4.1. Therapeutic indications

Metaperex 400 IU soft capsules is indicated in the following conditions for adults:

• Vitamin E deficiency in patients diagnosed with ataxia with vitamin E deficiency (AVED).

4.2. Posology and method of administration

Dosage should be adjusted to the type of disorder and the patient's clinical condition.

One international unit (IU) of vitamin E equals the biologic activity of 1 mg of all rac-α-tocopheryl acetate (dl-α-tocopheryl acetate).

For adults diagnosed with AVED the following doses should be administered:

• 800 IU (560 mg) vitamin E per day (2 capsules) divided into 2 doses.

Diagnosis of vitamin E deficiency should be documented and based on:

• measuring the plasma α-tocopherol level (level < 5μg/mL or <11.6 μmol/L indicates vitamin E deficiency) and/or

• ratio of plasma α-tocopherol to plasma lipid level (in adults; < 0.8 mg/g total lipid).

Plasma vitamin E level should be monitored monthly initially, to ensure levels return to the normal range, thereafter at 6-month intervals and the dose adjusted accordingly if necessary.

Method of administration

For oral use.

Vitamin E is absorbed with lipids, therefore advise patients to take vitamin E during or after a meal to ensure optimal absorption.

4.3. Contraindications

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

• Metaperex 400 IU soft capsules contains soya-bean oil. If you are allergic to peanut or soya, do not use this medicinal product.

• Vitamin K deficiency (increased risk of bleeding)

4.4. Special warnings and precautions for use

Prolonged use of vitamin E (doses >560 mg per day) has been associated with an increase in bleeding tendency in patients with vitamin K deficiency. Excessive use of vitamin E can antagonise the function of vitamin K.

A possible adjustment of the dose of anticoagulants /antiplatelet medication during and after treatment with Vitamin E may be required (see section 4.5). Therefore, anticoagulant assessments, including international normalised ratio (INR) or prothrombin time, should be conducted more frequently to detect any changes in haemostasis.

Vitamin E should be used with caution in patients taking concomitant anticoagulants or oestrogen.

In a long term study of dietary supplementation, Vitamin E (400 IU daily) was found to significantly increase the risk of prostate cancer among healthy men.

There is limited data on the use of vitamin E in patients with renal impairment. Based on the available data, the dose of vitamin E should be assessed for each patient with renal impairment depending on their clinical circumstances.

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

Haemostasis

Vitamin E may have antagonist activity with respect to vitamin K. K, and so may increase the tendancy to bleeding.

High doses of vitamin E may increase the risk of bleeding in patients taking concomitant:

• anticoagulants (e.g., warfarin or phenprocoumon)

• inhibitors of platelet aggregation (e.g., acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, eptifibatide, tirofiban and abciximab) or

• thrombolytics (e.g. recombinant tissue plasminogen activator).

Vitamin E should not be administered concomitantly with Ibrutinib as it may enhance the antiplatelet effect of Ibrutinib.

Tipranavir, used in the treatment of HIV-1 infection, is associated with an increased risk of bleeding and fatal and non-fatal intracranial haemorrhages and these risks may be increased with high dose vitamin E.

Vitamin E may increase the risk of thrombosis in patients taking oestrogens.

Sequestrants

Sequestrants bind to vitamin E and reduce absorption. Any of these agents should be administered more than two hours before or after vitamin E.Colestyramine and colestipol reduce gastrointestinal absorption of vitamin E.

Orlistat may impair absorption of fat-soluble vitamins, including vitamin E.

Concomitant use of iron-containing medicines reduces activity of vitamin E, therefore a few hours interval should be maintained between taking both medications.

Metabolic Interactions

High-dose vitamin E, either alone or in combination with other antioxidants, may alter the pharmacokinetics of ciclosporin and decrease its serum concentration.

Anticonvulsants (e.g., phenobarbital, phenytoin and carbamazepine), as inducers of P450 enzymes, may lower plasma vitamin E levels.

Vitamin E increases the absorption, utilisation and storage of vitamin A.

Vitamin E may be present in significant quantities as an excipient, for example Selumetinib contains D-alpha-tocopheryl and should not be taken with vitamin E (Selumetinib 10 mg capsule contains 32 mg vitamin E; 25 mg capsule contains 36 mg vitamin E).

Vitamin E has been shown to induce the expression of the cytochrome P450 enzyme CYP3A4. This enzyme is responsible for the reduced physiological effects of vitamin K and for the reduction in ciclosporin levels.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is limited data on the use of vitamin E in pregnant women. Doses of vitamin E above the recommended daily allowance should not be used in women during pregnancy. Therefore Metaperex should not be used in pregnancy.

Breastfeeding

There is insufficient information on the effects of vitamin E in newborns and infants.Vitamin Epasses into breast milk. Doses of vitamin E above the recommended daily allowance of 28.5 IU (19 mg) should not be used in nursing mothers. Therefore Metaperex should not be used during breastfeeding.

Fertility

No data available

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

General

Following extended periods of high doses of vitamin E (800 – 1,200 mg daily) (anti-platelet activity and associated with it, bleeding).

Undesirable effects are listed according to their frequencies as follows:

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)

Not known: (frequency cannot be estimated from the available data)

Safety information is based on data from Eudravigilance for vitamin E (tocopherol) and clinical trials. None of the available data allows an assessment of the frequency of undesired effects.

Doses higher than 1,000 mg daily may cause the following underirable effects:

MedDRA System Organ Class

Undesirable Effects

Frequency

General disorders and administration site conditions

Unusual tiredness or weakness

Not known

Gastrointestinal disorders

Nausea, diarrhoea, flatulence, abdominal pain and oral pain

Not known

Nervous systems disorders

Headaches and dizziness

Not known

Skin and subcutaneous tissue disorders

Rash

Not known

Eye disorders

Blurred vision

Not known

Immune system disorders

Anaphylaxis, urticaria, allergic oedema, erythema and blisters

Not known

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Not known

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

Great Britain

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Chronic hypervitaminosis E is unknown. The symptoms and signs of vitamin E overdose are nonspecific. Transient gastrointestinal disorders such as nausea, diarrhoea, flatulence have been reported with daily doses above 700 mg. Other symptoms may include tiredness, asthenia, headache, blurred vision and dermatitis. If an overdose is suspected, vitamin E treatment should be stopped. If necessary, general supportive measures should be taken. Consideration should be given to specific treatment, such as giving vitamin K to patients who are actively bleeding or have a severe haemorrhage.