ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in labeling:oHypermethioninemia and cerebral edema in patients with CBS deficiency [see Warnings and Precautions (5.1)].. oHypermethioninemia and cerebral edema in patients with CBS deficiency [see Warnings and Precautions (5.1)].. Most common adverse reactions (> 2%) are: nausea and gastrointestinal distress, based on physician survey. (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Lukare Medical, LLC at 1-855-752-9317, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of 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 survey study of 41 physicians, who treated 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 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 SurveyAdverse ReactionsNumber of PatientsNausea2Gastrointestinal distress2Diarrhea1Bad Taste1Caused Odor1Questionable psychological changes1Aspirated the powder1. 6.2 Postmarketing 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Severe cerebral edema and hypermethioninemia have been reported within weeks to 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 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Betaine Anhydrous for Oral Solution acts as methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Betaine occurs naturally in the body. It is 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) concentrations in patients with MTHFR deficiency and cbl defect. 12.3 Pharmacokinetics. Pharmacokinetic studies of Betaine Anhydrous for Oral Solution are not available. Plasma concentrations following administration of Betaine Anhydrous for Oral Solution have not been measured in patients and have not been correlated to homocysteine concentration.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Betaine Anhydrous for Oral Solution was studied in double-blind, placebo-controlled, crossover study in patients (3 males and females) with CBS deficiency, ages to 32 years at enrollment. Betaine Anhydrous for Oral Solution was administered at dosage of grams twice daily, for 12 months. Plasma homocystine concentrations 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. 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 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 gm/day, patients received less than gm/day, 12 patients received doses from to 15 gm/day, and patients received doses over 15 gm/day. Most patients were treated for more than months (n=57) and 30 patients were treated for year or longer (range 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 concentrations, and homocysteine decreased by 71 to 83%, regardless of 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 further reduction of either homocystine or homocysteine concentrations.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adults and Pediatric Patients Years of Age and OlderoThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily. (2.1)Pediatric Patients Less than Years of AgeoThe recommended starting dosage is 100 mg/kg/day, administered orally in divided doses of 50 mg/kg twice daily, and then increased weekly by 50 mg/kg increments. (2.1)oMonitor patient response by plasma homocysteine concentrations. (2.1)oIncrease the dosage gradually until the plasma total homocysteine concentration is undetectable or present only in small amounts. (2.1)Preparation and Administration InstructionsoPrescribed amount of Betaine Anhydrous for Oral Solution should be measured with the measuring scoop provided and then dissolved in to ounces of water, juice, milk, or formula until completely dissolved, or mixed with food for immediate ingestion. (2.2). oThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily. (2.1). oThe recommended starting dosage is 100 mg/kg/day, administered orally in divided doses of 50 mg/kg twice daily, and then increased weekly by 50 mg/kg increments. (2.1). oMonitor patient response by plasma homocysteine concentrations. (2.1). oIncrease the dosage gradually until the plasma total homocysteine concentration is undetectable or present only in small amounts. (2.1). oPrescribed amount of Betaine Anhydrous for Oral Solution should be measured with the measuring scoop provided and then dissolved in to ounces of water, juice, milk, or formula until completely dissolved, or mixed with food for immediate ingestion. (2.2). 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 Years of Age and OlderThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily. Pediatric Patients Less than Years of AgeThe recommended starting dosage is 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments. MonitoringMonitor 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 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 twice-daily dosing schedule and 150 mg/kg/day dosage for Betaine Anhydrous for Oral Solution. 2.2 Preparation and Administration Instructions. oShake bottle lightly before removing cap.oMeasure the number of scoops for the patients dose with the scoop provided. One level scoop (1.5 mL) is equivalent to gram of betaine anhydrous powder.oMix powder with to ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.oAlways replace the cap tightly after using and protect the bottle from moisture.. oShake bottle lightly before removing cap.. oMeasure the number of scoops for the patients dose with the scoop provided. One level scoop (1.5 mL) is equivalent to gram of betaine anhydrous powder.. oMix powder with to ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.. oAlways replace the cap tightly after using and protect the bottle from moisture.

INDICATIONS & USAGE SECTION.

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: oCystathionine beta-synthase (CBS) deficiencyo5,10-methylenetetrahydrofolate reductase (MTHFR) deficiencyoCobalamin cofactor metabolism (cbl) defect. oCystathionine beta-synthase (CBS) deficiency. o5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. oCobalamin cofactor metabolism (cbl) defect. Betaine Anhydrous for Oral Solution is methylating agent indicated in pediatric and adult patients for the treatment of homocystinuria to decrease elevated homocysteine blood concentrations. Included within the category of homocystinuria are (1):oCystathionine beta-synthase (CBS) deficiencyo5,10-methylenetetrahydrofolate reductase (MTHFR) deficiencyoCobalamin cofactor metabolism (cbl) defect. oCystathionine beta-synthase (CBS) deficiency. o5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. oCobalamin cofactor metabolism (cbl) defect.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Preparation and Administration Instructions Instruct patients and caregivers to administer Betaine Anhydrous for Oral Solution as follows:oShake bottle lightly before removing cap.oMeasure the number of scoops for the patients dose with the scoop provided. One level scoop (1.5 mL) is equivalent to gram of betaine anhydrous powder.oMix powder with to ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.oAlways replace the cap tightly after using and protect bottle from moisture.Manufactured for and Distributed by:Lukare Medical, LLC.Scotch Plains, NJ 07076Part No.: LUK 012. oShake bottle lightly before removing cap.. oMeasure the number of scoops for the patients dose with the scoop provided. One level scoop (1.5 mL) is equivalent to gram of betaine anhydrous powder.. oMix powder with to ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.. oAlways replace the cap tightly after using and protect bottle from moisture.

SPL UNCLASSIFIED SECTION.

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 Years of Age and OlderThe recommended dosage is grams per day, administered orally in divided doses of grams twice daily. Pediatric Patients Less than Years of AgeThe recommended starting dosage is 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments. MonitoringMonitor 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 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 twice-daily dosing schedule and 150 mg/kg/day dosage for Betaine Anhydrous for Oral Solution.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from limited number of published case reports and postmarketing 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 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 to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryThere 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 mothers 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 years of age may benefit from dose titration [see Dosage and Administration (2.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHypermethioninemia in Patients with CBS Deficiency:Betaine Anhydrous for Oral Solution may worsen elevated plasma methionine concentrations and cerebral edema has been reported. Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 micromol/L through dietary modification and, if necessary, reduction of Betaine Anhydrous for Oral Solution dosage. (5.1). oHypermethioninemia in Patients with CBS Deficiency:. 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, reduction of Betaine Anhydrous for Oral Solution dosage.