CYSTADANE 1g oral powder medication leaflet

Cystadane 1 g oral powder

1 g of powder contains 1 g of betaine anhydrous.

For the full list of excipients, see section 6.1.

Oral powder.

White crystalline free flowing powder.

Adjunctive treatment of homocystinuria, involving deficiencies or defects in:

* cystathionine beta-synthase (CBS),

* 5,10-methylene-tetrahydrofolate reductase (MTHFR),

* cobalamin cofactor metabolism (cbl).

Cystadane should be used as supplement to other therapies such as vitamin B6 (pyridoxine), vitamin

B12 (cobalamin), folate and a specific diet.

Cystadane treatment should be supervised by a physician experienced in the treatment of patients withhomocystinuria.

Children and Adult

The recommended total daily dose is 100 mg/kg/day given in 2 doses daily. However, the dose shouldbe individually titrated according to plasma levels of homocysteine and methionine. In some patientsdoses above 200 mg/ kg/day were needed to reach therapeutic goals. Caution should be exercised withup-titrating doses for patients with CBS deficiency due to the risk for hypermethioninaemia.

Methionine levels should be closely monitored in these patients.

Hepatic or renal impairment

Experience with betaine anhydrous therapy in patients with renal insufficiency or non-alcoholichepatic steatosis has demonstrated no need to adapt the dose regimen of Cystadane.

The bottle should be lightly shaken before opening. Three measuring spoons are provided whichdispense either 100 mg, 150 mg or 1 g of betaine anhydrous. It is recommended that a heapedmeasuring spoon is removed from the bottle and a flat surface e.g. base of a knife is drawn across thetop of the measure. This will give the following doses: small measure 100 mg, middle sizemeasure 150 mg and large measure 1 g of betaine anhydrous.

The powder should be mixed with water, juice, milk, formula or food until completely dissolved andingested immediately after mixing.

Therapeutic monitoring

The aim of treatment is to keep plasma levels of total homocysteine below 15 µM or as low aspossible. The steady-state response usually occurs within a month.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Uncommon cases of severe cerebral oedema associated with hypermethioninemia were reported withbetaine anhydrous therapy in patients with CBS deficiency (see section 4.8). Complete recovery wasseen after treatment discontinuation:

- The plasma methionine concentrations should be kept below 1000 µM. It is recommended tomeasure plasma methionine level at start of treatment and about annually or biannuallythereafter. If methionine increases particularly above the first safety threshold of 700 µmol/L,patient should be monitored more frequently and compliance with diet should be checked. Inorder to reduce methionine levels, modification of diet as well as dose reduction of Cystadane ortemporal interruption of Cystadane treatment should be considered.

- If any symptoms of cerebral oedema like morning headaches with vomiting and/or visual changesappear, plasma methionine level and compliance to the diet should be checked and treatment with

Cystadane interrupted.

- If symptoms of cerebral oedema recur after re-introduction of treatment then betaine anhydroustherapy should be discontinued indefinitely.

To minimise the risk of potential drug interactions, it is advisable to leave 30 minutes between theintake of betaine anhydrous and amino acids mixtures and/or medicinal products containing vigabatrinand GABA analogues (see section 4.5).

No interaction studies have been performed.

Based on in vitro data, betaine anhydrous might interact with amino acids mixtures and medicinalproducts containing vigabatrin and GABA analogues.

Data on a limited number of exposed pregnancies indicate no adverse event of betaine anhydrous onpregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiologic dataare available. Animal reproduction studies have not been conducted. During pregnancy, administeringbetaine anhydrous in addition to pyridoxine, folate, anticoagulant and diet under close monitoring ofplasma homocysteine would be compatible with good maternal and foetal outcomes. However,

Cystadane should not be used during pregnancy unless clearly necessary.

It is not known whether betaine anhydrous is excreted in human milk (although its metabolicprecursor, choline, occurs at high levels in human milk). Because of lack of data, caution should beexercised when prescribing Cystadane to breast-feeding women.

No data is available.

Cystadane has no or negligible influence on the ability to drive and use machines.

In general, adverse reactions seen with betaine anhydrous therapy appeared to be not serious and aremainly related to the gastrointestinal system. Gastrointestinal disorders like diarrhoea, glossitis, nausea,stomach discomfort, vomiting and dental disorders may occur uncommonly.

The most commonly reported adverse reaction during treatment is blood methionine increased.

Complete recovery was seen after treatment discontinuation (see section 4.4).

Reported adverse reactions are listed below, by system organ class and by frequency.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Metabolism and nutrition disorders Uncommon: anorexia

Psychiatric disorders Uncommon: agitation, irritability

Nervous system disorders Uncommon: brain oedema*

Gastrointestinal disorders Uncommon: diarrhoea, glossitis, nausea, stomachdiscomfort, vomiting

Skin and subcutaneous tissue disorders Uncommon: hair loss, hives, skin odour abnormal

Renal and urinary disorders Uncommon: urinary incontinence

Investigations Very common: blood methionine increased*

*Uncommon cases of severe cerebral oedema and hypermethioninemia were reported within 2 weeksto 6 months of starting betaine anhydrous therapy in patients with CBS deficiency, with completerecovery after treatment discontinuation.

Symptoms of cerebral oedema include morning headaches with vomiting and/or visual changes

High increases in plasma methionine levels in a range from 1,000 to 3,000 µM were noted in thesepatients. As cerebral oedema has also been reported in patients with hypermethioninemia, secondaryhypermethioninemia due to betaine anhydrous therapy has been postulated as a possible mechanism ofaction.

For specific recommendations, see section 4.4.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, ATC code: A16AA06.

Betaine anhydrous was shown to lower plasma homocysteine levels in the three types ofhomocystinuria, i.e. CBS deficiency; MTHFR deficiency and cbl defect. The extent of this effect wasdependent on the absolute degree of hyperhomocysteinemia, being higher in severehyperhomocysteinemia.

Betaine anhydrous acts as a methyl group donor in the remethylation of homocysteine to methioninein patients with homocystinuria. As a result, plasma levels of homocysteine should decrease in thesepatients, to 20-30 % of pre-treatment levels.

Betaine anhydrous has also been shown to increase plasma methionine and S-adenosyl methionine(SAM) levels in patients with MTHFR deficiency and cbl defects. In CBS-deficient patients withoutdietary restriction of methionine, excessive accumulation of methionine has been observed.

Betaine anhydrous supplementation was shown to improve the metabolic abnormalities in thecerebrospinal fluid of patients with homocystinuria.

Elevated homocysteine plasma levels are associated with cardiovascular events (such as thrombosis),osteoporosis, skeletal abnormalities, and optic lens dislocation. In observational studies, clinicalimprovement (cardiovascular and neurodevelopmental) was reported by the treating physician in about75% of patients taking betaine anhydrous. Most of these patients were also receiving other treatmentssuch as vitamin B6 (pyridoxine), vitamin B12 (cobalamin) and folate with variable biochemicalresponses. In most cases, adding betaine anhydrous resulted in a further reduction in plasmahomocysteine level. It is likely that due to the multiple nature of therapy (dietary, pharmaceutical,supportive) in these patients, there may be an element of overestimation in the clinical effects ofbetaine anhydrous treatment. Late detection of homocystinuria in symptomatic state is responsible forresidual morbidity due to irreversible damage to connective tissue (ophtalmological, skeletal) thatcannot be corrected by further therapy. The available clinical data do not allow correlating posologyand clinical efficacy. There is no evidence of development of tolerance.

In a few cases, increased plasma methionine levels were associated with cerebral oedema (see sections4.4 and 4.8).

Monitoring plasma homocysteine levels has demonstrated that the onset of action of betaineanhydrous occurred within several days and that a steady-state response was achieved within onemonth.

In paediatric patients less than 10 years of age, the usual effective dose regimen is 100 mg/kg/daygiven in 2 doses daily; increasing the frequency above twice daily and/or the dose above150 mg/kg/day does not improve the homocysteine-lowering effect.

Monitoring betaine plasma concentrations does not help to define the efficacy of treatment, since theseconcentrations do not directly correspond to the flux through the cytosolic betaine homocysteinemethyl transferase pathway.

The pharmacokinetic data of homocystinuric patients on long-term betaine anhydrous supplementationare very similar to those of healthy volunteers. This demonstrates that differences in betaine anhydrouskinetics are most probably due to betaine anhydrous depletion in untreated homocystinuria and areonly meaningful for the initial treatment.

The absolute bioavailability of betaine anhydrous has not been determined. In healthy adult volunteers(age between 21 to 49 years), after a single oral dose of betaine anhydrous (50 mg/kg), absorptionwas rapid (tmax = 0.9 ± 0.3 hours and a Cmax = 0.9 ± 0.2 mM).

After a repeated dose regimen of 100 mg/kg/day for 5 days, the absorption kinetics did not change.

Betaine anhydrous was rapidly distributed into a relatively large volume (V/F = 1.3 l/kg).

After a repeated dose regiment of 100 mg/kg/day for 5 days, the distribution half life was prolongedsignificantly (up to 36 h), indicating saturable transport and redistribution processes.

Betaine anhydrous is a methyl group donor

With a slow elimination rate (mean half life = 14 h, mean total body clearance, CL/F, = 84 ml/h/kg),renal clearance is negligible (5% of total body clearance), assuming 100% bioavailability.

At high doses, a CNS depressant effect and irritation of the gastrointestinal tract was seen in rats.

Long-term carcinogenicity and reproductive toxicity studies have not been conducted on betaineanhydrous. A standard battery of genotoxicity test reveals no specific hazard for humans.

None.

Not applicable.

Unopened bottle: 3 years

After the first opening: 3 months.

Do not store above 25°C.

Keep the bottle tightly closed in order to protect from moisture.

For storage conditions after first opening of the medicinal product, see section 6.3.

HDPE bottles with a child resistant closure.

Each pack contains 1 bottle with 180 g of powder and three measuring spoons.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Recordati Rare Diseases

Tour Hekla52 avenue du Général de Gaulle

F-92 800 Puteaux

France

EU/1/06/379/001

Date of first authorisation: 15 February 2007

Date of latest renewal: 21 November 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.