thionine 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.

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 ml) 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.

ot 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 reactions number of patients nausea 2 gastrointestinal distress 2 diarrhea 1 "bad taste" 1 "caused odor" 1 questionable psychological changes 1 “aspirated the powder” 1 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 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.

ld 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 )].

) 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.

tinuria 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 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 a further reduction of either homocystine or homocysteine concentrations.