Cystadane® (betaine anhydrous for oral solution) is an agent for the treatment of homocystinuria. Cystadane is a white, granular, hygroscopic powder. It contains no ingredients other than anhydrous betaine. Betaine anhydrous powder is very soluble in water, soluble in methanol and ethanol, and sparingly soluble in ether.

The chemical name of betaine anhydrous powder is trimethylglycine. It has a molecular weight of 117.15. The structural formula is:

Last updated on RxList: 6/1/2009

Cystadane (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within the category of homocystinuria are deficiencies or defects in:

1. cystathionine beta-synthase (CBS),
2. 5,10-methylenetetrahydrofolate reductase (MTHFR),
3. cobalamin cofactor metabolism (cbl).

Patient response to Cystadane can be monitored by homocysteine plasma levels (see DOSAGE AND ADMINISTRATION). Response usually occurs within a week and steady state within a month.

Cystadane has been administered concomitantly with vitamin B6 (pyridoxine), vitamin B12 (cobalamin), and folate.

The usual dosage used in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 grams two times per day. Dosages of up to 20 grams per day have been necessary to control homocysteine levels in some patients. In pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day and then increased weekly by 50 mg/kg increments. In one study by Matthewsⁱ et al., pharmacokinetic and pharmacodynamic simulation indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg/kg/day dosage for betaine. Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts. Plasma methionine concentrations should be monitored in patients with CBS-deficiency. See PRECAUTIONS: Hypermethioninemia.

The prescribed amount of Cystadane (betaine anhydrous for oral solution) should be measured with the measuring scoop provided (one level 1.7 cc scoop is equal to 1 gram of betaine anhydrous powder) and then dissolved in 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula, or mixed with food for immediate ingestion.

Cystadane is available in plastic bottles containing 180 grams of betaine anhydrous. Each bottle is equipped with a plastic child-resistant cap and is supplied with a polystyrene measuring scoop. One level scoop (1.7 cc) is equal to 1 gram of betaine anhydrous powder.

NDC 62161-004-20.......................180g/bottle
DIN 02238526

Store at room temperature, 15° - 30°C (59° - 86°F).

For questions of a medical nature in the U.S. or Canada, call 1-888-8ORPHAN (1-888-867-7426).

REFERENCES

ⁱ Matthews A, Johnson TN, Rostami-Hodjegan A, Chakrapani A, et al. An indirect response model of homocysteine suppression by betaine: optimizing the dosage regimen of betaine in homocystinuria. Br J Clin Pharmacol 2002; 54:140-146.

Cystadane® can be ordered by calling Orphan Medical, Inc. Customer Service at 1-800-359-4304 or by contacting your local wholesaler. Distributed in the U.S. by: Orphan Medical, Inc. Minnetonka, MN 55305. Distributed in Canada by: Orphan Medical, Inc. Scarborough, Ontario M1H 2W4. Revision Date: Nov 2005. Part No. 4040155.

Last updated on RxList: 6/1/2009

Adverse reactions to betaine have been minimal. In a survey study of physicians who had treated a total of 111 homocystinuria patients with betaine, the types of adverse effects and the number of patients experiencing them were as follows:

Nausea	2	“Caused odor”	1
GI distress	2	Questionable psychological changes	1
Diarrhea	1	“Aspirated the powder”	1
Unspecified problem	1

A few cases of cerebral edema have been reported secondary to severe hypermethioninemia in patients with cystathionine beta-synthase (CBS) deficiency treated with Cystadane. See PRECAUTIONS: Hypermethioninemia.

No information provided.

Last updated on RxList: 6/1/2009

No information provided.

General

Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria.

Hypermethioninemia

Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with Cystadane may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including a few patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasma methionine concentrations should be kept below 1,000 umol/L through dietary modification and, if necessary, a reduction of Cystadane dose.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity and fertility studies have not been conducted on betaine. No evidence of genotoxicity was demonstrated in the following tests: Metaphase Analysis of Human Lymphocytes; Bacterial Reverse Mutation Assay; and Mouse Micronucleus Test.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with betaine. It is also not known whether betaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystadane (betaine anhydrous for oral solution) should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether betaine is excreted in human milk (although its metabolic precursor, choline, occurs at high levels in human milk). Because many drugs are excreted in human milk, caution should be exercised when Cystadane is administered to a nursing woman.

Pediatric Use

The majority of case studies of homocystinuria patients treated with betaine have been pediatric patients. The disorder, in its most severe form, can be manifested within the first months or years of life by lethargy, failure to thrive, developmental delays, seizures, or optic lens displacement. Patients have been treated successfully without adverse effects within the first months or years of life with dosages of 6 grams per day or more of betaine with resultant biochemical and clinical improvement. However, dosage titration may be preferable in pediatric patients (see DOSAGE AND ADMINISTRATION).

Last updated on RxList: 6/1/2009

In an acute toxicology study in rats, death frequently occurred at doses equal to or greater than 10,000 mg/kg.

No information provided.

Last updated on RxList: 6/1/2009

When administered in recommended oral dosage to children or adults, Cystadane acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. As a result, toxic blood levels of homocysteine are reduced in these patients, usually to 20-30 percent or less of pre-treatment levels.

Elevated homocysteine blood levels are associated with clinical problems such as cardiovascular thrombosis, osteoporosis, skeletal abnormalities, and optic lens dislocation. Plasma levels of homocysteine were decreased in nearly all patients treated with betaine. In observational studies without concurrent controls, clinical improvement was reported by the treating physicians in about three-fourths of patients taking betaine. 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 studied, adding betaine resulted in a further reduction of homocysteine.

Betaine was observed to lower plasma homocysteine levels in the three types of homocystinuria, i.e., cystathionine beta-synthase (CBS) deficiency; 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency; and cobalamin cofactor metabolism (cbl) defect.

Betaine has also been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) levels in patients with MTHFR deficiency and cbl defect.

In CBS-deficient patients, large increases in methionine levels over baseline have been observed.

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.

Pharmacokinetic studies of betaine are not available. Plasma levels of betaine have not been measured in patients and have not been correlated to homocysteine levels. However, pharmacodynamic measurements, i.e., monitoring of plasma homocysteine levels, have demonstrated that the onset of action of betaine is within several days and that a steady state in response to dosage is achieved within several weeks. Patients have taken betaine for many years without evidence of tolerance.

Last updated on RxList: 6/1/2009

1. Shake bottle lightly before removing cap.
2. Measure with the scoop provided.
3. One level scoop (1.7 cc) is equivalent to 1 gram of betaine anhydrous powder. Measure the number of scoops your physician has prescribed.
4. Mix with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest immediately.

Always replace the cap tightly after using. Protect from moisture.

Last updated on RxList: 6/1/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BETAINE - ORAL

(BEE-tuh-een)

COMMON BRAND NAME(S): Cystadane

USES: This medication is used to treat high levels of a certain important body chemical (homocysteine) due to an inherited disorder (homocystinuria). Decreasing high homocysteine levels may help prevent serious blood clots, abnormal bone formation, brittle bones (osteoporosis), and eye problems (e.g., dislocated eye lens, nearsightedness). This medication works by decreasing blood levels of homocysteine. It does not correct the inherited disorder that causes the disease.

HOW TO USE: Take this medication by mouth, usually twice daily or as directed by your doctor. Shake the bottle lightly before each use. Using the scoop provided, measure out the number of scoops prescribed by your doctor. Mix the powder with 4 to 6 ounces (120 to 180 milliliters) of water, juice, milk, or formula until dissolved, and drink immediately. The powder may also be mixed with food instead of liquid and taken immediately. Replace cap tightly after use.

Dosage is based on your age, weight, medical condition, and response to therapy. Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Nausea, stomach upset, or diarrhea may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but very serious side effects occur: persistent headache, vision changes.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking betaine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high methionine levels (hypermethioninemia).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before taking this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., methionine/homocysteine blood levels) may be performed to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.