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.

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.

6.1 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):

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.

8.1 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)].

12.1 Mechanism of Action

CYSTADANE acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Betaine 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.

12.2 Pharmacodynamics

CYSTADANE was observed to lower plasma homocysteine concentrations 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 Betaine concentrations and homocysteine concentrations.

In CBS-deficient patients, large increases in methionine concentrations over baseline have been observed. CYSTADANE has also been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) concentrations in patients with MTHFR deficiency and cbl defect.

12.3 Pharmacokinetics

Pharmacokinetic studies of CYSTADANE are not available. Plasma betaine concentrations following adminstration of CYSTADANE have not been measured in patients and have not been correlated to homocysteine concentrations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Storage

Store at room temperature, 15 to 30 ˚C (59 to 86 ˚F). Protect from moisture.

Supplied by:

Recordati Rare Diseases

Puteaux, France

Licensed to and Distributed by:

Recordati Rare Diseases Inc.

Lebanon, NJ 08833 U.S.A.

For drug or ordering information please call AnovoRx Group, LLC, Customer service at 1-888-487-4703.

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.: Recordati Rare Diseases, OEP1000 V2