These Highlights Do Not Include All The Information Needed To Use Betaine Anhydrous For Oral Solution Safely And Effectively. See Full Prescribing Information For Betaine Anhydrous For Oral Solution.

Betaine Anhydrous Label:

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.

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:

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.

None.

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)] .

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.

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.

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 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.

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.

Betaine Anhydrous for Oral Solution is a white, granular, hygroscopic powder for oral solution

available in bottles containing 180 grams of betaine anhydrous.

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.

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

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)].

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 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.

• 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.

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.

Betaine Anhydrous Label:

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.

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:

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.

None.

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)] .

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.

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.

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 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.

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.

Betaine Anhydrous for Oral Solution is a white, granular, hygroscopic powder for oral solution

available in bottles containing 180 grams of betaine anhydrous.

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.

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

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)].

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 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.

• 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.

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.