1. Patient Information
2. Instruct Patients And Caregivers To Administer Cystadane As Follows:
3. Supplied By:
4. Licensed To And Distributed By:
5. Patients Should Be Advised Of The Following Information Before Beginning Treatment With Cystadane:
6. Instruct Patients And Caregivers To Administer Cystadane As Follows:
7. Manufactured For:
8. Under License From:
9. Distributed By:

Patient Information ⮝

Preparation and Administration Instructions

Instruct Patients And Caregivers To Administer Cystadane As Follows: ⮝

• Shake bottle lightly before removing cap.
• Measure the number of scoops for the patient s dose with the scoop provided. 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 bottle from moisture.

Supplied By: ⮝

Recordati Rare Diseases

Puteaux, France

Licensed 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.

CYSTADANEis a licensed trademark of Recordati Rare Diseases Inc.

This product label may have been updated. For the most recent prescribing information, please visitwww.recordatirarediseases.com.

Part No.: Recordati Rare Diseases, OEP1000 V2

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.

Manufactured For: ⮝

Rare Disease Therapeutics, Inc.
Franklin, TN 37067

Under License From: ⮝

Orphan Europe, s.a.r.l. Puteaux France

Distributed By: ⮝

AnovoRx Distribution, LLC
Memphis, TN 38134

Part No.: RDT C PI007
Part No.: Orphan Europe OEP 829

1. No Title 1572547451
2. Highlights Of Prescribing Information
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. 1 Indications And Usage
10. 2 Dosage And Administration
11. 3 Dosage Forms And Strengths
12. 4 Contraindications
13. 5 Warnings And Precautions
14. 6 Adverse Reactions
15. 8 Use In Specific Populations
16. 10 Overdosage
17. 11 Description
18. 12 Clinical Pharmacology
19. 13 Nonclinical Toxicology
20. 14 Clinical Studies
21. 16 How Supplied/storage And Handling
22. Package/label Display Panel
23. Package Leaflet: Information For The Patient
24. Health Care Provider Letter
25. Recent Major Changes
26. Use In Specific Populations
27. 1 Indications And Usage
28. 3 Dosage Forms And Strengths
29. 5 Warnings And Precautions
30. 6 Adverse Reactions
31. 8 Use In Specific Populations
32. 10 Overdosage
33. 11 Description
34. 14 Clinical Studies
35. 16 How Supplied/storage And Handling
36. No Title 1572455491

No Title 1572547451 ⮝

CYSTADANE betaine powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:66621-4000 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BETAINE (UNII: 3SCV180C9W) (BETAINE - UNII:3SCV180C9W) BETAINE 6 g

Product Characteristics Color white (none) Score Shape Size Flavor Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:66621-4000-1 180 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020576 10/25/1996

Labeler - Rare Disease Therapeutics, Inc. (966133100)

Registrant - Rare Disease Therapeutics, Inc. (966133100)

Establishment
Name	Address	ID/FEI	Business Operations
Rare Disease Therapeutics, Inc.		966133100	relabel(66621-4000)

Establishment
Name	Address	ID/FEI	Business Operations
Ropack Pharmaceutical		209989631	manufacture(66621-4000)

Revised: 1/2015 Document Id: d797121e-e13a-41b8-b7d7-e104ba26077c 34391-3 Set id: 84f7c21f-d0af-4ae6-9cd5-d5af96ade329 Version: 16 Effective Time: 20150109 Rare Disease Therapeutics, Inc.

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use Cystadane safely and effectively. See full prescribing information for Cystadane.



Cystadane (betaine anhydrous for oral solution) powder

Initial U.S. Approval: 1996

Indications And Usage ⮝

CYSTADANE 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 ( 1):

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

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 Adminstration Instructions

• 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 until completely dissolved, or mixed with food for immediate ingestion. ( 2.2)

Dosage Forms And Strengths ⮝

For oral solution: in bottles containing 180 grams of betaine anhydrous. ( 3)

Contraindications ⮝

• None ( 4)

Warnings And Precautions ⮝

• Hypermethioninemia in Patients with CBS Deficiency:

CYSTADANE 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 CYSTADANE dosage. ( 5.1)

Adverse Reactions ⮝

Most common adverse reactions (> 2%) are: nausea and gastrointestinal distress, based on physician survey ( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised 10/2019

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2019

1 Indications And Usage ⮝

CYSTADANE 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

2 Dosage And Administration ⮝

2.1 Dosage

Therapy with CYSTADANE 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 CYSTADANE by homocysteine plasma concnetration. 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 CYSTADANE.

2.2 Prepartion 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 (1.7 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 the bottle from moisture.

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 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 [ 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 CYSTADANE dosage.

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) ].

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 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

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.

Severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting CYSTADANE 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 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.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

Available data from a limited number of published case reports and postmarketing experience with CYSTADANE use in pregnancy have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with betaine.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of betaine in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for CYSTADANE and any potential adverse effects on the breastfed child from CYSTADANE or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of CYSTADANE have been established in pediatric patients. 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 ( 2.1)].

10 Overdosage ⮝

There is no information on CYSTADANE overdose in humans. 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 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. 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.

12.2 Pharmacodynamics

CYSTADANE was observed to lower plasma homocysteine concentrations 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 Betaine concentrations and homocysteine concentrations.

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

12.3 Pharmacokinetics

Pharmacokinetic studies of CYSTADANE are not available. Plasma betaine concentrations following adminstration of CYSTADANE have not been measured in patients and have not been correlated to homocysteine concentrations.

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 (3 males and 3 females) 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 concentrations were significantly reduced (p<0.01) compared to placebo. Plasma methionine concentrations were variable and not significantly different compared to placebo.

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 concentrations were reported numerically for 62 patients, and 61 of these patients showed decreases with CYSTADANE treatment. Homocystine decreased by 83 to 88% regardless of the pre-treatment concentration, and homocysteine decreased by 71 to 83%, regardless of the 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 CYSTADANE resulted in a further reduction of either homocystine or homocysteine concentrations.

16 How Supplied/storage And Handling ⮝

CYSTADANE is available in plastic bottles containing 180 grams of betaine anhydrous as a white, granular, hygroscopic powder. Each bottle is equipped with a plastic child-resistant cap and is supplied with a polypropylene measuring scoop. One level scoop (1.7 mL) is equal to 1 gram of betaine anhydrous powder.

NDC 52276-400-01 180 g/bottle

Storage

Store at room temperature, 15 to 30 C (59 to 86 F). Protect from moisture.

Package/label Display Panel ⮝

NDC 52276-400-01

CYSTADANE

betaine anhydrous for oral solution

1 gram of betaine anhydrous powder per scoopful

180 grams

CYSTADANE betaine powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52276-400 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BETAINE (UNII: 3SCV180C9W) (BETAINE - UNII:3SCV180C9W) BETAINE 1 g in 1 g

Product Characteristics Color white Score Shape Size Flavor Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:52276-400-01 180 g in 1 BOTTLE; Type 0: Not a Combination Product 04/13/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020576 10/25/1996

Labeler - Recordati Rare Diseases (767598352)

Registrant - Recordati Rare Diseases (767598352)

Establishment
Name	Address	ID/FEI	Business Operations
Ropack Pharmaceutical		209989631	manufacture(52276-400)

Revised: 10/2019 Document Id: 9405bf07-6373-08ac-e053-2a95a90aea78 34391-3 Set id: 31a684d0-cd98-4e46-b43a-ccbd17c41559 Version: 4 Effective Time: 20191003 Recordati Rare Diseases

Package Leaflet: Information For The Patient ⮝

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or your pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Cystadane is and what it is used for
2. What do you need to know before you take Cystadane
3. How to take Cystadane
4. Possible side effects
5. How to store Cystadane
6. Contents of the pack and other information

1. What Cystadane is and what it is used for

Cystadane contains betaine anhydrous which is intended to be an adjunctive treatment of homocystinuria, an inherited (genetic) disease where the amino acid methionine cannot be broken down completely by the body.
Methionine is present in regular food protein (e.g. meat, fish, milk, cheese, eggs). It is converted into homocysteine which is then normally converted into cysteine during digestion. Homocystinuria is a disease caused by the accumulation of homocysteine which is not converted to cysteine and is characterised by formation of clots in the veins, bone weakness, and skeletal and crystalline lens abnormalities. The use of Cystadane together with other treatments such as vitamin B6, vitamin B12, folate and a specific diet aims to reduce the elevated homocysteine levels in your body.
2. What you need to know before you take Cystadane
Do not take Cystadane
If you are allergic to betaine anhydrous.
Warnings and precautions
Talk to your doctor or pharmacist before taking Cystadane.
If you notice side effects like headaches, vomiting or a change in your vision and you are of the homocystinuria subtype called CBS (cystathionine beta-synthase deficiency), please contact your doctor immediately, they could be signs of a swelling in the brain (cerebral oedema). In that case your doctor will monitor your methionine level in your body and may review your diet. Your treatment with Cystadane may need to be interrupted.
If you are treated with Cystadane and with an amino-acid mixture and if you need to take other medicines at the same time, leave 30 minutes between the intake (see section Other medicines and Cystadane ).
Other medicines and Cystadane
Tell your doctor if you are taking, have recently taken or might take any other medicines.
If you are taking amino-acid mixture or medicines such as vigabatrin or Gaba analogues (medicine used to treat epilepsy), please tell your doctor as they might interact with your treatment with Cystadane.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will decide if you can use this medicine during pregnancy and breast-feeding.
Driving and using machines
Cystadane has no or negligible influence on the ability to drive and use machines.

3. How to take Cystadane
The use of this medicine will be supervised by a doctor experienced in the treatment of patients with homocystinuria.
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
The recommended dose in children and adults is 100mg/kg/day divided in 2 dosesper day. In some patients doses above 200 mg/kg/day were needed to reach therapeutic goals. Your doctor may adapt the dose depending on your laboratory values.
You will therefore need regular blood tests to determine the correct daily dose.
You should take Cystadane orally (by mouth).
To measure the dose:

• shake the bottle lightly before opening
• take the correct measuring spoon:
  • the small green spoon measures 100 mg of betaine anhydrous powder;
  • the middle size blue spoon measures 150 mg of betaine anhydrous powder;
  • the large pink spoon measures 1 g of betaine anhydrous powder.
  • take a heaped spoonful of powder out of the bottle
  • pass the flat back of a knife over the top of the spoon
  • the powder left in the spoon is one spoonful
  • take the correct number of spoonfuls of powder from the bottle

Mix the measured dose of powder with water, juice, milk, formula or food until completely dissolved and ingest immediately after mixing.
If you take more Cystadane than you should
If you accidentally take too much Cystadane, talk to a doctor or pharmacist immediately.
If you forget to take Cystadane
Do not take a double dose to make up for forgotten doses. If you forget to take a dose take it as soon as you remember it and continue the next dose as planned.

If you stop taking Cystadane
Do not stop the treatment without consulting your doctor. Contact your doctor or pharmacist before stopping.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most commonly side effect when taking Cystadane which may affect more than 1 in 10 people (frequency very common) is elevated levels of methionine in the blood.
Methionine level can be related to swelling in the brain (cerebral swelling), which may affect up to 1 in 100 people (frequency uncommon). If you experience morning headaches with vomiting and/or visual changes, contact immediately your doctor (they could be signs of a swelling in the brain).

Gastrointestinal disorders like diarrhoea, nausea, vomiting, stomach discomfort and inflammation of the tongue may occur uncommonly (may affect up to 1 in 100 people).
Other uncommon side effects (may affect up to 1 in 100 people) may include decreased appetite (anorexia), agitation, irritability, hair loss, hives, skin odour abnormal, lack of control over passing urine (urinary incontinence).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store Cystadane
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the bottle label and the carton after EXP. The expiry date refers to the last day of that month.

Do not store above 25 C.
Keep the bottle tightly closed in order to protect from moisture. After the first opening of the bottle, the medicine should be used within 3 months.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Cystadane contains

• The active substance is betaine anhydrous. 1 g of oral powder contains 1 g of betaine anhydrous.
• There is no other ingredient.

What Cystadane looks like and contents of the pack
Cystadane is a white crystalline free flowing powder. It is presented in bottles with child resistant closures. Each bottle contains 180 g of powder. Each carton contains one bottle and three measuring spoons.

Marketing Authorisation Holder
Orphan Europe SARL
Immeuble Le Wilson
70, avenue du General de Gaulle
F-92 800 Puteaux
France
Manufacturer
Orphan Europe SARL
Immeuble Le Wilson
70, avenue du G n ral de Gaulle
F-92800 Puteaux
France
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.
This leaflet was last revised in 8/12/2016
Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments.

Orphan Europe Ltd. Tel : + 44 (0)14 9141 4333
United Kingdom - Ireland

APPENDIX

UNITED KINGDOM

Reporting of side effects
Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Health Care Provider Letter ⮝

IMPORTANT PRESCRIBING INFORMATION

22 December 2017

Subject: Temporary importation of CYSTADANE (betaine anhydrous for oral solution) to address impending shortage

Dear Health Care Provider,

There has been a manufacturing issue with the CYSTADANE (betaine anhydrous for oral solution) approved for use and distribution in the United States ( U.S.-labeled CYSTADANE ), which has resulted in an interim shortage of this product in the U.S. market.

In order to alleviate the shortage of CYSTADANE in the U.S., Recordati Rare Diseases Inc. (Recordati) is coordinating with the U.S. Food and Drug Administration (FDA) to increase the availability of CYSTADANE. Recordati has initiated temporary importation of its CYSTADANE product approved for use in the United Kingdom into the U.S. market. This product is manufactured by Orphan Europe SARL in France. At this time, no other entity except Recordati, as the U.S. agent of Orphan Europe SARL, is authorized to import or distribute these products in the United States. FDA has not approved the product manufactured by Orphan Europe SARL s manufacturing facility in France. The imported CYSTADANE is lot CYP1705. It will be dispensed by the U.S. specialty pharmacy, AnovoRx Group LLC.

There are some key differences between the FDA-approved CYSTADANE and the imported CYSTADANE.

• Measuring scoops: FDA-approved CYSTADANE is packaged with one scoop (white) that dispenses 1g of betaine anhydrous. Imported CYSTADANE is packaged with 3 measuring scoops (green, blue, and pink) that dispense 100mg, 150mg, or 1g of betaine anhydrous. The large 1g pink scoop in the imported CYSTADANE is equivalent to the white 1g scoop in the FDA-approved CYSTADANE. Patients should pay careful attention to use the appropriate scoop to take their prescribed dose. Please pass this information along to the patients. If the incorrect scoop is utilized, improper dosing may result, and the CYSTADANE treatment can be ineffective. This may result in an increased risk for cognitive disability and/or stroke due to the progression of the underlying disease.

• Dosing: The labeled dosing in the FDA-approved CYSTADANE is 6 grams/day in divided doses of 3 grams twice daily, and, for pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day divided in twice daily doses and increased weekly by 50 mg/kg increments. The labeled dosing in the imported CYSTADANE is 100 mg/kg/day divided into 2 doses per day. Practitioners should be aware of these differences when prescribing and monitoring CYSTADANE.

A copy of the FDA-approved full prescribing information is being distributed with the imported CYSTADANE. Please refer to the FDA-approved package insert for full prescribing information. Storage conditions are the same as that of the FDA-approved product. Store at room temperature, 15 30 C (59 86 F). CYSTADANE is for oral use only. Protect from moisture. Keep this and all medications out of the reach of children.

U.S. FDA-approved Indication

CYSTADANE (betaine anhydrous for oral solution) is a methylating agent 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

For reporting of adverse events and more information

Any adverse effects or medication issues resulting from the use of this drug or quality issues should be reported to Recordati Rare Diseases Inc. at 1-888-575-8344.

Adverse events or quality problems experienced with the use of this product may also be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax:

• Complete and submit the report Online: www.fda.gov/medwatch/report.htm
• Regular mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178.

Important Safety Information

• Hypermethioninemia: CYSTADANE may worsen elevated plasma methionine concentrations in patients with CBS deficiency. Cerebral edema has been reported in patients receiving CYSTADANE.
• Monitoring: Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 mol/L through dietary modification and, if necessary, a reduction of CYSTADANE dose.
• Most common adverse reactions (incidence > 2%) were nausea and gastrointestinal distress, based on physician survey.
• Pregnancy: Animal reproduction studies have not been conducted with CYSTADANE. Use only if clearly needed.
• Nursing women: It is not known whether CYSTADANE is excreted in human milk. Use only if clearly needed.
• 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.

We are committed to helping address patients unmet needs through our corporate mission. If you have questions or concerns regarding this product, please call AnovoRx Group, the specialty pharmacy that dispenses CYSTADANE, at 1 888-487-4703 or Recordati Rare Diseases Medical Information at 1 888-575-8344.

Steven R. Peltier

Vice President, Regulatory & Quality Compliance

Chief Compliance Officer

Recordati Rare Diseases Inc.

FDA-approved (U.S.) Bottle Label:

Imported (U.K.) Bottle Label:

Imported (U.K.) Carton:

Recent Major Changes ⮝

Changes of Address 08/2008
Address of adverse reactions 07/2010
Change of distributor 07/2014
Manufactured For / Under License From 07/2014

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.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 7/2014

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
  

3 Dosage Forms And Strengths ⮝

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

5 Warnings And Precautions ⮝

5.1 Hypermethioninemia

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 mol/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

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 M). 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:

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 AnovoRx Group, LLC, Customer service at 1-888-487-4703

16.1 Storage

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

No Title 1572455491 ⮝

CYSTADANE betaine powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:66621-4000 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BETAINE (UNII: 3SCV180C9W) (BETAINE - UNII:3SCV180C9W) BETAINE 6 g

Product Characteristics Color white (none) Score Shape Size Flavor Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:66621-4000-1 180 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020576 10/25/1996

Labeler - Rare Disease Therapeutics, Inc. (966133100)

Registrant - Rare Disease Therapeutics, Inc. (966133100)

Establishment
Name	Address	ID/FEI	Business Operations
Rare Disease Therapeutics, Inc.		966133100	relabel(66621-4000)

Establishment
Name	Address	ID/FEI	Business Operations
Ropack Pharmaceutical		209989631	manufacture(66621-4000)

Revised: 1/2015 Document Id: d797121e-e13a-41b8-b7d7-e104ba26077c 34391-3 Set id: 84f7c21f-d0af-4ae6-9cd5-d5af96ade329 Version: 16 Effective Time: 20150109 Rare Disease Therapeutics, Inc.