The following Structured Product Label (SPL) was submitted to the FDA by Recordati Rare Diseases for the product Cystadane (NDC 52276-400). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 dosage, 2.2 administration, 3 dosage forms and strengths, 4 contraindications, 5.1 hypermethioninemia, 6.1 adverse reactions in clinical studies, 6.2 postmarketing experience, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Cystadane® (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within the category of homocystinuria are:
The usual dosage in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 grams twice daily. In pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments. Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria. Patient response to Cystadane can be monitored by homocysteine plasma levels. Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts.Response (by homocysteine plasma levels) usually occurs within several days and steady state within a month.Plasma methionine concentrations should be monitored in patients with CBS deficiency [See Warnings and Precautions (5.1)].
Dosages of up to 20 grams per day have been necessary to control homocysteine levels in some patients. However, one pharmacokinetic and pharmacodynamic in vitro simulation study indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg/kg/day dosage for Cystadane.
The prescribed amount of Cystadane should be measured with the measuring scoop provided (one level 1.7 mL scoop is equal to 1 gram of betaine anhydrous powder) and then dissolved in 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula, or mixed with food for immediate ingestion.
Cystadane is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams of betaine anhydrous.
None.
Risk of Hypermethioninemia in Patients with CBS Deficiency
Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with Cystadane may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasma methionine concentrations should be kept below 1,000 µmol/L through dietary modification and, if necessary, a reduction of Cystadane dose.
The most serious adverse reaction reported with Cystadane treatment is the development of hypermethioninemia and cerebral edema in patients with CBS Deficiency [see Warnings and Precautions (5.1)].
The assessment of clinical adverse reactions is based on a survey study of 41 physicians, who treated a total of 111 homocystinuria patients with Cystadane. Adverse reactions were retrospectively recalled and were not collected systematically in this open-label, uncontrolled, physician survey. Thus, this list may not encompass all types of potential adverse reactions, reliably estimate their frequency, or establish a causal relationship to drug exposure.The following adverse reactions were reported (Table 1):
| Adverse Reactions | Number of Patients |
|---|---|
Nausea | 2 |
Gastrointestinal distress | 2 |
Diarrhea | 1 |
"Bad Taste" | 1 |
"Caused Odor" | 1 |
Questionable psychological changes | 1 |
“Aspirated the powder” | 1 |
The following adverse reactions have been identified during post approval use of Cystadane. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In postmarketing experience with Cystadane, severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting betaine therapy, with complete recovery after discontinuation of Cystadane. All patients who developed cerebral edema had homocystinuria due to CBS deficiency and had severe elevation in plasma methionine levels (range 1,000 to 3,000 µM). As cerebral edema has also been reported in patients with hypermethioninemia, secondary hypermethioninemia due to betaine therapy has been postulated as a possible mechanism of action.
The following adverse reactions have been reported in patients during postmarketing use of Cystadane: anorexia, agitation, depression, irritability, personality disorder, sleep disturbed, dental disorders, diarrhea, glossitis, nausea, stomach discomfort, vomiting, hair loss, hives, skin odor abnormalities, and urinary incontinence.
Pregnancy Category C: Animal reproduction studies have not been conducted with Cystadane. It is also not known whether Cystadane can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystadane should be given to a pregnant woman only if clearly needed.
It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.
The majority of case studies of homocystinuria patients treated with Cystadane have been pediatric patients, including patients ranging in age from 24 days to 17 years [see Clinical Studies (14)]. Children younger than 3 years of age may benefit from dose titration [see Dosage and Administration (2)].
In an acute toxicology study in rats, death occurred frequently at doses equal to or greater than 10 g/kg.
Cystadane (betaine anhydrous for oral solution) is an agent for the treatment of homocystinuria. It contains no ingredients other than anhydrous betaine. Cystadane is a white, granular, hygroscopic powder, which is diluted in water and administered orally. The chemical name of betaine anhydrous powder is trimethylglycine. It has a molecular weight of 117.15. The structural formula is:
Betaine Anhydrous Structural Formula (Image 01)
Cystadane acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Cystadane occurs naturally in the body. It is a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals, and seafood.
Cystadane was observed to lower plasma homocysteine levels in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect. Patients have taken Cystadane for many years without evidence of tolerance. There has been no demonstrated correlation between Cystadane levels and homocysteine levels.
In CBS-deficient patients, large increases in methionine levels over baseline have been observed. Cystadane has also been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) levels in patients with MTHFR deficiency and cbl defect.
Pharmacokinetic studies of Cystadane are not available. Plasma levels of Cystadane have not been measured in patients and have not been correlated to homocysteine levels.
Long-term carcinogenicity and fertility studies have not been conducted with Cystadane. No evidence of genotoxicity was demonstrated in the following tests: metaphase analysis of human lymphocytes; bacterial reverse mutation assay; and mouse micronucleus test.
Cystadane was studied in a double-blind, placebo-controlled, crossover study in 6 patients with CBS deficiency, ages 7 to 32 years at enrollment. Cystadane was administered at a dosage of 3 grams twice daily, for 12 months. Plasma homocystine levels were significantly reduced (p<0.01) compared to placebo. Plasma methionine levels were variable and not significantly different compared to placebo.
No adverse events were reported in any patient.
Cystadane has also been evaluated in observational studies without concurrent controls in patients with homocystinuria due to CBS deficiency, MTHFR deficiency, or cbl defect.A review of 16 case studies and the randomized controlled trial previously described was also conducted, and the data available for each study were summarized; however, no formal statistical analyses were performed. The studies included a total of 78 male and female patients with homocystinuria who were treated with Cystadane. This included 48 patients with CBS deficiency, 13 with MTHFR deficiency, and 11 with cbl defect, ranging in age from 24 days to 53 years. The majority of patients (n=48) received 6 gm/day, 3 patients received less than 6 gm/day, 12 patients received doses from 6 to 15 gm/day, and 5 patients received doses over 15 gm/day. Most patients were treated for more than 3 months (n=57) and 30 patients were treated for 1 year or longer (range 1 month to 11 years). Homocystine is formed nonenzymatically from two molecules of homocysteine, and both have been used to evaluate the effect of Cystadane in patients with homocystinuria. Plasma homocystine or homocysteine levels were reported numerically for 62 patients, and 61 of these patients showed decreases with Cystadane treatment. Homocystine decreased by 83-88% regardless of pre-treatment level, and homocysteine decreased by 71-83%, regardless of the pre-treatment level. Clinical improvement, such as improvement in seizures, or behavioral and cognitive functioning, was reported by the treating physicians in about three-fourths of patients. Many of these patients were also taking other therapies such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), and folate with variable biochemical responses. In most cases, adding Cystadane resulted in a further reduction of either homocystine or homocysteine.
Cystadane is available in plastic bottles containing 180 grams of betaine anhydrous. Each bottle is equipped with a plastic child-resistant cap and is supplied with a polystyrene measuring scoop. One level scoop (1.7 mL) is equal to 1 gram of betaine anhydrous powder.
NDC 52276-400-01 180 g/bottle
Store at room temperature, 15 – 30 ˚C (59 – 86 ˚F). Protect from moisture.
Patients should be advised of the following information before beginning treatment with Cystadane:
Supplied by:
Orphan Europe SARL
Puteaux, France
Licensed to and Distributed by:
Recordati Rare Diseases Inc.
Lebanon, NJ 08833 U.S.A.
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For drug or ordering information please call AnovoRx Group, LLC, Customer service at 1-888-487-4703.
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Cystadane® is a licensed trademark of Recordati Rare Diseases Inc.
This product label may have been updated. For the most recent prescribing information, please visit www.recordatirarediseases.com.
Part No.: Orphan Europe OEP1000
Cystadane (betaine Anhydrous) For Oral Solution Label (Image 05)
NDC 52276-400-01
CYSTADANE®
betaine anhydrous for oral solution
1 gram of betaine anhydrous powder per scoopful
180 grams
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