BETAINE ANHYDROUS powder, for solution

Betaine Anhydrous by

Drug Labeling and Warnings

Betaine Anhydrous by is a Prescription medication manufactured, distributed, or labeled by Eton Pharmaceuticals, Inc., University of Iowa Pharmaceuticals. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 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

  • 2. DOSAGE AND 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 Dosage
    Dosages 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 (1.5 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.
  • 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.

  • 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 ReactionsNumber of Patients
    Nausea2
    Gastrointestinal distress2
    Diarrhea1
    "Bad Taste"1
    "Caused Odor"1
    Questionable pyschological1
    "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)].

  • 10. OVERDOSAGE

    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.

  • 11. DESCRIPTION

    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

  • 12. CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Betaine Anhydrous for Oral Solution acts as a methyl group donor in the remethylation of
    homocysteine to methionine in patients with homocystinuria. Betaine occurs naturally in the body.
    It is a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals,
    and seafood.

    12.2 Pharmacodynamics

    Betaine Anhydrous for Oral Solution was observed to lower plasma homocysteine concentration
    in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect.
    Patients have taken Betaine Anhydrous for Oral Solution for many years without evidence of
    tolerance. There has been no demonstrated correlation between Betaine concentration and
    homocysteine concentration.


    In CBS-deficient patients, large increases in methionine concentration over baseline have been
    observed. Betaine Anhydrous for Oral Solution has also been demonstrated to increase low plasma
    methionine and S-adenosylmethionine (SAM) concentration in patients with MTHFR deficiency
    and cbl defect.

    12.3 Pharmacokinetics

    Pharmacokinetic studies of Betaine Anhydrous for Oral Solution are not available. Plasma betaine
    concentrations following administration of Betaine Anhydrous for Oral Solution have not been
    measured in patients and have not been correlated to homocysteine concentration.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Long-term carcinogenicity and fertility studies have not been conducted with Betaine Anhydrous
    for Oral Solution. No evidence of genotoxicity was demonstrated in the following tests: metaphase
    analysis of human lymphocytes; bacterial reverse mutation assay; and mouse micronucleus test.

  • 14. CLINICAL STUDIES

    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.

  • 16. HOW SUPPLIED/STORAGE AND HANDLING

    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.

  • 17. PATIENT COUNSELING INFORMATION

    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

  • PRINCIPAL DISPLAY PANEL

    Betaine Anhydrous Label:

    Betaine Anhydrous Label

  • INGREDIENTS AND APPEARANCE
    BETAINE ANHYDROUS 
    betaine anhydrous powder, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-115
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    BETAINE (UNII: 3SCV180C9W) (BETAINE - UNII:3SCV180C9W) BETAINE1 g  in 1 g
    Product Characteristics
    ColorwhiteScore    
    ShapeSize
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-115-18180 g in 1 BOTTLE; Type 0: Not a Combination Product01/28/2022
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21050801/28/2022
    Labeler - Eton Pharmaceuticals, Inc. (080870465)
    Registrant - Eton Pharmaceuticals, Inc. (080870465)
    Establishment
    NameAddressID/FEIBusiness Operations
    Amino GmbH507524424api manufacture(71863-115)
    Establishment
    NameAddressID/FEIBusiness Operations
    University of Iowa Pharmaceuticals968854286manufacture(71863-115) , pack(71863-115)
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