ADVERSE REACTIONS SECTION.

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) ]. Hypermethioninemia and cerebral edema in patients with CBS deficiency see Warnings and Precautions 5.1) ]. Most common adverse reactions (> 2%) are: nausea and gastrointestinal distress, based on physician survey 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION.Revised 10/2019. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of 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 survey study of 41 physicians, who treated 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 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 SurveyAdverse ReactionsNumber of PatientsNausea2Gastrointestinal distress2Diarrhea1Bad Taste1Caused Odor1Questionable psychological changes1Aspirated the powder1. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of CYSTADANE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Severe cerebral edema and hypermethioninemia have been reported within weeks to 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 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.

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. Betaine 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. CYSTADANE was studied in double-blind, placebo-controlled, crossover study in patients (3 males and females) with CBS deficiency, ages to 32 years at enrollment. CYSTADANE was administered at dosage of grams twice daily, for 12 months. Plasma homocystine concentrations were significantly reduced (p<0.01) compared to placebo. Plasma methionine concentrations were variable and not significantly different compared to placebo.CYSTADANE has also been evaluated in observational studies without concurrent controls in patients with homocystinuria due to CBS deficiency, MTHFR deficiency, or cbl defect. 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 been used to evaluate the effect of CYSTADANE in patients with homocystinuria. Plasma homocystine or homocysteine concentrations were reported numerically for 62 patients, and 61 of these patients showed decreases with CYSTADANE treatment. Homocystine decreased by 83 to 88% regardless of the pre-treatment concentration, and homocysteine decreased by 71 to 83%, regardless of the pre-treatment concentration. 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 concentrations.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adults and Pediatric Patients Years of Age and OlderThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily. 2.1) Pediatric Patients Less than Years of AgeThe recommended starting dosage is 100 mg/kg/day, administered orally in divided doses of 50 mg/kg twice daily, and then increased weekly by 50 mg/kg increments. 2.1) Monitor patient response by plasma homocysteine concentrations. 2.1) Increase the dosage gradually until the plasma total homocysteine concentration is undetectable or present only in small amounts. 2.1) Preparation and Adminstration InstructionsPrescribed amount of CYSTADANE should be measured with the measuring scoop provided and then dissolved in to ounces of water, juice, milk, or formula until completely dissolved, or mixed with food for immediate ingestion. 2.2) The recommended dosage is grams per day, administered orally in divided doses of grams twice daily. 2.1) The recommended starting dosage is 100 mg/kg/day, administered orally in divided doses of 50 mg/kg twice daily, and then increased weekly by 50 mg/kg increments. 2.1) Monitor patient response by plasma homocysteine concentrations. 2.1) Increase the dosage gradually until the plasma total homocysteine concentration is undetectable or present only in small amounts. 2.1) Prescribed amount of CYSTADANE should be measured with the measuring scoop provided and then dissolved in to ounces of water, juice, milk, or formula until completely dissolved, or mixed with food for immediate ingestion. 2.2) 2.1 Dosage. Therapy with CYSTADANE should be directed by physicians knowledgeable in the management of patients with homocystinuria.Adults and Pediatric Patients Years of Age and OlderThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily.Pediatric Patients Less than Years of AgeThe recommended starting dosage is 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments.MonitoringMonitor 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 month.Monitor plasma methionine concentrations in patients with CBS deficiency [See Warnings and Precautions 5.1)]. Maximum DosageDosages 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 twice-daily dosing schedule and 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 patients dose with the scoop provided. 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 the bottle from moisture.. Shake bottle lightly before removing cap.. Measure the number of scoops for the patients dose with the scoop provided. 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 the bottle from moisture.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. CYSTADANE (R) 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) 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. CYSTADANE is methylating agent indicated in pediatric and adult patients for the treatment of homocystinuria to decrease elevated homocysteine blood concentrations. 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. Preparation and Administration InstructionsInstruct patients and caregivers to administer CYSTADANE as follows:Shake bottle lightly before removing cap.Measure the number of scoops for the patients dose with the scoop provided. 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 bottle from moisture.. Shake bottle lightly before removing cap.. Measure the number of scoops for the patients dose with the scoop provided. 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 bottle 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 (R) is 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. RECORDATI RARE DISEASES logo. CYSTADANE(R) betaine anhydrous for oral solution logo.

SPL UNCLASSIFIED SECTION.

2.1 Dosage. Therapy with CYSTADANE should be directed by physicians knowledgeable in the management of patients with homocystinuria.Adults and Pediatric Patients Years of Age and OlderThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily.Pediatric Patients Less than Years of AgeThe recommended starting dosage is 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments.MonitoringMonitor 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 month.Monitor plasma methionine concentrations in patients with CBS deficiency [See Warnings and Precautions 5.1)]. Maximum DosageDosages 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 twice-daily dosing schedule and 150 mg/kg/day dosage for CYSTADANE.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from 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 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 to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryThere 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 mothers 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 years of age may benefit from dose titration [see Dosage and Administration 2.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypermethioninemia in Patients with CBS Deficiency:CYSTADANE may worsen elevated plasma methionine concentrations and cerebral edema has been reported. Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 micromol/L through dietary modification and, if necessary, reduction of CYSTADANE dosage. 5.1) Hypermethioninemia in Patients with CBS Deficiency:. 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, reduction of CYSTADANE dosage.