Betaine Anhydrous

1. INDICATIONS AND USAGE Betaine Anhydrous for Oral Solution 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 Betaine Anhydrous for Oral Solution is a 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:
• Cystathionine beta-synthase (CBS) deficiency
• 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
• Cobalamin cofactor metabolism (cbl) defect

3. DOSAGE FORMS AND STRENGTHS Betaine Anhydrous for Oral Solution is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams of betaine anhydrous. For oral solution: in bottles containing 180 grams of betaine anhydrous.

4. CONTRAINDICATIONS None. 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 Betaine Anhydrous for Oral Solution 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 Betaine Anhydrous for Oral Solution [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 Betaine Anhydrous for Oral Solution dosage. Hypermethioninemia in Patients with CBS Deficiency: Betaine Anhydrous for Oral Solution 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, a reduction of Betaine Anhydrous for Oral Solution dosage. (5.1)

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)] . Most common adverse reactions (> 2%) are: nausea and gastrointestinal distress, based on physician survey (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . See 17 for PATIENT COUNSELING INFORMATION.

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 Betaine Anhydrous for Oral Solution. 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 Betaine Anhydrous for Oral Solution by Physician Survey Adverse Reactions Number of Patients Nausea 2 Gastrointestinal distress 2 Diarrhea 1 "Bad Taste" 1 "Caused Odor" 1 Questionable pyschological 1 "Aspirated the powder" 1

6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of Betaine Anhydrous for Oral Solution. 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 Betaine Anhydrous for Oral Solution therapy, with complete recovery after discontinuation of Betaine Anhydrous for Oral Solution. 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 post-marketing experience with Betaine Anhydrous for Oral Solution 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 Betaine Anhydrous for Oral Solution and any potential adverse effects on the breastfed child from Betaine Anhydrous for Oral Solution or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of Betaine Anhydrous for Oral Solution have been established in pediatric patients. The majority of case studies of homocystinuria patients treated with Betaine Anhydrous for Oral Solution 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) ].