USE IN SPECIFIC POPULATIONS SECTION.

Pregnancy: Animal reproduction studies have not been conducted with Cystadane. Use only if clearly needed.(8.1) Nursing women: It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.(8.3)Pediatrics: Pediatric patients ranging in age from 24 days to 17 years have been treated with Cystadane. Children younger than years of age may benefit from dose titration.. Pregnancy: Animal reproduction studies have not been conducted with Cystadane. Use only if clearly needed.(8.1) Nursing women: It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.(8.3). Pediatrics: Pediatric patients ranging in age from 24 days to 17 years have been treated with Cystadane. Children younger than years of age may benefit from dose titration.

WARNINGS AND PRECAUTIONS SECTION.

Hypermethioninemia: Cystadane may worsen elevated plasma methionine concentrations in patients with CBS deficiency. Cerebral edema has been reported in patients receiving Cystadane.( 5.1) Monitoring: Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 umol/L through dietary medication and, if necessary, reduction of Cystadane dose. 5.1). Hypermethioninemia: Cystadane may worsen elevated plasma methionine concentrations in patients with CBS deficiency. Cerebral edema has been reported in patients receiving Cystadane.( 5.1) Monitoring: Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 umol/L through dietary medication and, if necessary, reduction of Cystadane dose. 5.1).

ADVERSE REACTIONS SECTION.

Most common adverse reactions (incidence 2%) were nausea and gastrointestinal distress, based on physician survey. To report SUSPECTED ADVERSE REACTIONS, contact 877-828-8874, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions (incidence 2%) were nausea and gastrointestinal distress, based on physician survey. To report SUSPECTED ADVERSE REACTIONS, contact 877-828-8874, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cystadane acts as methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Cystadane occurs naturally in the body. It is 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Cystadane was studied in double-blind, placebo-controlled, crossover study in patients with CBS deficiency, ages to 32 years at enrollment. Cystadane was administered at dosage of 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 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 gm/day, patients received less than gm/day, 12 patients received doses from to 15 gm/day, and patients received doses over 15 gm/day. Most patients were treated for more than months (n=57) and 30 patients were treated for year or longer (range month to 11 years). Homocystine is formed nonenzymatically from two molecules of homocysteine, and both have be 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 further reduction of either homocystine or homocysteine.

DESCRIPTION SECTION.

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 white, granular, hygroscopic powder, which is diluted in water and administered orally. The chemical name of betaine anhydrous powder is trimethylglycine. It has molecular weight of 117.15. The structural formula is:. Chemical Structure for Betaine.

DOSAGE & ADMINISTRATION SECTION.

Usual dose in adult and pediatric patients is grams per day, administered orally in divided doses of grams two times day.(2)In children less than years of age, may initiate dosing at 100 mg/kg/day, divided in twice daily doses, and then increased weekly by 50 mg/kg increments.(2)Dose can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts.(2)Monitor patient response by plasma homocysteine levels.(2)Prescribed amount of Cystadane should be measured with the measuring scoop provided and then dissolved in to ounces of water, juice, milk, or formula, or mixed with food for immediate ingestion.(2) Usual dose in adult and pediatric patients is grams per day, administered orally in divided doses of grams two times day.(2). In children less than years of age, may initiate dosing at 100 mg/kg/day, divided in twice daily doses, and then increased weekly by 50 mg/kg increments.(2). Dose can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts.(2). Monitor patient response by plasma homocysteine levels.(2). Prescribed amount of Cystadane should be measured with the measuring scoop provided and then dissolved in to ounces of water, juice, milk, or formula, or mixed with food for immediate ingestion.(2).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Cystadane is available in plastic bottles containing 180 grams of betaine anhydrous. Each bottle is equipped with plastic child-resistant cap and is supplied with polystyrene measuring scoop. One level scoop (1.7 mL) is equal to gram of betaine anhydrous powder.NDC 66621-4000-1 180 g/bottleCystadane can be ordered by calling AnovoRx Group, LLC, Customer service at 1-888-487-4703. 16.1 Storage. Store at room temperature, 15 30 (59 86 F). Protect from moisture.

INDICATIONS & USAGE SECTION.

Cystadane is methylating agent indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within the category of homocystinuria are (1): Cystathionine beta-synthase (CBS) deficiency5,10-methylenetetrahydrofolate reductase (MTHFR) deficiencyCobalamin cofactor metabolism (cbl) defect Cystathionine beta-synthase (CBS) deficiency. 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. Cobalamin cofactor metabolism (cbl) defect.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients should be advised of the following information before beginning treatment with Cystadane:. 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 gram of betaine anhydrous powder. Mix powder with to 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 37067Under License From:Orphan Europe, s.a.r.l. Puteaux France Distributed By:AnovoRx Distribution, LLCMemphis, TN 38134 Part No.: RDT PI007Part No.: Orphan Europe OEP 829 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.