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Home , Homocystinuria, Hypermethioninemia, Phenylketonuria

Living with Classical

This brochure will help you understand what classical homocystinuria is, how it affects your body, and how you can manage your condition A few words about this brochure What is homocystinuria?

Has your doctor diagnosed you or your child You may have heard the word “homocystinuria” with homocystinuria (HO-mo-SIS-tin-YUR- for the first time when your doctor talked to ee-uh)? There are three types of genetic you about possibly having this condition. disorders that cause homocystinuria. Each Homocystinuria is a rare disorder involving type has a different cause and different the (HO-mo-SIS- health issues. This brochure will talk about teen). Amino acids are building blocks that your classical homocystinuria. The information body uses to make proteins. Homocystinuria will help you understand classical occurs when there is a buildup of the amino acid homocystinuria and how you can manage homocysteine in your and . your condition. High levels of homocysteine can be harmful to your body. You may be reading this brochure because you have classical homocystinuria or Why is there homocysteine because your child or a sibling or a friend in your body? has it. Or perhaps you’re a healthcare professional. Please note the brochure It starts with the foods you eat. Your body addresses “you,” but it’s understood that makes homocysteine from another amino acid “you,” the reader, may not have classical called (meh-THIGH-uh-neen). Most homocystinuria yourself. foods contain some methionine. But high- foods such as meat, fish, eggs, or cheese tend to have the most methionine. Plant-based foods such as beans, tofu, and nuts also have higher amounts of methionine. So when you eat these types of foods, more methionine enters your body. Then your body breaks down or metabolizes the methionine you’ve eaten into homocysteine.

2 3 Jason Danielle What causes classical Why do you have Unaffected Unaffected homocystinuria? classical homocystinuria? “carrier” “carrier” R r R r

You have classical homocystinuria Classical homocystinuria is a genetic R R R r R r r r if you have an abnormal variation of the condition, which is another way of saying CBS (cystathionine beta-synthase) gene. you inherited it from your parents. Classical The job of the CBS gene is to make CBS homocystinuria occurs when you inherit . This enzyme helps your body two copies of an abnormal variation of break down homocysteine into , the CBS gene, one from each parent. (The another amino acid that your body needs. medical term for this kind of inheritance If you have classical homocystinuria, your is autosomal recessive.) Since classical CBS gene makes too little CBS enzyme or homocystinuria is caused by , it is none at all, or it makes CBS enzyme that a lifelong condition. Kayla Brady Jennifer James does not work properly. Without enough Unaffected Unaffected “carrier” Affected 1 in 4 chance 2 in 4 chance 1 in 4 chance CBS enzyme activity, your body cannot break down enough homocysteine to keep If you have classical homocysteine levels within the normal range. homocystinuria, you were born So homocysteine levels build up in your body, This diagram shows with it, even if you didn’t have how classical Both of them could potentially pass which can cause serious health problems. homocystinuria may affect families. In this the abnormal variation of the CBS gene symptoms right away. family, the parents, Jason and Danielle, are to their future children. Kayla has two carriers of classical homocystinuria. Each child normal copies of the CBS gene. She will Other names for classical in the family has a 1 in 4 chance of having pass on a normal copy of the CBS gene homocystinuria are CBS If you have classical homocystinuria and classical homocystinuria. In this case, James, to any future children that she has. your parents do not, then they are carriers their son, has the condition because he inherited deficiency and homocystinuria Being a carrier of classical of the condition. This means they have one two abnormal variations of the CBS gene. The homocystinuria is much more common caused by CBS deficiency. normal copy and one abnormal variation other children – Jennifer, Brady, and Kayla – do than having the condition. That’s why of the CBS gene. They don’t have classical not have classical homocystinuria. But Jennifer many people who are diagnosed with homocystinuria because their normal copy and Brady are carriers of the condition because classical homocystinuria have no known of the CBS gene produces enough of the they have one normal copy and one abnormal family history of the condition. CBS enzyme to keep homocysteine levels variation of the CBS gene. at normal levels.

4 5 How is classical homocystinuria diagnosed? Are there different types of classical homocystinuria?

Your doctor will order blood tests screening is not perfect and may not catch Yes – your classical homocystinuria can be: If your body is making enough CBS to determine if you have classical all newborns with the condition. In some • Vitamin B6-responsive or enzyme, then vitamin B6 – also called homocystinuria. If the results show high newborns, the level of methionine may not (PEER-uh-DOX-een)-responsive pyridoxine – may help the CBS enzyme levels of homocysteine and methionine be high enough at the time of the screening do its job. If your body is not making in your blood, then most likely you have test to trigger a positive result. Also, some • Partially vitamin B6-responsive enough CBS enzyme, then vitamin B6 classical homocystinuria. Your doctor may babies who are born early (premature) may or partially pyridoxine-responsive probably won’t help. also suggest more blood testing to identify not be developed enough for the screening • Vitamin B6-non-responsive It is important for your doctor to know the variation in your CBS gene. This is known to be accurate. or pyridoxine-non-responsive what type of classical homocystinuria as “DNA sequencing,” and it’s done by a Some people are not diagnosed with Your doctor will need to do another test you have in order to develop the right special lab. can confirm homocystinuria until after symptoms appear. to determine which type of classical treatment plan for you. a diagnosis of classical homocystinuria. Symptoms may develop at different times homocystinuria you have. This test is called The results from your CBS gene In the , every state screens for different people, so diagnosis can occur a vitamin B6 challenge or a pyridoxine testing may suggest whether you will newborns for classical homocystinuria. at any age. And because homocystinuria is challenge. The purpose is to find out how you be vitamin B-6-responsive, but the The screening test measures blood levels rare, some doctors may not recognize the will respond to vitamin B6. only way to know for sure is to do the of methionine. If the test symptoms right away and the diagnosis can vitamin B6 challenge test. result is positive, then your doctor will order be delayed. more testing to confirm the result. Newborn

“Until I was diagnosed with homocystinuria at age 54, the doctors thought I had . When I was around 2 years old, “Samantha had an abnormal newborn screening, I developed dislocated lenses so I had to start wearing really thick and a month or two later a genetic test confirmed her glasses. In high school, I developed scoliosis so I had to wear a back homocystinuria diagnosis. She started treatment right brace 23 hours a day for over a year. I wasn’t allowed to participate away. She’s 2 now, and she’s doing really well. in PE because of my back. Years later I started having trouble She hasn’t had any symptoms.” with blood clots, and at age 46 I had a .” Amber G., mother of Samantha, – Pam P., person living with classical homocystinuria who has classical homocystinuria

6 7 Here’s how the B6 challenge test may be done: How can classical homocystinuria affect your health?

1. While on your normal , your blood 4. Two days after being on the higher dose, High homocysteine levels can be harmful to your Bones: homocysteine and methionine levels will your blood homocysteine and methionine body, mainly in four areas: brain, eyes, bones, and • Bones that grow longer than normal, be measured. After your blood sample levels will be measured again. blood. Complications in each of these areas may for example, tall body with long has been drawn, you will take a specific include: 5. If no change has occurred, then you will arms, legs, fingers, and toes amount of vitamin B6 by mouth for 2 days take a final, larger amount of vitamin B6. Brain: • Abnormally curved spine (scoliosis) in a row. 6. Your blood homocysteine and methionine • Learning problems and developmental delays, • Brittle or weak bones () 2. Two days after your first dose, your blood levels will be measured a final time for such as being slow to sit up, walk, or talk – homocysteine and methionine levels will Blood: the test. common early symptoms in children be measured again. • Behavioral problems, such as anxiety • Development of blood clots in veins 3. If no significant change has occurred, and depression or arteries that can obstruct blood flow. These may occur in the arms, you will take a larger amount of vitamin B6 • for 2 days in a row. legs, brain (resulting in stroke), • Increased risk of (from blood clots or lungs (resulting in pulmonary developing in the brain or traveling to the brain) embolism) Test results Eyes: Vitamin B6-responsive Partially vitamin B6- Vitamin B6-non-responsive • Near-sightedness (often severe) – The medical term for or pyridoxine-responsive responsive or partially or pyridoxine-non-responsive a common and early symptom in children a blood clot is thrombus. If the levels of homocysteine pyridoxine-responsive If the levels of homocysteine • Lens dislocation – a common and early When a blood clot breaks and methionine in your blood If the levels of homocysteine and methionine in your blood symptom in children off and travels through the are greatly reduced with the and methionine in your blood are not reduced with the use • Quivering of the iris (the colored part bloodstream to another use of vitamin B6, then you are are somewhat reduced with of vitamin B6, then you are of the eye) part of the body, the vitamin B6-responsive the use of vitamin B6, then vitamin B6-non-responsive • Increased pressure in the eye () medical term or pyridoxine-responsive. you are partially vitamin or pyridoxine-non-responsive. is thromboembolism. B6-responsive or partially pyridoxine-responsive.

8 9 How can classical What vitamins may be helpful homocystinuria be managed? for classical homocystinuria?

Hearing from your doctor that you have Your treatment Vitamin B6 (pyridoxine) classical homocystinuria may be unsettling plan for classical supplements for you and your family. But even though homocystinuria Vitamin B6 is a “helper” classical homocystinuria is a rare disorder, may include: in the body. It plays a lot is known about how to treat it. a key role in helping the CBS enzyme break down • Taking vitamin B6 and additional homocysteine. So vitamin B6 supplements can Ideally you should be treated by a metabolic B vitamins be an important part of therapy for some people specialist who is familiar with managing with classical homocystinuria. classical homocystinuria. A metabolic • Eating a low-protein diet If you have B6-responsive classical specialist is a doctor who specializes in • Taking a methionine-free formula treating genetic conditions that involve homocystinuria, then you may be able to lower the body’s . Most centers that “Do some research to find the right • Taking certain medicines and maintain your target homocysteine levels treat metabolic disorders have specialist doctor – a metabolic specialist with vitamin B6 supplements alone. Vitamin B6-non-responsive dietitians on staff to help people whose who knows about classical homocystinuria tends to be more If you have either B6-non-responsive or partially conditions require special diets. Your homocystinuria and has experience severe and needs more treatment. vitamin B6-responsive classical homocystinuria, healthcare team will develop a treatment with other patients. It might take then vitamin B6 supplements will not lower your plan based on your needs. You should work you a little while and you might homocysteine levels enough, and you will need closely with the team to develop your plan. have to travel, but things will other therapies. The goal of treatment is to prevent or be much better in the long run. reduce symptoms or complications by Samantha’s healthcare team has Additional B vitamin keeping homocysteine levels in your body been a lifesaver. Whenever I have supplements as close to normal as possible. Your doctor a question, I can email and they’ll Other B vitamins – B12 and – also play may use the words, “achieving your target respond right away. They know important roles in breaking down methionine blood homocysteine levels.” the answer and they know how in the body. and folate supplements may be part of your treatment plan if the levels to take care of things.” of these vitamins in your body are too low. – Amber G., mother of Samantha, who has classical homocystinuria

10 11 What about diet? Are changes required? What about diet? Are changes required?

If you cannot lower your homocysteine Your low-protein diet plan may A methionine-free formula levels enough with vitamin B6, then you will include three lists of foods: need to eat a special diet to help manage If you have to eat a low-protein diet to lower • Foods you cannot eat because they will your condition. and then maintain lower homocysteine levels, raise blood homocysteine levels. These your body may not get enough of the essential A low-protein diet foods may include meat, fish, eggs, amino acids it needs through the food that you and cheese. Foods such as beans, soy eat. You can buy methionine-free formulas that A low-protein diet limits the methionine products, and nuts may also be on this list. contain the additional amino acids that your you eat in order to keep your homocysteine body needs. Taking formula will help prevent levels under control. Specialist dietitians can • Foods you can eat a little of. These “in malnutrition that can occur if you don’t eat suggest low-protein foods and menus that between” foods contain some protein, but not as much as foods such as meat and enough protein. However, some people may you like and that also fit into your lifestyle. “Samantha gets upset when eggs. Your dietitian will explain what these not like the taste of the formula. If you are one foods are and how much of them you can I tell her she can’t have of these people, you can ask your specialist eat each day. some of the foods her dietitian for creative formula mixtures that may “At parties or during holidays brother eats. Sometimes he work better for you. I usually take at least one dish • Foods you can eat a lot more of, such wants to try her low-protein as most fruits and vegetables which The combination of diet and formula can help I know I can eat. My best foods, but I tell him he contain little or no protein. These foods you maintain target blood homocysteine levels friends all know I’ll bring my are sometimes called “free” foods. can’t because it wouldn’t so you can lower your chances of developing own food. Sometimes it’s still be fair to Samantha. He’s symptoms or complications. The combination hard, though, when I’m with Staying on your special diet may be hard such a big help. He’s can also provide the nutrients you need to grow to do, especially when everyone else in your my family and they’ve ordered starting to read labels at and be healthy. life is eating foods on your “cannot eat” list. steak or prime rib. But then A plan may look good on paper, but it won’t grocery stores. He’ll say, I tell myself that if I don’t do work if it stresses you out or you just can’t “Mommy, this has 2 grams what I’m supposed to, I could stick to it. Be honest with your dietitian of protein per serving. end up with problems.” and ask for help so that your diet plan Samantha can have this.” – Pam P., person living with is achievable and realistic. – Amber G., mother of Samantha, classical homocystinuria who has classical homocystinuria

12 13 What medicines may be helpful Indications and Usage Important Safety Information in classical homocystinuria?

Aspirin or warfarin Cystadane® (betaine anhydrous CYSTADANE® (betaine anhydrous • in Patients with CBS for oral solution) for oral solution) is indicated in Deficiency: CYSTADANE may worsen high If you have had a blood clot or if you children and adults for the treatment methionine blood levels and accumulation have a higher risk of developing a blood CYSTADANE is a prescription medicine that of homocystinuria to decrease of excess fluid in the brain has been reported. clot, your doctor may want you to take provides a different “pathway” in your body high homocysteine blood levels. If you have been told you have CBS deficiency, a medicine that can help prevent blood to convert homocysteine back to methionine, Homocystinuria is a rare genetic your doctor will be monitoring your methionine clots from developing. Aspirin and lowering the levels of homocysteine in your disorder in which there is an blood levels to see if changes in your diet and warfarin are two medicines used blood. CYSTADANE is powdered betaine. abnormal accumulation of the amino dosage are necessary. for this purpose. Betaine is produced naturally in the body. acid homocysteine in the blood and • Most common side effects were nausea and Some foods, such as beets, spinach, cereals, urine. The following are considered gastrointestinal distress, based on a survey and seafood, also contain tiny amounts to be homocystinuria disorders: of betaine. of doctors. • Cystathionine beta-synthase Your doctor may add CYSTADANE to • To report SUSPECTED SIDE EFFECTS, (CBS) deficiency your treatment plan to help lower your contact Recordati Rare Diseases Inc. at “It’s been 6 years since homocysteine blood levels. People with • 5,10-methylenetetrahydrofolate 1-888-575-8344, or FDA at 1-800-FDA-1088 I was properly diagnosed classical homocystinuria may have high blood reductase (MTHFR) deficiency or www.fda.gov/medwatch. with classical homocystinuria, levels of both homocysteine and methionine. • Cobalamin metabolism and I feel like I’ve gotten CYSTADANE may worsen high methionine (cbl) defect a second chance at life. levels, possibly causing excess fluid to build Since I started eating up in the brain. So if you take CYSTADANE, a low-protein diet and taking your doctor will regularly monitor your the medicines my doctor methionine blood levels to see if changes to has prescribed, my blood your CYSTADANE dosage or diet are needed. homocysteine levels have The most common side effects of CYSTADANE been well-controlled.” are nausea and gastrointestinal distress, – Pam P., person living based on a survey of doctors. For more CYSTADANE is a licensed trademark of Please see accompanying Prescribing with classical homocystinuria information, visit www.cystadane.com. Recordati Rare Diseases Inc. Information.

14 15 Why is it important to follow What are some good ways to meet the challenges your treatment plan? caused by classical homocystinuria?

Losing control of blood homocysteine “When you first get the There are many things you can do to meet the • Work with a specialist dietitian levels at any age may lead to serious diagnosis, don’t panic challenges of living with classical homocystinuria. to plan and periodically update health problems, such as learning and don’t go internet- Working well with your healthcare team is very your low-protein diet plan when problems and delays in child crazy. Homocystinuria is important. Here are things you can do that may needed. Be sure your diet plan development, mental health problems, help you get the most out of your doctor visits: is manageable for you. If it’s not, manageable, even though it seizures, vision problems, and weak keep working with your dietitian. • See your doctor regularly to check your bones. Some complications, such may not seem so at first.” blood homocysteine and methionine • See other doctors as needed. as blood clots, may be potentially – Amber G., mother of Samantha, who has classical homocystinuria levels. Your blood test results will allow your Your overall health and well- life-threatening. doctor to see how well your treatment plan being are very important, and, However, much evidence shows that and diet are working and to adjust these as someone with classical controlling homocysteine levels can plans as necessary. For adults, blood testing homocystinuria, you’ll have added lower your chances of developing may be done every 6 months, or potentially needs. Specifically, you should complications. more often if homocysteine levels are higher see doctors to monitor your than desired. For children who need to eat vision, bone health, and heart If you already have some complications, a low-protein diet, blood testing may be done health. These areas of your body proper treatment may slow or stop their more frequently since they are still growing are more likely to be affected progression or prevent them from and their needs may change as they grow. by classical homocystinuria. happening again.

16 17 Here are more things you can These tools may be useful do for yourself and your family: if you need to follow a low-protein diet:

• Follow your treatment plan – every day! • Find additional information • AccuGo for HCU – This app for iPhones, • CookForLove.org – This The goal of your plan is to help you achieve and support through patient sponsored by HCU Network , website provides step-by-step your target homocysteine levels. By following advocacy organizations. provides a quick and easy way to estimate instructions and cooking videos your plan, you can prevent or lessen further and track protein and methionine in foods. for making tasty and nutritious • Be your own best advocate damage to areas of your body that are The app uses data from Australia/New low-protein recipes. Most by following your instincts and affected by high homocysteine levels. Zealand and USDA food lists, a community ingredients can be found doing your own research if food list, and a personal food list. in local grocery stores. • Eat a low-protein diet without having something doesn’t seem quite to buy lots of expensive foods online. right. But always talk to your • HowMuchPhe.org – This website provides Grocery stores may carry low-protein foods, doctor and healthcare team access, by subscription, to a list of more such as some non-dairy cheeses and rice before making any changes than 7,000 low-protein foods. You can milk. Many grocery stores may also have to your treatment plan. search for foods by name using any mobile a gluten-free section, and some packaged device that connects to the internet. The • Encourage family members gluten-free foods may be lower in protein site was originally developed for people with to talk to their doctors about content compared to the non-gluten-free (PKU), a rare genetic disease getting tested for classical versions. Always read food labels, and check that also requires a low-protein diet. homocystinuria. Early diagnosis with your dietitian about any foods you aren’t and lifelong treatment are sure about. Also, there are many low-protein the best ways to prevent recipes and other diet management tools complications. Also encourage online. family members to get tested • Eat as many “free” foods as you want, even to see if they are carriers. if you must follow a low-protein diet. Many A confirmed carrier may also vegetables and fruits are “free” foods, so want to find out if their partner here’s to watermelon and green peppers! is a carrier, too, so that they can best plan for their family’s future.

18 19 HIGHLIGHTS OF PRESCRIBING INFORMATION • Increase the dosage gradually until the plasma total homocysteine concentration is These highlights do not include all the information needed to use CYSTADANE safely undetectable or present only in small amounts. (2.1) and effectively. See full prescribing information for CYSTADANE. Preparation and Administration Instructions ® • Prescribed amount of CYSTADANE should be measured with the measuring scoop Cystadane provided and then dissolved in 4 to 6 ounces of water, juice, milk, or formula until (betaine anhydrous for oral solution) completely dissolved, or mixed with food for immediate ingestion. (2.2) DOSAGE FORMS AND STRENGTHS Initial U.S. Approval: 1996 For oral solution: in bottles containing 180 grams of betaine anhydrous. (3) INDICATIONS AND USAGE CONTRAINDICATIONS CYSTADANE is a methylating agent indicated in pediatric and adult patients for the None (4) treatment of homocystinuria to decrease elevated homocysteine blood concentrations. WARNINGS AND PRECAUTIONS Included within the category of homocystinuria are (1): • Hypermethioninemia in Patients with CBS Deficiency: CYSTADANE may worsen • Cystathionine beta-synthase (CBS) deficiency elevated plasma methionine concentrations and cerebral edema has been reported. • 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency Monitor plasma methionine concentrations in patients with CBS deficiency. Keep What resources provide information about • Cobalamin cofactor metabolism (cbl) defect plasma methionine concentrations below 1,000 micromol/L through dietary DOSAGE AND ADMINISTRATION modification and, if necessary, a reduction of CYSTADANE dosage. (5.1) homocystinuria and a low-protein diet? Adults and Pediatric Patients 3 Years of Age and Older ADVERSE REACTIONS • The recommended dosage is 6 grams per day, administered orally in divided doses of Most common adverse reactions (> 2%) are: nausea and gastrointestinal distress, based 3 grams twice daily. (2.1) on physician survey. (6.1) Pediatric Patients Less than 3 Years of Age To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at • The recommended starting dosage is 100 mg/kg/day, administered orally in divided 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. These organizations provide information about “Be your own best doses of 50 mg/kg twice daily, and then increased weekly by 50 mg/kg increments. (2.1) See 17 for PATIENT COUNSELING INFORMATION. classical homocystinuria: advocate. Follow your • Monitor patient response by plasma homocysteine concentrations. (2.1) Revised 10/2019 • HCU Network America – The mission of instincts and do your own FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation 1 INDICATIONS AND USAGE 8.4 Pediatric Use HCU Network America is to help people with research if something 2 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 2.1 Dosage 11 DESCRIPTION homocystinuria (HCU) and related disorders doesn’t seem quite right. 2.2 Preparation and Administration Instructions 12 CLINICAL PHARMACOLOGY 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action manage their disease and to find a cure. Join online support groups 4 CONTRAINDICATIONS 12.2 Pharmacodynamics 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics where others can help you 5.1 Hypermethioninemia in Patients with CBS Deficiency 13 NONCLINICAL TOXICOLOGY • HCU Network Australia – The aims of HCU 6 ADVERSE REACTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility find the right resources.” 6.1 Clinical Trials Experience 14 CLINICAL STUDIES Network Australia are to provide support and 6.2 Postmarketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING education for people affected by homocystinuria, – Pam P., person living with 8 USE IN SPECIFIC POPULATIONS 17 PATIENT COUNSELING INFORMATION 8.1 Pregnancy *Sections or subsections omitted from the full prescribing information are not listed. improve diagnosis to enable appropriate classical homocystinuria treatment, and support clinical research. FULL PRESCRIBING INFORMATION • Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until 1 INDICATIONS AND USAGE completely dissolved, or mix with food, then ingest mixture immediately. CYSTADANE® is indicated for the treatment of homocystinuria to decrease elevated • Always replace the cap tightly after using and protect the bottle from moisture. • EHOD – European Network and Registry for homocysteine blood concentrations in pediatric and adult patients. Included within the 3 DOSAGE FORMS AND STRENGTHS category of homocystinuria are: CYSTADANE is a white, granular, hygroscopic powder for oral solution available in bottles Homocystinurias and Methylation Defects • Cystathionine beta-synthase (CBS) deficiency containing 180 grams of betaine anhydrous. – The aim of E-HOD is to improve the health • 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency 4 CONTRAINDICATIONS • Cobalamin cofactor metabolism (cbl) defect None. of people affected with homocystinurias and 2 DOSAGE AND ADMINISTRATION 5 WARNINGS AND PRECAUTIONS 2.1 Dosage 5.1 Hypermethioninemia in Patients with CBS Deficiency methylation defects by developing a patient Therapy with CYSTADANE should be directed by physicians knowledgeable in the Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may management of patients with homocystinuria. also have elevated plasma methionine concentrations. Treatment with CYSTADANE may registry, developing diagnostic and clinical care Adults and Pediatric Patients 3 Years of Age and Older further increase methionine concentrations due to the remethylation of homocysteine The recommended dosage is 6 grams per day, administered orally in divided doses of to methionine. Cerebral edema has been reported in patients with hypermethioninemia, protocols, and evaluating newborn screening 3 grams twice daily. including patients treated with CYSTADANE [see Adverse Reactions (6.2)]. Monitor programs. Pediatric Patients Less than 3 Years of Age plasma methionine concentrations in patients with CBS deficiency. Plasma methionine The recommended starting dosage is 100 mg/kg/day divided in twice daily doses, and concentrations should be kept below 1,000 micromol/L through dietary modification and, then increased weekly by 50 mg/kg increments. if necessary, a reduction of CYSTADANE dosage. Monitoring 6 ADVERSE REACTIONS Monitor patient response to CYSTADANE by homocysteine plasma concentration. The following serious adverse reactions are described elsewhere in labeling: Increase the dosage in all patients gradually until the plasma total homocysteine • Hypermethioninemia and cerebral edema in patients with CBS deficiency Thank you to Dr. James Weisfeld-Adams for his contributions to the development and review of this brochure. concentration is undetectable or present only in small amounts. An initial response in [see Warnings and Precautions (5.1)]. homocysteine plasma concentrations usually occurs within several days and steady state 6.1 Clinical Trials Experience plasma concentrations occur within a month. Because clinical trials are conducted under widely varying conditions, adverse reaction Monitor plasma methionine concentrations in patients with CBS deficiency[See Warnings 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. © 2019 Recordati Rare Diseases Inc. and Precautions (5.1)]. Recordati Rare Diseases Inc. • Lebanon, NJ 08833 Maximum Dosage The assessment of clinical adverse reactions is based on a survey study of 41 physicians, www.recordatirarediseases.com/us • PP-CYS-US-0134 Dosages of up to 20 grams/day have been necessary to control homocysteine who treated a total of 111 homocystinuria patients with CYSTADANE. Adverse reactions concentrations in some patients. However, one pharmacokinetic and pharmacodynamic were retrospectively recalled and were not collected systematically in this open-label, in vitro simulation study indicated minimal benefit from exceeding a twice-daily dosing uncontrolled, physician survey. Thus, this list may not encompass all types of potential schedule and a 150 mg/kg/day dosage for CYSTADANE. adverse reactions, reliably estimate their frequency, or establish a causal relationship to drug exposure. The following adverse reactions were reported (Table 1): 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 (1.7 mL) is equivalent to 1 gram of betaine anhydrous powder. Table 1: Number of Patients with Adverse Reactions to CYSTADANE by Physician In CBS-deficient patients, large increases in methionine concentrations over baseline Survey have been observed. CYSTADANE has also been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) concentrations in patients with MTHFR Adverse Reactions Number of Patients deficiency and cbl defect. Nausea 2 12.3 Pharmacokinetics Gastrointestinal distress 2 Pharmacokinetic studies of CYSTADANE are not available. Plasma betaine concentrations Diarrhea 1 following administration of CYSTADANE have not been measured in patients and have not been correlated to homocysteine concentrations. “Bad Taste” 1 13 NONCLINICAL TOXICOLOGY “Caused Odor” 1 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Questionable psychological changes 1 Long-term carcinogenicity and fertility studies have not been conducted with CYSTADANE. “Aspirated the powder” 1 No evidence of genotoxicity was demonstrated in the following tests: metaphase analysis of human lymphocytes; bacterial reverse assay; and mouse micronucleus test. 6.2 Postmarketing Experience 14 CLINICAL STUDIES The following adverse reactions have been identified during post approval use of CYSTADANE was studied in a double-blind, placebo-controlled, crossover study in 6 CYSTADANE. Because these reactions are reported voluntarily from a population of patients (3 males and 3 females) with CBS deficiency, ages 7 to 32 years at enrollment. uncertain size, it is not always possible to reliably estimate their frequency or establish a CYSTADANE was administered at a dosage of 3 grams twice daily, for 12 months. Plasma causal relationship to drug exposure. homocystine concentrations were significantly reduced (p<0.01) compared to placebo. Severe cerebral edema and hypermethioninemia have been reported within 2 weeks to Plasma methionine concentrations were variable and not significantly different compared 6 months of starting CYSTADANE therapy, with complete recovery after discontinuation to placebo. of CYSTADANE. All patients who developed cerebral edema had homocystinuria due to CYSTADANE has also been evaluated in observational studies without concurrent controls CBS deficiency and had severe elevation in plasma methionine concentrations (range in patients with homocystinuria due to CBS deficiency, MTHFR deficiency, or cbl defect. 1,000 to 3,000 microM). As cerebral edema has also been reported in patients with A review of 16 case studies and the randomized controlled trial previously described hypermethioninemia, secondary hypermethioninemia due to betaine therapy has been was also conducted, and the data available for each study were summarized; however, postulated as a possible mechanism of action [see Warnings and Precautions (5.1)]. no formal statistical analyses were performed. The studies included a total of 78 male Other adverse reactions include: anorexia, agitation, depression, irritability, personality and female patients with homocystinuria who were treated with CYSTADANE. This disorder, sleep disturbed, dental disorders, diarrhea, glossitis, nausea, stomach included 48 patients with CBS deficiency, 13 with MTHFR deficiency, and 11 with cbl discomfort, vomiting, hair loss, hives, skin odor abnormalities, and urinary incontinence. defect, ranging in age from 24 days to 53 years. The majority of patients (n=48) received 8 USE IN SPECIFIC POPULATIONS 6 gm/day, 3 patients received less than 6 gm/day, 12 patients received doses from 8.1 Pregnancy 6 to 15 gm/day, and 5 patients received doses over 15 gm/day. Most patients were treated Risk Summary for more than 3 months (n=57) and 30 patients were treated for 1 year or longer (range Available data from a limited number of published case reports and postmarketing 1 month to 11 years). Homocystine is formed nonenzymatically from two molecules experience with CYSTADANE use in pregnancy have not identified any drug associated of homocysteine, and both have been used to evaluate the effect of CYSTADANE in risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal patients with homocystinuria. Plasma homocystine or homocysteine concentrations reproduction studies have not been conducted with betaine. 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- The estimated background risk of major birth defects and miscarriage for the indicated treatment concentration, and homocysteine decreased by 71 to 83%, regardless of the population is unknown. All pregnancies have a background risk of birth defect, loss, or pre-treatment concentration. Clinical improvement, such as improvement in seizures, or other adverse outcomes. In the U.S. general population, the estimated background risk behavioral and cognitive functioning, was reported by the treating physicians in about of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and three-fourths of patients. Many of these patients were also taking other therapies such 15 to 20%, respectively. as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), and folate with variable biochemical 8.2 Lactation responses. In most cases, adding CYSTADANE resulted in a further reduction of either Risk Summary homocystine or homocysteine concentrations. There are no data on the presence of betaine in human or animal milk, the effects on 16 HOW SUPPLIED/STORAGE AND HANDLING the breastfed child, or the effects on milk production. The developmental and health CYSTADANE is available in plastic bottles containing 180 grams of betaine anhydrous as a benefits of breastfeeding should be considered along with the mother’s clinical need for white, granular, hygroscopic powder. Each bottle is equipped with a plastic child-resistant CYSTADANE and any potential adverse effects on the breastfed child from CYSTADANE or cap and is supplied with a polypropylene measuring scoop. One level scoop (1.7 mL) is from the underlying maternal condition. equal to 1 gram of betaine anhydrous powder. 8.4 Pediatric Use NDC 52276-400-01 180 g/bottle The safety and effectiveness of CYSTADANE have been established in pediatric patients. The majority of case studies of homocystinuria patients treated with CYSTADANE have Storage been pediatric patients, including patients ranging in age from 24 days to 17 years [see Store at room temperature, 15 to 30 ˚C (59 to 86 ˚F). Protect from moisture. Clinical Studies (14)]. Children younger than 3 years of age may benefit from dose 17 PATIENT COUNSELING INFORMATION titration [see Dosage and Administration (2.1)]. Preparation and Administration Instructions 10 OVERDOSAGE Instruct patients and caregivers to administer CYSTADANE as follows: There is no information on CYSTADANE overdose in humans. In an acute toxicology • Shake bottle lightly before removing cap. study in rats, death occurred frequently at doses equal to or greater than 10 g/kg. • 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. 11 DESCRIPTION • Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until CYSTADANE (betaine anhydrous for oral solution) is an agent for the treatment of completely dissolved, or mix with food, then ingest mixture immediately. homocystinuria. It contains no ingredients other than anhydrous betaine. CYSTADANE is • Always replace the cap tightly after using and protect bottle from moisture. a white, granular, hygroscopic powder, which is diluted in water and administered orally. The chemical name of betaine anhydrous powder is . It has a molecular Supplied by: weight of 117.15. The structural formula is: Recordati Rare Diseases Puteaux, Licensed to and Distributed by: Recordati Rare Diseases Inc. Lebanon, NJ 08833 U.S.A.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action For drug or ordering information please call AnovoRx Group, LLC, Customer service at CYSTADANE acts as a methyl group donor in the remethylation of homocysteine to 1-888-487-4703. 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, CYSTADANE cereals, and seafood. betaine anhydrous for oral solution

12.2 Pharmacodynamics ® CYSTADANE was observed to lower plasma homocysteine concentrations in three CYSTADANE is a licensed trademark of Recordati Rare Diseases Inc. types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect. This product label may have been updated. For the most recent prescribing information, Patients have taken CYSTADANE for many years without evidence of tolerance. There please visit www.recordatirarediseases.com. has been no demonstrated correlation between Betaine concentrations and homocysteine Part No.: Recordati Rare Diseases, OEP1000 V2 PP-CYS-US-0128 concentrations.