Cystagon

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

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 1⁄4 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/m 2 /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/1⁄2 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/1⁄2 cystine/mg protein. The CYSTAGON ® dose can be increased to a maximum of 1.95 grams/m 2 /day to achieve this level. The dose of 1.95 grams/m 2 /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/m 2 /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/1⁄2 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.

CONTRAINDICATIONS CYSTAGON ® is contraindicated in patients who have developed hypersensitivity to it or to cysteamine or penicillamine.

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/m 2 /day as compared to 1.30 grams/m 2 /day. Dose in Grams/m 2 /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 ).

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.

Mechanism of Action Cystinosis is an autosomal recessive inborn error of metabolism in which the transport of cystine out of lysosomes is abnormal; in the nephropathic form, accumulation of cystine and formation of crystals damage various organs, especially the kidney, leading to renal tubular Fanconi Syndrome and progressive glomerular failure, with end stage renal failure by the end of the first decade of life. In four studies of cystinosis patients before cysteamine was available, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Patients with cystinosis also experience growth failure, rickets, and photophobia due to cystine deposits in the cornea. With time most organs are damaged, including the retina, muscles and central nervous system. Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.

DESCRIPTION CYSTAGON ® (cysteamine bitartrate) Capsules for oral administration, contain cysteamine bitartrate, a cystine depleting agent which lowers the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport. CYSTAGON ® is the bitartrate salt of cysteamine, an aminothiol, beta-mercaptoethylamine. Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227 and the molecular formula C 2 H 7 NS • C 4 H 6 O 6 . It has the following chemical structure: Each CYSTAGON ® Capsule contains 50 mg or 150 mg of cysteamine free base as cysteamine bitartrate. CYSTAGON ® Capsules contain the following inactive ingredients: ammonium hydroxide, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, microcrystalline cellulose, pharmaceutical glaze, pregelatinized starch, propylene glycol, sodium lauryl sulfate and titanium dioxide. Cysteamine Bitartrate Structural Formula

OVERDOSAGE A single oral dose of cysteamine at 660 mg/kg was lethal to rats. Symptoms of acute toxicity were reduction of motor activity and generalized hemorrhage in gastrointestinal tract and kidneys. Two cases of human overdosage have been reported. In one case, the patient immediately vomited the drug and did not develop any symptoms. The second incident involved an accidental ingestion of a 200 to 250 mg/kg dose by a healthy 13 month old child. Vomiting and dehydration were experienced. The child was hospitalized and fluids were administered. A full recovery was made. Should overdose occur, the respiratory and cardiovascular systems should be supported appropriately. No specific antidote is known. Hemodialysis may be considered since cysteamine is poorly bound to plasma proteins.

HOW SUPPLIED CYSTAGON ® (cysteamine bitartrate) Capsules are hard gelatin capsules which provide 50 mg or 150 mg of cysteamine free base as cysteamine bitartrate: CYSTAGON ® Capsules, 50 mg are white, opaque capsules printed with CYSTA 50 on the body and MYLAN on the cap. They are available as follows: NDC 0378-9040-05 bottles of 500 capsules CYSTAGON ® Capsules, 150 mg are white, opaque capsules printed with CYSTAGON 150 on the body and MYLAN on the cap. They are available as follows: NDC 0378-9045-05 bottles of 500 capsules Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient. The following information is available for patients and/or guardians in the patient leaflet.