Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 06 November 2017

Indication(s)

INDICATIONS AND USAGE CYSTAGON® is indicated for the management of nephropathic cystinosis in children and adults.

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Advisory information

contraindications
CONTRAINDICATIONS CYSTAGON® is contraindicated in patients who have developed hypersensitivity to it or to cysteamine or penicillamine.
Special warnings and precautions
PRECAUTIONS General Gastrointestinal tract symptoms including nausea, vomiting, anorexia and abdominal pain have been associated with cysteamine, sometimes severe. In addition, gastrointestinal ulceration and bleeding have been reported in patients on cysteamine therapy. If these develop, therapy may have to be interrupted and the dose adjusted. A cysteamine dose of 1.95 grams/m2/day (approximately 80 to 90 mg/kg/day) was associated with an increased number of withdrawals from treatment due to intolerance and an increased incidence of adverse events. Cysteamine has occasionally been associated with reversible leukopenia and abnormal liver function studies. Therefore, blood counts and liver function studies should be monitored. There have been reports of benign intracranial hypertension (or pseudotumor cerebri; PTC) and/or papilledema associated with CYSTAGON® treatment that has resolved with the addition of diuretic therapy. PTC may be more common in cystinotic patients because of concurrent medication and renal transplantation. Although a causal relationship of PTC to CYSTAGON® has not been established, physicians should monitor patients receiving CYSTAGON® for this condition. Physicians should instruct patients to report any of the following symptoms: headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye or pain with eye movement. A periodic eye examination is needed to identify this condition early and timely treatment should be provided when it occurs to prevent vision loss. There have been reports of serious skin lesions in patients treated with high doses of CYSTAGON® or other cysteamine salts that have responded to cysteamine dose reduction. These skin lesions are purplish hemorrhagic lesions over the elbow area on both arms and have been described as molluscoid pseudotumors. Skin striae, bone lesions (that have been described as osteopenia, compression fractures, scoliosis and genu valgum) along with leg pain and joint hyperextension may also be present. One patient with serious skin lesions subsequently died of acute cerebral ischemia with marked vasculopathy. Physicians should routinely monitor the skin and bones of patients receiving CYSTAGON®. If similar skin or bone abnormalities appear, the dose of CYSTAGON® should be reduced. Information for Patients and Parents and/or Guardians See attached information for patients and parents and/or guardians. Laboratory Tests Leukocyte cystine measurements are useful to determine adequate dosage and compliance. When measured 5 to 6 hours after CYSTAGON® administration, the goal should be a level < 1 nmol/½ cystine/mg protein. In some patients with poorer tolerability for CYSTAGON®, patients may still receive benefit with a white cell cystine level of less than 2 nmol/½ cystine/mg protein. Measurements should be done every three months, more frequently when patients are transferred from cysteamine hydrochloride or phosphocysteamine solutions to CYSTAGON®. Physicians should follow patients for signs and symptoms of gastrointestinal ulceration and bleeding, and should inform patients and/or guardians of the importance of this follow-up. Drug Interactions None have been described. CYSTAGON® can be administered with electrolyte and mineral replacements necessary for management of the Fanconi Syndrome as well as vitamin D and thyroid hormone. Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Pregnancy Teratogenic Effects Pregnancy Category C Teratology studies have been performed in rats at oral doses in a range of 37.5 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 and fetotoxic. Observed teratogenic findings were cleft palate, Kyphosis, heart ventricular septal defects, microcephaly and exencephaly. There are no adequate and well-controlled studies in pregnant women. CYSTAGON® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether 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. Pediatric Use The safety and effectiveness of CYSTAGON® for cystinotic children have been established. Cysteamine therapy should be initiated as soon as the diagnosis of nephropathic cystinosis has been confirmed.
Adverse reactions
ADVERSE REACTIONS In three clinical trials, cysteamine or phosphocysteamine have been administered to 246 children with cystinosis. Causality of side effects is sometimes difficult to determine because adverse effects may result from the underlying disease. The most frequent adverse reactions seen involve the gastrointestinal and central nervous systems. These are especially prominent at the initiation of cysteamine therapy. Temporarily suspending treatment, then gradual re-introduction may be effective in improving tolerance. Adverse reactions were not collected systematically in the NCCS, but were often listed by investigators. The following rates may therefore be underestimated. The most common events (> 5%) were vomiting 35%, anorexia 31%, fever 22%, diarrhea 16%, lethargy 11%, and rash 7%. Less common adverse events are: Body as a whole: Dehydration. Cardiovascular: Hypertension. Digestive: Nausea, bad breath, abdominal pain, dyspepsia, constipation, gastroenteritis, duodenitis, gastrointestinal ulceration and bleeding. Central Nervous System: Somnolence, encephalopathy, headache, seizures, ataxia, confusion, tremor, hyperkinesia, decreasing hearing, dizziness, jitteriness. Psychiatric: Nervousness, abnormal thinking, depression, emotional lability, hallucinations, nightmares. Integumentary: Urticaria. Urogenital: Interstitial nephritis, renal failure (see WARNINGS). Clinical Laboratory: Abnormal liver function, anemia, leukopenia. Adverse reactions or intolerance leading to cessation of treatment occurred in 8% of patients in the U.S. Studies. Withdrawals due to intolerance, vomiting associated with medication, anorexia, lethargy, and fever appeared dose related, occurring more frequently in those patients receiving 1.95 grams/m2/day as compared to 1.30 grams/m2/day. Dose in Grams/m2/day 1.30 (n = 42) % 1.95 (n = 51) % Vomiting Considered Related to Medicine 31 67 Anorexia 33 51 Lethargy 17 27 Diarrhea 31 31 Fever 28 45 Sudden deaths have been reported in this disease state. Post-marketing surveillance Benign intracranial hypertension (or pseudotumor cerebri; PTC) with papilledema; skin lesions, molluscoid pseudotumors, skin striae, skin fragility; joint hyperextension, leg pain, genu valgum, osteopenia, compression fracture and scoliosis have been reported (see PRECAUTIONS).

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION For the management of nephropathic cystinosis, cysteamine therapy should be initiated promptly once the diagnosis is confirmed (i.e., increased white cell cystine). New patients should be started on ¼ to 1/6 of the maintenance dose of CYSTAGON®. The dose should then be raised gradually over four to six weeks to avoid intolerance. The recommended CYSTAGON® maintenance dose for children up to age 12 years is 1.30 grams/m2/day of the free base, given in four divided doses. Intact CYSTAGON® capsules should not be administered to children under the age of approximately six years due to the risk of aspiration. CYSTAGON® capsules may be administered to children under the age of approximately six years by sprinkling the capsule contents over food. Patients over age 12 and over 110 pounds weight should receive 2.0 grams/day, divided four times daily. If a dose is missed, it should be taken as soon as possible. If it is within two hours of the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double dose. When CYSTAGON® is well tolerated, the goal of therapy is to keep leukocyte cystine levels below 1 nmol/½ cystine/mg protein five to six hours following administration of CYSTAGON®. Patients with poorer tolerability still receive significant benefit if white cell cystine levels are below 2 nmol/½ cystine/mg protein. The CYSTAGON® dose can be increased to a maximum of 1.95 grams/m2/day to achieve this level. The dose of 1.95 grams/m2/day has been associated with an increased rate of withdrawal from treatment due to intolerance and an increased incidence of adverse events. Cystinotic patients taking cysteamine hydrochloride or phosphocysteamine solutions may be transferred to equimolar doses of CYSTAGON® capsules. The recommended maintenance dose of 1.30 grams/m2/day can be approximated by administering CYSTAGON® according to the following table, which takes surface area as well as weight into consideration. Weight in Pounds mg of Cysteamine Free Base Every 6 Hours 0–10 100 11–20 150 21–30 200 31–40 250 41–50 300 51–70 350 71–90 400 91–110 450 > 110 500 Patients over age 12 and over 110 pounds should receive 2.0 grams/day given in four divided doses as a starting maintenance dose. This dose should be reached after 4 to 6 weeks of incremental dosage increases as stated above. The dose should be raised if the leukocyte cystine level remains > 2 nmol/½ cystine/mg/protein. Leukocyte cystine measurements, taken 5 to 6 hours after dose administration, are recommended for new patients after the maintenance dose is achieved. Patients being transferred from cysteamine hydrochloride or phosphocysteamine solutions to capsules should have their white cell cystine levels measured in 2 weeks, and thereafter every 3 months to assess optimal dosage as described above. If CYSTAGON® is poorly tolerated initially due to gastrointestinal tract symptoms or transient skin rashes, therapy should be temporarily stopped, then re-instituted at a lower dose and gradually increased to the proper dose.
Pregnancy and lactation
Nursing Mothers It is not known whether 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.

Interactions

Drug Interactions None have been described. CYSTAGON® can be administered with electrolyte and mineral replacements necessary for management of the Fanconi Syndrome as well as vitamin D and thyroid hormone.

More information

Category Value
Authorisation number NDA020392
Agency product number QO84GZ3TST
Orphan designation No
Product NDC 0378-9045,0378-9040
Date First Approved 15-08-1994
Date Last Revised 19-09-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 209788
Marketing authorisation holder Mylan Pharmaceuticals Inc.