CYSTADANE

Cystadane treatment should be supervised by a physician experienced in the treatment of patients with homocystinuria. Posology Children and Adult The recommended total daily dose is 100 mg/kg/day given in 2 doses daily. However, the dose should be individually titrated according to plasma levels of homocysteine and methionine.

In some patients doses above 200 mg/ kg/day were needed to reach therapeutic goals. Caution should be exercised with up-titrating doses for patients with CBS deficiency due to the risk for hypermethioninaemia. Methionine levels should be closely monitored in these patients.

Special populations Hepatic or renal impairment Experience with betaine anhydrous therapy in patients with renal insufficiency or non-alcoholic hepatic steatosis has demonstrated no need to adapt the dose regimen of Cystadane. Method of administration The bottle should be lightly shaken before opening.

Three measuring spoons are provided which dispense either 100 mg, 150 mg or 1 g of betaine anhydrous. g. base of a knife is drawn across the top of the measure. This will give the following doses: small measure 100 mg, middle size measure 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 and ingested immediately after mixing. Therapeutic monitoring The aim of treatment is to keep plasma levels of total homocysteine below 15 μM or as low as possible.

The steady-state response usually occurs within a month.

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. 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 Investigations Very common: blood methionine increased* 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.

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

5).

Hypersensitivity to the active substance.