2.1 Dosage

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.

2.2 Administration

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.

5.1 Hypermethioninemia

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.

6.1 Adverse Reactions in Clinical Studies

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):

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

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.

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.

8.1    Pregnancy

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.

8.3    Nursing Mothers

It is not known whether Cystadane is excreted in human milk.  Use only if clearly needed.

8.4    Pediatric Use

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)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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.

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.

16.1    Storage

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

17.1    Dosing and Administration

• Instruct patients and caregivers that Cystadane should only be taken as directed by their healthcare professional.
• Instruct patients and caregivers to administer Cystadane as follows:
• Shake bottle lightly before removing cap.

- Measure with the scoop provided.

- Measure the number of scoops as prescribed by their healthcare professional. 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 powder from moisture.

Manufactured For:
Rare Disease Therapeutics, Inc.
Franklin, TN 37067

Under License From:
Orphan Europe, s.a.r.l. Puteaux France

Distributed By:
AnovoRx Distribution, LLC
Memphis, TN 38134

Part No.:    RDT C PI007
Part No.: Orphan Europe OEP 829