CYSTAGON Capsule Ref.[27453] Active ingredients: Mercaptamine

If a skin rash develops, CYSTAGON should be withheld until the rash clears. CYSTAGON may be restarted at a lower dose under close supervision, then slowly titrated to the therapeutic dose. If a severe skin rash develops such as erythema multiforme bullosa or toxic epidermal necrolysis, CYSTAGON should not be readministered.

CNS symptoms such as seizures, lethargy, somnolence, depression, and encephalopathy have been associated with cysteamine. If CNS symptoms develop, the patient should be carefully evaluated and the dose adjusted as necessary. Neurological complications have been described in some cystinotic patients not on cysteamine treatment. This may be a manifestation of the primary disorder. Patients should not engage in hazardous activities until the effects of CYSTAGON on mental performance are known.

Gastrointestinal ulceration and bleeding have been reported in patients receiving cysteamine bitartrate. Physicians should remain alert for signs of ulceration and bleeding and should inform patients and/or guardians about the signs and symptoms of serious G.I. toxicity and what steps to take if they occur.

Post-marketing reports include one report of interstitial nephritis with early renal failure. A causal relationship between this event and cysteamine bitartrate therapy has not been established.

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.

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).

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.

See attached information for patients and parents and/or guardians.

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.

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.

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.

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.

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.

CYSTAGON has not been associated with abuse potential, psychological or physical dependence in humans.