CYSTADANE Oral powder Ref.[6303] Active ingredients: Betaine

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

The plasma methionine concentrations should be kept below 1000 µM. It is recommended to measure plasma methionine level at start of treatment and about annually or biannually thereafter. 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. In order to reduce methionine levels, modification of diet as well as dose reduction of Cystadane or temporal interruption of Cystadane treatment should be considered.

If any symptoms of cerebral oedema like morning headaches with vomiting and/or visual changes appear, 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 anhydrous therapy should be discontinued indefinitely.

To minimise the risk of potential drug interactions, it is advisable to leave 30 minutes between the intake of betaine anhydrous and amino acids mixtures and/or medicinal products containing vigabatrin and 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 medicinal products containing vigabatrin and GABA analogues.

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse event of betaine anhydrous on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiologic data are available. Animal reproduction studies have not been conducted. During pregnancy, administering betaine anhydrous in addition to pyridoxine, folate, anticoagulant and diet under close monitoring of plasma homocysteine would be compatible with good maternal and foetal outcomes. However, Cystadane should not be used during pregnancy unless clearly necessary.

Breast-feeding

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

Fertility

No data is available.

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

Summary of the safety profile

In general, adverse reactions seen with betaine anhydrous therapy appeared to be not serious and are mainly 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).

Tabulated list of adverse reactions

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 frequency grouping, 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, stomach discomfort, vomiting

Skin and subcutaneous tissue disorders

Uncommon: hair loss, hives, skin odour abnormal

Renal and urinary disorders

Uncommon: urinary incontinence

Description of selected adverse reactions

* Uncommon cases of severe cerebral oedema and hypermethioninemia were reported within 2 weeks to 6 months of starting betaine anhydrous therapy in patients with CBS deficiency, with complete recovery 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 these patients. As cerebral oedema has also been reported in patients with hypermethioninemia, secondary hypermethioninemia due to betaine anhydrous therapy has been postulated as a possible mechanism of action.

For specific recommendations, see section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

Ireland, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Ireland, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@hpra.ie.

Not applicable.