NDC 52276-400 Cystadane

Betaine

NDC Product Code 52276-400

NDC CODE: 52276-400

Proprietary Name: Cystadane What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Betaine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • 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.

Product Characteristics

Color(s):
WHITE (C48325)

NDC Code Structure

  • 52276 - Recordati Rare Diseases

NDC 52276-400-01

Package Description: 180 g in 1 BOTTLE

NDC Product Information

Cystadane with NDC 52276-400 is a a human prescription drug product labeled by Recordati Rare Diseases. The generic name of Cystadane is betaine. The product's dosage form is powder, for solution and is administered via oral form.

Labeler Name: Recordati Rare Diseases

Dosage Form: Powder, For Solution - An intimate mixture of dry, finely divided drugs and/or chemicals, which, upon the addition of suitable vehicles, yields a solution.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Cystadane Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • BETAINE 1 g/g

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Methylating Activity - [MoA] (Mechanism of Action)
  • Methylating Agent - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Recordati Rare Diseases
Labeler Code: 52276
FDA Application Number: NDA020576 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-25-1996 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Betaine

Betaine is pronounced as (bee' ta een)

Why is betaine medication prescribed?
Betaine is used to treat homocystinuria (an inherited condition in which the body cannot break down a certain protein, causing build-up of homocysteine in the blood). Inc...
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Cystadane Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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

2.1 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 (5.1)].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.

5.1 Hypermethioninemia

Risk of Hypermethioninemia in Patients with CBS DeficiencyPatients 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.

6.1 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 SurveyAdverse ReactionsNumber of PatientsNausea2Gastrointestinal distress2Diarrhea1"Bad Taste"1"Caused Odor"1Questionable psychological changes1“Aspirated the powder”1

6.2 Postmarketing Experience

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.

8.1 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:

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.

13.1 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 been 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 52276-400-01 180 g/bottle

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.Supplied by:Orphan Europe SARLPuteaux, FranceLicensed to and Distributed by:Recordati Rare Diseases Inc.Lebanon, NJ 08833 U.S.A.For drug or ordering information please call AnovoRx Group, LLC, Customer service at 1-888-487-4703.Cystadane® is a licensed trademark of Recordati Rare Diseases Inc.This product label may have been updated. For the most recent prescribing information, please visit www.recordatirarediseases.com.Part No.: Orphan Europe OEP1000

Package/Label Display Panel

NDC 52276-400-01CYSTADANE®betaine anhydrous for oral solution1 gram of betaine anhydrous powder per scoopful180 grams

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