Cystadane

CYSTADANE- betaine powder, for solution
Recordati Rare Diseases

1 INDICATIONS AND USAGE

CYSTADANE ® is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood concentrations in pediatric and adult patients. Included within the category of homocystinuria are:

  • Cystathionine beta-synthase (CBS) deficiency
  • 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
  • Cobalamin cofactor metabolism (cbl) defect

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

Therapy with CYSTADANE should be directed by physicians knowledgeable in the management of patients with homocystinuria.

Adults and Pediatric Patients 3 Years of Age and Older

The recommended dosage is 6 grams per day, administered orally in divided doses of 3 grams twice daily.

Pediatric Patients Less than 3 Years of Age

The recommended starting dosage is 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments.

Monitoring

Monitor patient response to CYSTADANE by homocysteine plasma concnetration. Increase the dosage in all patients gradually until the plasma total homocysteine concentration is undetectable or present only in small amounts. An initial response in homocysteine plasma concentrations usually occurs within several days and steady state plasma concentrations occur within a month.

Monitor plasma methionine concentrations in patients with CBS deficiency [See Warnings and Precautions ( 5.1)].

Maximum Dosage

Dosages of up to 20 grams/day have been necessary to control homocysteine concentrations 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.

2.2 Prepartion and Administration Instructions

  • Shake bottle lightly before removing cap.
  • Measure the number of scoops for the patient’s dose with the scoop provided. One level scoop (1.7 mL) is equivalent to 1 gram of betaine anhydrous powder.
  • Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.
  • Always replace the cap tightly after using and protect the bottle from moisture.

3 DOSAGE FORMS AND STRENGTHS

CYSTADANE is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams of betaine anhydrous.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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 [ see Adverse Reactions ( 6.2) ]. Monitor plasma methionine concentrations in patients with CBS deficiency. Plasma methionine concentrations should be kept below 1,000 micromol/L through dietary modification and, if necessary, a reduction of CYSTADANE dosage.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in labeling:

  • Hypermethioninemia and cerebral edema in patients with CBS deficiency [ see Warnings and Precautions ( 5.1) ].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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):

Table 1: Number of Patients with Adverse Reactions to CYSTADANE by Physician Survey
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

6.2 Postmarketing Experience

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.

Severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting CYSTADANE 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 concentrations (range 1,000 to 3,000 microM). 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 [ see Warnings and Precautions ( 5.1) ].

Other adverse reactions include: 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from a limited number of published case reports and postmarketing experience with CYSTADANE use in pregnancy have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with betaine.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of betaine in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CYSTADANE and any potential adverse effects on the breastfed child from CYSTADANE or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of CYSTADANE have been established in pediatric patients. 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 ( 2.1)].

10 OVERDOSAGE

There is no information on CYSTADANE overdose in humans. In an acute toxicology study in rats, death occurred frequently at doses equal to or greater than 10 g/kg.

11 DESCRIPTION

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 formulaBetaine anhydrous structural formula
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