Betaine Anhydrous

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 white, granular, hygroscopic powder for oral solution
available in bottles containing 180 grams of betaine anhydrous.

None.

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.

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)] .

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)].

There is no information on Betaine Anhydrous for Oral Solution overdose in humans. In an acute
toxicology study in rats, death occurred frequently at doses equal to or greater than 10 g/kg.

Betaine Anhydrous for Oral Solution is an agent for the treatment of homocystinuria. It contains

no ingredients other than anhydrous betaine. Betaine Anhydrous for Oral Solution is a white,
granular, hygroscopic powder, which is diluted in water and administered orally. The chemical
name of betaine anhydrous powder is trimethylglycine. It has a molecular weight of 117.15. The
structural formula is:

Structural Formula

Betaine Anhydrous for Oral Solution was studied in a double-blind, placebo-controlled, crossover
study in 6 patients (3 males and 3 females) with CBS deficiency, ages 7 to 32 years at enrollment.
Betaine Anhydrous for Oral Solution was administered at a dosage of 3 grams twice daily, for 12
months. Plasma homocystine concentration were significantly reduced (p<0.01) compared to
placebo. Plasma methionine concentrations were variable and not significantly different compared
to placebo.

Betaine Anhydrous for Oral Solution 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 a total of 78 male and female patients
with homocystinuria who were treated with Betaine Anhydrous for Oral Solution. 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 6 gm/day, 3 patients
received less than 6 gm/day, 12 patients received doses from 6 to 15 gm/day, and 5 patients
received doses over 15 gm/day. Most patients were treated for more than 3 months (n=57) and 30
patients were treated for 1 year or longer (range 1 month to 11 years). Homocystine is formed
nonenzymatically from two molecules of homocysteine, and both have been used to evaluate the
effect of Betaine Anhydrous for Oral Solution in patients with homocystinuria. Plasma
homocystine or homocysteine concentrations were reported numerically for 62 patients, and 61 of
these patients showed decreases with Betaine Anhydrous for Oral Solution 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 Betaine Anhydrous for Oral Solution
resulted in a further reduction of either homocystine or homocysteine concentrations.

Betaine Anhydrous for Oral Solution is available in plastic bottles containing 180 grams of betaine
anhydrous as a white, granular, hygroscopic powder. Each bottle is equipped with a plastic child-resistant
cap and is supplied with a polypropylene measuring scoop. One level scoop (1.5 cc) is
equal to 1 gram of betaine anhydrous powder.

NDC 71863-115-18 (180 g/bottle)

Storage
Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) [ See USP
Controlled Room Temperature ].

Protect from moisture.

Preparation and Administration Instructions

Instruct patients and caregivers to administer Betaine Anhydrous for Oral Solution as follows:
• Shake bottle lightly before removing cap.
• Measure the number of scoops for the patient’s dose with the scoop provided. One level
scoop (1.5 cc) 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.

Distributed by:
Eton Pharmaceuticals, Inc.
Deer Park, IL 60010

Issued: 02/2023

Betaine Anhydrous Label:

Betaine Anhydrous Label