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Home , Cofactor (biochemistry)

Living with a Cobalamin Defect

This brochure will help you understand the different types of cobalamin cofactor metabolism defects that cause homocystinuria, how they affect 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 be reading this brochure because You may have heard the word “homocystinuria” with a cobalamin (co-BAL-uh-min) cofactor you have a cobalamin cofactor metabolism for the first time when your doctor talked metabolism defect? Cobalamin cofactor defect or because your child or a sibling to you about possibly having a cbl defect. metabolism defects are one of three types of or a friend has one. Or perhaps you’re Homocystinuria caused by cbl defects is the genetic disorders that cause homocystinuria a healthcare professional. Please note name for a group of rare disorders involving the (HO-mo-SIS-tin-YUR-ee-uh). The information the brochure addresses “you,” but it’s amino acid homocysteine (HO-mo-SIS-teen). in this brochure will help you understand understood that “you,” the reader, may not Amino acids are building blocks that your body these defects and how you can manage have a cobalamin cofactor metabolism uses to make . Homocystinuria occurs your condition. defect yourself. when there is a buildup of homocysteine in your blood and urine. High levels of homocysteine For the remainder of this brochure, can be harmful to your body. cobalamin (cbl) cofactor metabolism defects will be referred to as cbl defects. How does homocysteine get in your body? It starts with the foods you eat. Your body makes homocysteine from another amino acid called (meh-THIGH-uh-neen). Most 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 How do cbl defects cause homocystinuria? Are there different types of cbl defects?

Since too much homocysteine can harm However, the process can break down if: Yes – there are many types of cbl a certain reaction cannot take place. your body, it needs to convert some of the defects. Each type is named with a This results in the buildup of a substance called - Your body cannot successfully homocysteine back to methionine. This different letter of the alphabet. The methylmalonic (MEH-thul-muh-LON-ik) acid complete the steps to produce enough process involves cobalamin – also called type of cbl defect you have depends on (MMA) that your body makes when it digests . B12—that you get from the foods you what gene is affected and where the protein. High levels of MMA in your blood can eat. Your body goes through a series of steps - Your body cannot produce the process breaks down. Some cbl defects cause harmful symptoms to develop. This to convert into methylcobalamin it needs for the to occur, also cause a second disorder along condition is called . (MEH-thul-co-BAL-uh-min). This is the form or your body makes enzymes that do not with homocystinuria. These are called of cobalamin that your body needs to convert work properly. “combined disorders.” Individuals who have a combined disorder homocysteine back to methionine. have both homocystinuria and methylmalonic Why would this happen? Your body uses Combined disorders acidemia. Both disorders can cause serious When the process is working the way it many genes to convert cobalamin to health problems. should, your body uses methylcobalamin methylcobalamin and to make the enzymes Combined disorders occur in people who and a few enzymes to convert homocysteine that are needed to complete this process. cannot successfully complete the steps back to methionine. Enzymes are proteins If something is wrong with any of these to produce enough methylcobalamin CblC defect is the most common genes, then the process can break down. and also a second form of cobalamin that help chemical reactions take place in cbl defect. About 1 in every 100,000 the body. that your body needs. These disorders If any step in the process does not occur, are known as: cblC defect (cblC), cblD babies is born with cblC defect then your body cannot convert homocysteine defect (cblD), cblF defect (cblF), cblJ in the United States. back to methionine through this pathway. defect (cblJ), and cblX defect (cblX). This causes homocysteine to build up in your body. It also causes methionine to decrease. When your body undergoes the steps Both can to serious health problems. to make methylcobalamin, it uses many of the same steps to help make a second type of cobalamin called (uh-DEEN-oh-sil- co-BAL-uh-min). When your body does not produce enough adenosylcobalamin,

4 5 Are there different types of cbl defects? Why do you have a cbl defect?

Single disorders Cbl defects are genetic disorders, which is another way of saying that the conditions Homocystinuria without methylmalonic Methylmalonic acidemia without are inherited from your parents. How you acidemia occurs when a person’s body homocystinuria occurs when a person does inherited your disorder depends on the cannot complete the final steps in the not produce enough adenosylcobalamin. specific type of cbl defect you have. Since process to produce methylcobalamin, or a These disorders are known as: cblA defect homocystinuria due to cbl defects is caused person’s body does not properly produce (cblA), cblB defect (cblB), and cblD defect by genetics, it is a lifelong condition. an enzyme that is needed to interact with variant 2 (cblD variant 2). These cbl defects methylcobalamin. These disorders are known will not be covered any further in this brochure. Inheritance pattern for all as: cblD defect variant 1 (cblD variant 1), cbl cblX The different types of cbl defects affect defects except cblE defect (cblE), and cblG defect (cblG). the body in different ways and can lead Cbl defects (except cblX) occur when you to different symptoms. Knowing the type inherit two copies of an abnormal variation of cbl defect you have is important for of a specific gene, one from each parent. developing a treatment plan that will help The medical term for this kind of inheritance you manage homocysteine, methionine, and is autosomal recessive. methylmalonic acid (MMA) levels in your If you have homocystinuria due to a cbl body on a day-to-day basis. defect and your parents do not, then they are carriers of the condition. This means they have one normal copy and one abnormal variation of the affected gene. They don’t have homocystinuria because their normal copy of the gene is able to keep their homocysteine levels at normal levels.

6 7 Brandon Nicole Unaffected Unaffected Why do you have a cbl defect? “carrier” “carrier” R r R r

As an example, this diagram Inheritance pattern for cblX defect shows how homocystinuria R R R r R r r r due to cblC defect may affect CblX defect is caused by an abnormal Females have two X chromosomes. If a families. CblC defect is due variation in the HCFC1 gene, which is female inherits two abnormal HCFC1 genes, to an abnormal variation in located on the X chromosome. CblX one from each parent, then she will have cblX a gene called MMACHC. defect follows X-linked recessive defect. However, if a female inherits only one This gene helps convert inheritance in families. X-linked genes abnormal gene on the X chromosome from vitamin B12 that you get affect males and females differently. either her mother or her father, then she is a from the foods you eat into carrier of the condition. She is not likely to Males have one X and one Y methylcobalamin, the form Angela Justin Brianna Anthony have any symptoms of the disorder, or if she chromosome. If a male inherits an of cobalamin that your Unaffected Unaffected “carrier” Affected does, they are not likely to be severe. This is 1 in 4 chance 2 in 4 chance 1 in 4 chance abnormal HCFC1 gene on the X body needs. because her second copy of the HCFC1 gene chromosome from his mother, then he is usually working the way it should. will have cblX defect. He cannot inherit cblX defect from his father, even if his father has cblX defect, since he inherits a Y chromosome from his father. In this family, the parents, Brandon and Both of them could potentially pass on the Nicole, are carriers of cblC defect. Each affected gene to their future children. Angela child in the family has a 1 in 4 chance of has two normal copies of the gene. She will having cblC defect. In this case, Anthony, pass on a normal copy of the gene to any their son, has cblC defect because he future children that she has. inherited two abnormal variations of Being a carrier of homocystinuria due the MMACHC gene. The other children to cblC defect is much more common – Brianna, Justin, and Angela – do not than having the condition. That’s why have cblC defect. But Brianna and Justin many people who are diagnosed with cblC are carriers of the defect because they defect have no known family history of have one normal copy and one abnormal homocystinuria or methylmalonic acidemia. variation of the MMACHC gene.

8 9 How and when are cobalamin defects diagnosed? How can a cbl defect affect your health?

Homocystinuria caused by cbl defects If the newborn screening test result is Different cbl defects can affect Combined disorders is diagnosed by lab tests that measure the positive, then your doctor will order more health in different ways. The If you have a combined disorder, you have both blood levels of: testing to confirm the result. Newborn symptoms you develop – or may homocystinuria and methylmalonic acidemia. Since • Homocysteine – usually higher than normal screening is not perfect and may not catch be at risk of developing – depend cblC is the most common cbl defect, more is known in all cbl defects all newborns with the condition. Some on where in the homocysteine- about this disorder. babies who are born early (premature) may to-methionine conversion process • Methionine – usually lower than normal not be developed enough for the screening the error is occurring and whether Early-onset form of cblC defect in all cbl defects to be accurate. you have a single or combined Most people with cblC defect develop signs • Methylmalonic acid – usually higher than disorder. Symptoms may affect and symptoms before they are a year old. This Some people are not diagnosed with a normal in all combined disorders your brain and change how you is the “early-onset” form of cblC defect. Vision cbl defect until after symptoms appear. think, move, and act. Symptoms symptoms are common and may appear as early as Your doctor may also suggest more blood Symptoms may develop at different times may also affect other parts of several weeks after birth. Symptoms may include testing to identify the specific gene that’s for different people, so diagnosis can occur your body, such as your eyes, “wandering” eye movements, repetitive, uncontrolled causing your cbl defect. This is known as at any age. And because cbl defects are heart, lungs, and bone marrow. eye movements, and lack of ability to fixate on “DNA sequencing,” and it’s done by a special rare, some doctors may not recognize the Symptoms may vary, depending things. These symptoms may lead to vision loss lab. Because many cbl defects share similar symptoms right away and the diagnosis on what age they develop, and problems with depth perception, balance, and blood test results, gene “panel” testing is can be delayed. and they can range from mild done to assess many relevant genes at the coordination. In some children, vision problems to severe. same time. This type of genetic testing can may become severe. Other symptoms that affect confirm the diagnosis. different parts of the body may also develop – If you have homocystinuria due some very early, and some later in life. In the United States, most states screen to a cbl defect, you were born newborns for cbl defects with combined with the disorder, even if you homocystinuria and methylmalonic acidemia, didn’t have symptoms right away. such as cblC and cblD, by looking for markers in the blood caused by high levels of methylmalonic acid (MMA). A positive newborn screening will lead to diagnostic lab testing.

10 11 How can a cbl defect affect your health? How can a cbl defect affect your health?

Medical problems that may occur in individuals with early-onset Late-onset form of Single disorders form of cblC defect cblC defect If you have cblD (variant 1), cblE, or cblG defect, then Physical symptoms related to the brain Eyes People with a milder form of you have homocystinuria without methylmalonic cblC defect may not develop acidemia. These cbl defects are very rare, and more and spinal cord • Rapid, uncontrolled, or wandering/scanning symptoms until later in life – from is being learned as more people are being diagnosed. • Small head and brain size (microcephaly) eye movements childhood to adulthood. This is • Buildup of fluid in the brain (hydrocephaly) • Visual impairment the “late-onset” form of cblC Medical problems that may occur defect. It is less common than in individuals with cblD (variant 1), • Seizures Learning ability or performance the early-onset form. cblE, or cblG defects • Drowsiness or lack of energy • Developmental delay or disability, such as These conditions tend to cause some of the same • Low muscle tone (floppy muscles slow to sit up, walk, or talk Medical problems that symptoms as cblC defect. Symptoms may include: and joints) may occur in individuals with late-onset form of • Failure to grow and gain weight as expected Eating/feeding cblC defect • Seizures • Acting fussy and not wanting to nurse • Blood clots • Developmental delays or take a bottle People with other combined • Abnormal walking • Vision problems • Failure to grow and gain weight disorders may have some of the • Muscle stiffness • Movement or muscle problems as expected same symptoms. Doctors are • Learning problems • Problems with red blood cells (anemia) Blood/heart/lungs/kidneys still learning about the full range of symptoms. • Mental health problems • Anemia (problems with red blood cells) Eye problems that are common • Heart disease in babies and young children • Blood clots with cblC defect are less likely • Kidney problems (damaged red blood cells to occur in people with a milder cause blockages in kidneys and prevent form of cblC defect. them from functioning properly)

12 13 How can cbl defects be managed? What or medicines may be helpful for cbl defects?

Learning from your doctor that you have a The goal of treatment is to Hydroxocobalamin is usually given by self- cbl defect may be unsettling for you and your prevent or reduce symptoms injections injections – giving yourself or your child family. But even though cbl defects are rare, or complications by keeping injections at home. At first you might feel there is knowledge about how to treat them, homocysteine, methionine, and Vitamin B12 or cobalamin plays a key nervous or unsure about the idea, but many especially cblC defect. methylmalonic acid (MMA) levels role in helping to control homocysteine people, such as individuals with diabetes, in your body as close to normal and methylmalonic acid (MMA) levels, learn to give themselves injections. Ideally you should be treated by a metabolic as possible. Your doctor may say so hydroxocobalamin injections are an specialist who is familiar with managing Your treatment team can train you so that that your goal is to have “good important part of treatment for people cbl defects. A metabolic specialist is you know how to: metabolic control.” with cbl defects. a doctor who specializes in treating • Clean injection sites genetic conditions that involve the body’s A low-protein diet is often needed Hydroxocobalamin is the only form of vitamin B12 that has been found to be metabolism. Some conditions are so rare for people who have a different type • Give injections that your metabolic specialist may need of homocystinuria called classical effective. It must be given as injections to consult with another specialist who has homocystinuria. However, a low- and not taken by mouth. These injections • Rotate injection sites to different parts experience treating a particular condition. protein diet also reduces methionine, help your body make methylcobalamin of the body on different days which is usually already lower than and adenosylcobalamin, which helps Your healthcare team will develop a normal if you have a cbl defect. keep levels of homocysteine and MMA treatment plan based on your needs. Your Because low methionine levels can down and levels of methionine normal. treatment plan may include certain vitamins be harmful to the body, a low-protein and medicines. You should work closely with Hydroxocobalamin is generally given diet is not recommended for people the team to develop your plan. daily at first, then less often if you have with cblC defect. good metabolic control.

14 15 What vitamins or medicines may be helpful Indications and Usage Important Safety Information for cbl defects?

CYSTADANE® (betaine Other therapies CYSTADANE® (betaine anhydrous • Hypermethioninemia in Patients with CBS for oral solution) is indicated in Deficiency: CYSTADANE may worsen high anhydrous for oral Your doctor may add other therapies to solution) children and adults for the treatment methionine blood levels and accumulation your treatment plan, including carnitine of homocystinuria to decrease of excess fluid in the brain has been reported. CYSTADANE is a prescription medicine that (a chemical made from two amino acids), high homocysteine blood levels. If you have been told you have CBS deficiency, provides a different “pathway” in your body or folinic acid (vitamin B9) and Homocystinuria is a rare genetic your doctor will be monitoring your methionine to convert homocysteine back to methionine, methionine. However, it is unknown disorder in which there is an blood levels to see if changes in your diet and lowering the levels of homocysteine in your how much these and other treatments abnormal accumulation of the amino dosage are necessary. blood. CYSTADANE is powdered betaine. may help. acid homocysteine in the blood and • Most common side effects were nausea and Betaine is produced naturally in the body. urine. The following are considered gastrointestinal distress, based on a survey Some foods, such as beets, spinach, and to be homocystinuria disorders: some cereals, also contain tiny amounts of doctors. of betaine. • Cystathionine beta- • To report SUSPECTED SIDE EFFECTS, (CBS) deficiency Your doctor may add CYSTADANE to your contact Recordati Rare Diseases Inc. at treatment plan to help lower homocysteine • 5,10-methylenetetrahydrofolate 1-888-575-8344, or FDA at 1-800-FDA-1088 blood levels. The most common side (MTHFR) deficiency or www.fda.gov/medwatch. effects of CYSTADANE are nausea and • Cobalamin cofactor metabolism gastrointestinal distress, based on a survey (cbl) defect of doctors.

Hydroxocobalamin and CYSTADANE may work together to lower homocysteine blood levels and increase methionine blood levels.

CYSTADANE is a licensed trademark of Please see accompanying Prescribing Recordati Rare Diseases Inc. Information.

16 17 Why is it important to follow your treatment plan? What are some good ways to meet the challenges caused by cbl defects?

Losing control of blood homocysteine, There are many things you can do to methionine, and methylmalonic acid (MMA) methionine, and methylmalonic acid (MMA) meet the challenges of living with a cbl in your blood as close to normal as possible. levels at any age may lead to serious health defect. Working well with your healthcare By following your plan, you may be able problems. Having good metabolic control may team is very important. Here are things to prevent or lessen further damage to reduce or even prevent some complications. you can do that may help you get the areas of your body that are affected by your most out of your doctor visits: cbl defect. For individuals with cblC defect, appropriate treatment may reduce or, in some cases, • See your doctor regularly to • Develop a routine to give B12 injections prevent complications, such as: check your blood homocysteine, at home, and follow your treatment team’s methionine, and (if relevant) instructions. • Failure to grow and gain weight methylmalonic acid (MMA) levels. • Find additional information and support as expected Your blood test results will allow your through patient advocacy organizations. • The buildup of fluid in the brain doctor to see how well your treatment • Be your own best advocate by following (hydrocephalus) plan is working and to adjust you plan your instincts and doing your own research as necessary. if something doesn’t seem quite right. But • Kidney problems always talk to your doctor and healthcare For individuals with other types of • See other doctors as needed. Your • Blood disorders, such as blood clots team before making any changes to your cbl defects, the effects of treatment overall health, development, and well-being are very important. And treatment plan. However, treatment may not be effective are not as well established since the as someone with a cbl defect, you’ll in preventing, delaying, or controlling vision conditions are so rare and less is • Encourage family members to talk to have added needs. Doctors will be problems. known about them. their doctors about getting tested for the on the lookout for problems that can type of cbl defect you have. Early diagnosis Research does show that for people result from your type of cbl defect. and lifelong treatment are the best ways with homocystinuria due to cblE or to prevent complications. Also encourage Here are more things you can do for cblG defects, some problems, such family members to get tested to see if they yourself and your family: as anemia and impaired thinking are carriers. A confirmed carrier may also or reasoning skills, may respond • Follow your treatment plan – want to find out if their partner is a carrier, to treatment. every day! The goal of your plan is too, so that they can best plan for their to keep the levels of homocysteine, 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 cbl DOSAGE AND ADMINISTRATION modification and, if necessary, a reduction of CYSTADANE dosage. (5.1) homocystinuria due to defects? 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 homocystinuria due doses of 50 mg/kg twice daily, and then increased weekly by 50 mg/kg increments. (2.1) See 17 for PATIENT COUNSELING INFORMATION. to cbl defects: • Monitor patient response by plasma homocysteine concentrations. (2.1) Revised 10/2019

- HCU Network America – The mission of HCU Network America is to FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation 1 INDICATIONS AND USAGE 8.4 Pediatric Use help people with homocystinuria (HCU) and related disorders manage 2 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 2.1 Dosage 11 DESCRIPTION their disease and to find a cure. 2.2 Preparation and Administration Instructions 12 CLINICAL 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action 4 CONTRAINDICATIONS 12.2 Pharmacodynamics - HCU Network Australia – The aims of HCU Network Australia are to 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics 5.1 Hypermethioninemia in Patients with CBS Deficiency 13 NONCLINICAL TOXICOLOGY provide support and education for people affected by homocystinuria, 6 ADVERSE REACTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6.1 Clinical Trials Experience 14 CLINICAL STUDIES improve diagnosis to enable appropriate treatment, and support clinical 6.2 Postmarketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING research. 8 USE IN SPECIFIC POPULATIONS 17 PATIENT COUNSELING INFORMATION 8.1 Pregnancy *Sections or subsections omitted from the full prescribing information are not listed.

- EHOD – European Network and Registry for Homocystinurias FULL PRESCRIBING INFORMATION • Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until and Methylation Defects – The aim of E-HOD is to improve the health 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. of people affected with homocystinurias and methylation defects by 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 developing a patient registry, developing diagnostic and clinical care • Cystathionine beta-synthase (CBS) deficiency containing 180 grams of betaine anhydrous. protocols, and evaluating newborn screening programs. • 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency 4 CONTRAINDICATIONS • Cobalamin cofactor metabolism (cbl) defect None. 2 DOSAGE AND ADMINISTRATION 5 WARNINGS AND PRECAUTIONS - Organic Acidemia Association – This patient advocacy organization 2.1 Dosage 5.1 Hypermethioninemia in Patients with CBS Deficiency Therapy with CYSTADANE should be directed by physicians knowledgeable in the Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may provides support and information for people with inherited metabolic management of patients with homocystinuria. also have elevated plasma methionine concentrations. Treatment with CYSTADANE may Adults and Pediatric Patients 3 Years of Age and Older further increase methionine concentrations due to the remethylation of homocysteine disorders. Homocystinuria caused by several cbl defects—cblC, cblD 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, cblF, cblJ, and cblX—is included as part of the group’s advocacy 3 grams twice daily. including patients treated with CYSTADANE [see Adverse Reactions (6.2)]. Monitor Pediatric Patients Less than 3 Years of Age plasma methionine concentrations in patients with CBS deficiency. Plasma methionine activities. 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 concentration is undetectable or present only in small amounts. An initial response in [see Warnings and Precautions (5.1)]. review of this brochure. 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 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 The assessment of clinical adverse reactions is based on a survey study of 41 physicians, www.recordatirarediseases.com/us • PP-CYS-US-0153 Maximum Dosage 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 mutation 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 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, France 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 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 ® 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.