Betaine anhydrous is an orally administered methyl group donor for the treatment of patients with homocystinuria. Betaine is involved in the normal metabolic cycle of methionine. Dietary sources that supply small amounts of betaine include beets, spinach, cereals, and seafood. Betaine is also a metabolite of choline. In patients with homocystinuria due to an inborn error of metabolism, dietary sources and endogenous production supply insufficient amounts of betaine to control the greatly elevated plasma homocysteine concentrations. Care should be taken not to confuse betaine anhydrous with the betaine hydrochloride (HCl) salt form. Betaine HCl is available primarily as a dietary supplement but has been used clinically to lower gastric pH. Betaine anhydrous does not have the same effect on gastric pH and should not be used for this purpose. The FDA first approved the use of betaine anhydrous as a nutritional pharmaceutical for primary homocystinuria in October 1996.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Regular administration of betaine is required to maintain the effects of the drug; betaine effects will cease upon discontinuation of therapy.
-Shake bottle lightly before removing the cap.
-Measure the appropriate number of scoops for the prescribed dose with the scoop provided. One level scoop (1.7 mL) of powder equals 1 g of betaine anhydrous.
-Mix the dose with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved. Alternatively, mix the dose with food. Ingest immediately.
-Replace the cap tightly after use and protect the bottle from moisture.
Betaine appears to be well-tolerated. Adverse reaction data were reported based on a survey of physicians treating patients with homocystinuria (n = 111). The most common adverse reactions reported were nausea (> 2%), gastrointestinal distress (dyspepsia, > 2%), and diarrhea (0.9%). Adverse reactions reported with postmarketing use include anorexia, glossitis, abdominal pain, and vomiting.
Serious reactions to betaine are very rare. Cerebral edema has been reported, and may necessitate either dosage reduction or complete withdrawal of betaine therapy, along with typical treatment measures for cerebral edema.
Central nervous system adverse reactions that have been reported in patients with postmarketing use of betaine include: agitation, depression, irritability, and insomnia. Additionally, questionable psychological change (emotional lability) occurred as single case reports.
Drug-induced body odor was reported by 1 patient. Alopecia and urticaria were reported with postmarketing use of betaine.
Urinary incontinence was reported as a postmarketing adverse reaction of betaine.
Betaine would be contraindicated for use in those with known betaine hypersensitivity. However, reports of allergy to betaine anhydrous do not exist.
Pediatric patients (children and infants) are the primary treatment group for which there is experience with betaine therapy. These patients have been treated successfully with betaine in the first months to years of life. Biochemical and clinical improvements have been noted without significant adverse reactions. However, compared with adults, it is often recommended that dosage be titrated to achieve the appropriate effects.
Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations (hypermethioninemia). Treatment with betaine may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including a few patients treated with betaine. Plasma methionine concentrations should be monitored in patients afflicted with CBS deficiency. Plasma methionine concentrations should be kept below 1000 umol/L through dietary modification and, if necessary, a reduction of betaine dose.
Available data from a limited number of published case reports and postmarketing experience with betaine 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 performed with betaine. Betaine should be given to pregnant women only when clearly needed. There is a published case report of the continuation of betaine and other management therapies in a pregnant woman with homocystinuria; the woman experienced two successful pregnancies, and 2 healthy infants were delivered. However, the woman had experienced a miscarriage in a prior pregnancy, details of which were unknown. Because of the rarity of the base disease, it is unlikely that sufficient data will be available to judge whether betaine, when given in pharmacologic doses, can affect reproduction capacity or cause fetal harm. Clearly, because betaine is found naturally in the diet, the normal daily intake of betaine from dietary food sources is not thought harmful.
It is not known whether betaine is excreted in human milk (although its metabolic precursor, choline, occurs at high levels in human milk). As many drugs are excreted in human milk, caution should be exercised when betaine is administered to a woman who is breast-feeding. Because of the rarity of homocystinuria it is unlikely that sufficient data will be available to judge whether betaine, when given in pharmacologic doses, has an effect on breast-feeding. Clearly, because betaine is found naturally in the diet, the normal daily intake of betaine from dietary food sources is not thought harmful.
Administration of betaine therapy requires an experienced clinician skilled in the management of patients with homocystinuria.
For the adjunct treatment of homocystinuria in order to reduce plasma homocysteine levels; including in those patients with deficiencies or defects in 1) cystathionine beta-synthase (CBS); 2) 5,10-methylenetetrahydrofolate reductase (MTHFR); and 3) cobalamin cofactor metabolism (cbl):
NOTE: Betaine is designated as an orphan drug by the FDA for this indication.
NOTE: In patients with CBS-deficiency, monitor plasma methionine concentrations.
NOTE: Response to treatment is usually evident within 1 week, and steady state is reached within roughly 1 month.
Oral dosage:
Adults: The usual dosage is 3 g PO twice daily (6 g/day total). Higher dosages (up to 20 g/day) have been necessary to control plasma homocysteine levels in some patients. However, dosages in all patients can be gradually increased until plasma homocysteine concentrations are undetectable or present only in small amounts. One pharmacokinetic and pharmacodynamic study of 6 children (6 to 17 years of age) indicated a potential plateau of benefit at roughly 150 mg/kg/day PO.
Children and Adolescents 3 years and older: The usual dosage is 3 g PO twice daily (6 g/day total). Higher dosages (up to 20 g/day) have been necessary to control plasma homocysteine levels in some patients. However, dosages in all patients can be gradually increased until plasma homocysteine concentrations are undetectable or present only in small amounts. One pharmacokinetic and pharmacodynamic study of 6 children (6 to 17 years of age) indicated a potential plateau of benefit at roughly 150 mg/kg/day PO.
Neonates, Infants, and Children younger than 3 years: Dosage may be started at 100 mg/kg/day PO given in divided doses twice daily. Dosage may be increased weekly by 50 mg/kg increments. Dosages in all patients can be gradually increased until plasma homocysteine concentrations are undetectable or present only in small amounts. Of note, one pharmacokinetic and pharmacodynamic study of 6 children (6 to 17 years of age) indicated a potential plateau of benefit at roughly 150 mg/kg/day PO.
Maximum Dosage Limits:
Maximum dosage information is not available. Dosage and therapy should be guided by clinical status and the reduction of plasma homocysteine levels to undetectable or small amounts.
Patients with Hepatic Impairment Dosing
No data are available.
Patients with Renal Impairment Dosing
No data are available.
*non-FDA-approved indication
There are no drug interactions associated with Betaine Anhydrous products.
Betaine serves as a methyl donor in one of the two pathways in humans that methylate homocysteine to methionine. In therapeutic doses, betaine facilitates the remethylation of homocysteine to methionine. Administration of betaine reduces elevated plasma homocysteine levels by roughly 20-30% and improves the clinical symptoms of the disease. Response usually occurs within 1 week and steady-state response to any given dosage within 1 month.
Pharmacokinetics:
Betaine is administered orally. Detailed pharmacokinetic data are not available. The plasma levels of betaine have not been measured in patients and have not been correlated with plasma homocysteine levels. However, the measurement of homocysteine levels in the presence of betaine administration indicate that betaine's onset of action is within a few days of beginning therapy and that a steady-state response to any given dose is achieved within several weeks to 1 month's time.
-Special Populations
Hepatic Impairment
No data exist in regard to patients with hepatic dysfunction.
Renal Impairment
No data exist in regard to patients with renal dysfunction.
Pediatrics
Compared to adults, children are expected to exhibit similar responses to betaine. A pharmacokinetic and pharmacodynamic study of 6 children (age 6-17 years of age) indicated a potential plateau of benefit at roughly 150 mg/kg/day PO.