BETAINE: 848 Adverse Event Reports & Safety Profile

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 to off-white, crystalline, 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: structure

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 Betaine Anhydrous for Oral Solution is a 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:
• Cystathionine beta-synthase (CBS) deficiency
• 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
• Cobalamin cofactor metabolism (cbl) defect

2.

Dosage And Administration

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. (2.1)

Pediatric Patients

Less than 3 Years of Age

• The 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)
• Monitor patient response by plasma homocysteine concentrations. (2.1)
• Increase the dosage gradually until the plasma total homocysteine concentration is undetectable or present only in small amounts. (2.1) Preparation and Administration Instructions
• Prescribed amount of Betaine Anhydrous for Oral Solution should be measured with the measuring scoop provided and then dissolved in 4 to 6 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 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.

None. None ( 4 )

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)] . Most common adverse reactions (> 2%) are: nausea and gastrointestinal distress, based on physician survey (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

See

17 for PATIENT COUNSELING INFORMATION.

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 Reactions Number of Patients Nausea 2 Gastrointestinal distress 2 Diarrhea 1 "Bad Taste" 1 "Caused Odor" 1 Questionable pyschological 1 "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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> . 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.

AND PRECAUTIONS Hypermethioninemia 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, a reduction of Betaine Anhydrous for Oral Solution dosage. (5.1)

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.

ACTIVE INGREDIENTS/PURPOSE AURUM METALLICUM 12X ANTIDEPRESSANT BRAIN DERIVED NEUROTROPHIC FACTOR 4C HELPS MENTAL ACTIVITY BUFO RANA 12X HELPS MENTAL ACTIVITY CALCAREA CARBONICA 3X IMMUNE STRENGTHENING CHROMIUM SULPHURICUM 3X DETOXIFICATION CICUTA VIROSA 12X ANTISPASTIC COBALAMIN 3X ANTIOXIDANT COENZYME Q 3X ANTIOXIDANT CUPRUM METALLICUM 12X ANTISPASTIC FERRUM METALLICUM 3X ANTIOXIDANT FOLIC ACID 3X ANTIOXIDANT FRONTAL LOBE 6X SUPPORTS COORDINATING BEHAVIOR LACHESIS MUTUS 12X ANTI-INFLAMMATORY MELATONIN 4C ANTISTRESS MOLYBDENUM METALLICUM 3X ANTIAGING NEUROTROPHIN 3 4C SUPPORTS MENTAL ACTIVITY NEUROTROPHIN 4 4C SUPPORTS MENTAL ACTIVITY OXYTOCIN 6X STIMULATES ADRENAL CORTEX SILICEA 12X IMMUNE STRENGTHENING TEMPORAL LOBE 6X SUPPORTS AUDITORY PROCESSING THYROTROPIN-RELEASING HORMONE 3X HELPS MENTAL ACTIVITY TRIMETHYLGLYCINE 3X DETOXIFICATION VANADIUM METALLICUM 6X ANTIOXIDANT ZINCUM METALLICUM 3X ANTISTRESS

INACTIVE INGREDIENTS Water, Triethylhexanoin, Glycerin, Hydrogenated Poly(C6-14 Olefin), Butylene Glycol, Human Adipose Derived Stem Cell Conditioned Media, Pentylene Glycol, Alcohol Denat., Steareth-2, Phenoxyethanol, Hydrogenated Lecithin, Algin, Citrus Aurantium Bergamia (Bergamot)

Fruit

Oil, Citrus Grandis (Grapefruit)

Peel

Oil, Plankton Extract, Hydroxypropyl Cyclodextrin, Thioctic Acid, 1,2-Hexanediol, Tremella Fuciformis (Mushroom) Extract, Potassium Hydroxide