Betaine Anhydrous

BETAINE ANHYDROUS — betaine for solution
Novitium Pharma LLC

1 INDICATIONS & 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

2 DOSAGE & ADMINISTRATION

2.1 Dosage

Therapy with Betaine Anhydrous for Oral Solution 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 Betaine Anhydrous for Oral Solution by homocysteine plasma concentration. 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 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 a twice-daily dosing schedule and a 150 mg/kg/day dosage for Betaine Anhydrous for Oral Solution.

2.2 Preparation 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 (1.9cc) 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.

3 DOSAGE FORMS & STRENGTHS

Betaine Anhydrous for Oral Solution is a white to off-white crystalline, hygroscopic powder for oral solution available in bottles containing 180 grams of betaine anhydrous.

4 CONTRAINDICATIONS

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.

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)].

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
“Bad Taste” 1
“Caused Odor” 1
Questionable psychological changes 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 6months of startingBetaine 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.

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