Cystadane(Betaine HCl caps)

药用名称为CYSTADANE

甜菜碱无水1G;每scoopful; PWD稀释和口服。

法律分类：
接收

类药物为CYSTADANE
甲基化剂。

制造商的CYSTADANE
罕见疾病治疗公司

主治为CYSTADANE
对于治疗胱氨酸尿症（例如，胱硫醚β-合成酶[CBS]亏虚，5，10 - 甲基四氢叶酸还原酶[MTHFR的缺乏，钴胺素，辅酶代谢[CBL缺陷），以降低同型半胱氨酸的血液水平升高。

成人和儿童：
溶解在4-6盎司的水，果汁，牛奶，配方一畚箕一畚箕（1G甜菜碱无水PWD），或立即摄入的食物混合。 <3岁：最初100mg/kg/day分为每日两次剂量，可能会增加每周50mg/kg的增量。 ≥3岁：3G，每日两次。直到血浆总同型半胱氨酸是无法检测或目前只有少量逐渐增加。截至到20g/day已被使用。

为CYSTADANE警告/注意事项
Hypermethioninemia。监控与CBS缺乏患者血浆中蛋氨酸含量。怀孕（Cat.C）。哺乳的母亲。

CYSTADANE的不良反应
胃肠不适; hypermethioninemia，脑水肿。

如何CYSTADANE提供？
瓶- 180G（W.测量舀）

Cystadane ® 含有180克甜菜碱无水的塑料瓶 。 Each bottle is equipped with a plastic child-resistant cap and is supplied with a polystyrene measuring scoop. 每瓶配用塑料防儿童帽，并提供测量舀聚苯乙烯

HIGHLIGHTS OF PRESCRIBING INFORMATION
Indications And Usage
Cystadane is a methylating agent indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels.  Included within the category of homocystinuria are (1):

Cystathionine beta-synthase (CBS) deficiency
5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
Cobalamin cofactor metabolism (cbl) defect

Dosage And Administration
Usual dose in adult and pediatric patients is 6 grams per day, administered orally in divided doses of 3 grams two times a day.(2)
In children less than 3 years of age, may initiate dosing at 100 mg/kg/day, divided in twice daily doses, and then increased weekly by 50 mg/kg increments.(2)
Dose can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts.(2)
Monitor patient response by plasma homocysteine levels.(2)
Prescribed amount of Cystadane should be measured with the measuring scoop provided and then dissolved in 4 to 6 ounces of water, juice, milk, or formula, or mixed with food for immediate ingestion.(2)

Dosage And Administration 2
Powder for oral solution available in bottles containing 180 grams of betaine anhydrous.(3)

Contraindications
None (4)
Warnings And Precautions
Hypermethioninemia:  Cystadane may worsen elevated plasma methionine concentrations in patients with CBS deficiency.  Cerebral edema has been reported in patients receiving Cystadane.( 5.1)
Monitoring:  Monitor plasma methionine concentrations in patients with CBS deficiency.  Keep plasma methionine concentrations below 1,000 µmol/L through dietary medication and, if necessary, a reduction of Cystadane dose. ( 5.1)
Adverse Reactions
Most common adverse reactions (incidence > 2%) were nausea and gastrointestinal distress, based on physician survey.

Use In Specific Populations
Pregnancy: Animal reproduction studies have not been conducted with Cystadane.  Use only if clearly needed.(8.1)
Nursing women: It is not known whether Cystadane is excreted in human milk.  Use only if clearly needed.(8.3)
Pediatrics: Pediatric patients ranging in age from 24 days to 17 years have been treated with Cystadane.  Children younger than 3 years of age may benefit from dose titration.
CONTRAINDICATIONS
1 INDICATIONS AND USAGE
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:  

Cystathionine beta-synthase (CBS) deficiency
5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
Cobalamin cofactor metabolism (cbl) defect

2 DOSAGE AND ADMINISTRATION
2.1 Dosage
The usual dosage in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 grams twice daily.  In pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments. 
Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria.  Patient response to Cystadane can be monitored by homocysteine plasma levels.  Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts. Response (by homocysteine plasma levels) usually occurs within several days and steady state within a month.  Plasma methionine concentrations should be monitored in patients with CBS deficiency [See Warnings and Precautions (15.2)].

Dosages of up to 20 grams per day have been necessary to control homocysteine levels 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 Cystadane.

2.2 Administration
The prescribed amount of Cystadane should be measured with the measuring scoop provided (one level 1.7 mL 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.

3 DOSAGE FORMS AND STRENGTHS
Cystadane is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams of betaine anhydrous.

4 CONTRAINDICATIONS
None.

5 WARNINGS AND PRECAUTIONS
5.1    Risk of 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 Cystadane 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 Cystadane.  Plasma methionine concentrations should be monitored in patients with CBS deficiency.  Plasma methionine concentrations should be kept below 1,000 µmol/L through dietary modification and, if necessary, a reduction of Cystadane dose.

6 ADVERSE REACTIONS
 6.1    Adverse Reactions in Clinical Studies
The most serious adverse reaction reported with Cystadane treatment is the development of hypermethioninemia and cerebral edema in patients with CBS Deficiency [see Warnings and Precautions (5.1)].

The assessment of clinical adverse reactions is based on a survey study of 41 physicians, who treated a total of 111 homocystinuria patients with Cystadane.  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 Cystadane 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

The following adverse reactions have been identified during post approval use of Cystadane.  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.

In postmarketing experience with Cystadane, severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting betaine therapy, with complete recovery after discontinuation of Cystadane.  All patients who developed cerebral edema had homocystinuria due to CBS deficiency and had severe elevation in plasma methionine levels (range 1,000 to 3,000 µM).  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.

The following adverse reactions have been reported in patients during postmarketing use of Cystadane: 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.

8 USE IN SPECIFIC POPULATIONS
8.1    Pregnancy
Pregnancy Category C: Animal reproduction studies have not been conducted with Cystadane.  It is also not known whether Cystadane can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  Cystadane should be given to a pregnant woman only if clearly needed.

8.3    Nursing Mothers
It is not known whether Cystadane is excreted in human milk.  Use only if clearly needed.

8.4    Pediatric Use
The majority of case studies of homocystinuria patients treated with Cystadane 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)].

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

11 DESCRIPTION
Cystadane (betaine anhydrous for oral solution) is an agent for the treatment of homocystinuria.  It contains no ingredients other than anhydrous betaine. Cystadane 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:

Chemical Structure for Betaine
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Cystadane acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria.  Cystadane 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.

12.2 Pharmacodynamics
Cystadane was observed to lower plasma homocysteine levels in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect.  Patients have taken Cystadane for many years without evidence of tolerance.  There has been no demonstrated correlation between Cystadane levels and homocysteine levels.

In CBS-deficient patients, large increases in methionine levels over baseline have been observed.  Cystadane has also been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) levels in patients with MTHFR deficiency and cbl defect.

12.3 Pharmacokinetics
Pharmacokinetic studies of Cystadane are not available.  Plasma levels of Cystadane have not been measured in patients and have not been correlated to homocysteine levels.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity and fertility studies have not been conducted with Cystadane.  No evidence of genotoxicity was demonstrated in the following tests: metaphase analysis of human lymphocytes; bacterial reverse mutation assay; and mouse micronucleus test.

14 CLINICAL STUDIES
Cystadane was studied in a double-blind, placebo-controlled, crossover study in 6 patients with CBS deficiency, ages 7 to 32 years at enrollment.  Cystadane was administered at a dosage of 3 grams twice daily, for 12 months. Plasma homocystine levels were significantly reduced (p<0.01) compared to placebo. Plasma methionine levels were variable and not significantly different compared to placebo. No adverse events were reported in any patient.

Cystadane 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 Cystadane. 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 be used to evaluate the effect of Cystadane in patients with homocystinuria. Plasma homocystine or homocysteine levels were reported numerically for 62 patients, and 61 of these patients showed decreases with Cystadane treatment. Homocystine decreased by 83-88% regardless of pre-treatment level, and homocysteine decreased by 71-83%, regardless of the pre-treatment level. 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 Cystadane resulted in a further reduction of either homocystine or homocysteine.

16 HOW SUPPLIED/STORAGE AND HANDLING
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 mL) is equal to 1 gram of betaine anhydrous powder.

NDC 66621-4000-1    180 g/bottle

Cystadane can be ordered by calling Accredo Health Group, Inc., Customer service at 1-888-454-8860

16.1    Storage
Store at room temperature, 15 – 30 ˚C (59 – 86 ˚F).  Protect from moisture.

17 PATIENT COUNSELING INFORMATION
Patients should be advised of the following information before beginning treatment with Cystadane:

17.1  Dosing and Administration

Instruct patients and caregivers that Cystadane should only be taken as directed by their healthcare professional.
Instruct patients and caregivers to administer Cystadane as follows:
Shake bottle lightly before removing cap.
- Measure with the scoop provided.

- Measure the number of scoops as prescribed by their healthcare professional. One level scoop (1.7 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 powder from moisture.