Cystagon Drug Information
Generic name: CYSTEAMINE BITARTRATE
Uses of Cystagon
CYSTAGON ® is indicated for the management of nephropathic cystinosis in children and adults.
Dosage & Administration of Cystagon
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/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/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/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. 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.
| 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 |
Side Effects of Cystagon
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. 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. 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 ).
| 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 |
Warnings & Cautions for Cystagon
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.
Drug Interactions with Cystagon
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.
Pregnancy Safety for Cystagon
Pregnancy 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.
Pediatric Use of Cystagon
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.
Contraindications for Cystagon
CYSTAGON ® is contraindicated in patients who have developed hypersensitivity to it or to cysteamine or penicillamine.
Overdosage Information for Cystagon
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.
Clinical Studies of Cystagon
Clinical Studies There are approximately 200 pre-transplant cystinosis patients in the United States with nephropathic cystinosis and clinical studies have included almost all of them, in addition to about 40 studied in the United Kingdom. For all patients, mean age at entry into studies was just under 4 years. Patients were approximately equally divided between genders and about 85% were white, 9% were black, and 3% were hispanic.
The National Collaborative Cysteamine Study (NCCS) treated 94 children (mainly from the United States) with nephropathic cystinosis with increasing doses of cysteamine HCl (mean dose 54 mg/kg/day) to attain white cell cystine levels of less than 2 nmol/½ cystine/mg protein 5 to 6 hours post-dose, and compared their outcome with an historical control group of 17 children who had been in the placebo group of a randomized placebo-controlled trial of ascorbic acid. Cysteamine treated patients had been diagnosed at a mean age of 22 months and were a mean age of 46 months old at study entry; placebo patients had been diagnosed at about 29 months and were a mean age of about 52 months old at study entry. The principal measures of effectiveness were serum creatinine and calculated creatinine clearance and growth (height).
The average median white cell cystine level attained during treatment in the NCCS was 1.7 ± 0.2 nmol/½ cystine/mg protein. There were 70 cysteamine patients with baseline serum creatinine less than 2 mg/dL who were followed for at least a year and 17 placebo patients. Twelve of the 94 cysteamine treated patients required early dialysis or renal transplant.
Median follow-up of cysteamine patients was over 32 months and 20% were followed more than 5 years. For the placebo group median follow-up was 20 months and only one was followed more than 24 months. Among cysteamine patients glomerular function was maintained over time despite the longer period of treatment and follow-up.
Placebo treated patients, in contrast, experienced a gradual rise in serum creatinine. Height, corrected for age, was compared for treated patients with the height, at the various ages patients appeared, of the 143 patients initially screened for inclusion in the NCCS. Patients on treatment maintained growth (did not show increasing growth failure compared to normals) although growth velocity did not increase enough to allow patients to catch up to age norms.
Renal tubular function was not affected by treatment. Calculated creatinine clearances were evaluated for two groups of children, one with poor white cell cystine depletion and one with good white cell cystine depletion as shown in Table I. The final mean creatinine clearance of the good depletion group was 20.8 ml/min/1.73 m 2 greater than the mean for the poor depletion group, despite the older mean age of the good depletion group.
TABLE 1: CREATININE CLEARANCE CHANGES BY WHITE CELL CYSTINE DEPLETION The Long Term Study, initiated in 1988, utilized both cysteamine HCl and phosphocysteamine (patient’s choice) in 46 patients who had completed the NCCS (averaging 6.5 years of treatment) and 93 new patients. Patients had cystinosis diagnosed by elevated white cell cystine (mean 3.63 nmol/½ cystine/mg). New patients and 46 continuing patients were required to have serum creatinine less than 3.0 mg/dL and 4.0 mg/dL, respectively.
Doses could be raised if white cell cystine levels were approximately 2 nmol/½ cystine/mg protein and lowered due to intolerance. In new patients, a group similar in age to the NCCS group, serum creatinine was essentially unchanged over the period of follow-up (about half of the patients were followed for 24 months) and phosphocysteamine and cysteamine HCl had similar effects. The long-term follow-up group, about nine years old on average at entry, stayed in the study (almost 80% were followed at least 2 years) and had essentially no change in renal function.
In four studies of untreated cystinosis, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Both groups maintained height (although they did not catch up from baseline). There was no apparent difference between the two doses.
| Age (years) | Creatinine Clearance (ml/min/1.73m 2 ) | |||
|---|---|---|---|---|
| Initial | Final | Initial | Final | |
| (95% confidence limits on difference between final creatinine clearances, 6.1 and 35.5 ml/min/1.73m 2, despite older mean age of good depletion group.) | ||||
| Poor Depletion Median leukocyte cystine levels were over 3 nmol/½ cystine/mg protein or were not measured at least 2 times per year. Patients did receive cysteamine for at least 1 year. (n = 18) | 4.2 ± 1.8 | 6.5 ± 0.5 | 33.6 ± 17.0 | 29.7 ± 5.4 |
| Good Depletion Median leukocyte cystine levels were less than 1 nmol/½ cystine/mg protein and received cysteamine for at least 1 year. (n = 19) | 3.3 ± 2.2 | 7.2 ± 0.7 | 44.3 ± 15.0 | 50.5 ± 5.1 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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