4.1. Therapeutic indications

Betaine is indicated as adjunctive treatment of homocystinuria, involving deficiencies or defects in:

• cystathionine beta-synthase (CBS),

• 5,10 methylene tetrahydrofolate reductase (MTHFR),

• cobalamin cofactor metabolism (cbl).

Betaine should be used as supplement to other therapies such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), folate and a specific diet.

4.2. Posology and method of administration

Betaine treatment should be supervised by a physician experienced in the treatment of patients with homocystinuria.

Posology

Children and adults

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 Betaine.

Therapeutic monitoring

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

Method of administration

Oral use

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. It is recommended that a heaped measuring spoon is removed from the bottle and a flat surface e.g. base of a knife is drawn across the top of the measure. This will give the following doses: the green measuring spoon dispenses 100 mg, the blue measuring spoon dispenses 150 mg and the purple measuring spoon dispenses 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.

4.3. Contraindications

Hypersensitivity to the active substance.

4.4. Special warnings and precautions for use

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 1,000 µmol/L. 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 Betaine or temporal interruption of Betaine 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 Betaine 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).

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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, Betaine 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 Betaine to breast-feeding women.

Fertility

No data is available.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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

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 μmol/L 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 the Yellow Card Scheme on the MHRA website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.