemic exposure of cysteamine; however in clinical studies, administration with 4 ounces applesauce or orange juice did not affect the rate or extent of absorption.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

About 52%.

Stability

Storage

Oral

Immediate-release Capsules

20–25°C (excursions permitted to 15–30°C). Protect from light and moisture.

Delayed-release Capsules and Oral Granules

Store in refrigerator at 2°C to 8°C.

Dispense delayed-release capsules and oral granules in original packaging with a 4 month discard date; keep bottles tightly closed and in a dry place protected from light and moisture.

Actions

• A cystine-depleting agent that lowers the cellular cystine content in patients with nephropathic cystinosis, an inherited defect of lysosomal transport.

• Reacts with cystine within lysosomes to convert it to cysteine and cysteine-cysteamine mixed disulfides, which can pass through the lysosomal membrane, resulting in cystine depletion from the cell.

Advice to Patients

• Importance of advising patients to take cysteamine bitartrate exactly as prescribed. Importance of strict adherence to dosing schedule since WBC cystine levels may rise if a dose is delayed or missed.

• Importance of advising patients of specific administration instructions for each preparation.

• Importance of routine laboratory monitoring to determine the appropriate dosage of cysteamine.

• Importance of advising patients not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to the drug's effects.

• Risk of GI ulceration and/or bleeding; importance of informing clinicians of any signs or symptoms of GI ulceration or bleeding.

• Advise patients and caregivers that fibrosing colonopathy has been reported with delayed-release cysteamine. Advise patients to contact their physician immediately if they experience severe, persistent and/or worsening stomach pain, vomiting, bloody or persistent diarrhea, or inability to control bowel movements.

• Importance of promptly contacting a clinician if a skin rash occurs.

• Risk of benign intracranial hypertension; importance of monitoring and contacting a clinician promptly if headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, or eye pain occurs.

• Risk of Ehlers-Danlos-like syndrome; importance of monitoring and contacting a clinician if any abnormalities of the skin, bones, or joints occur.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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