Idebenone

In vivo idebenone is a mild inhibitor of CYP3A4. Data from a drug-drug interaction study in 32 healthy volunteers indicate that on the first day of oral administration of 300 mg idebenone t.i.d., the metabolism of midazolam, a CYP3A4 substrate, was not modified when both medicinal products were administered together. After repeated administration C_max and AUC of midazolam were increased by 28% and 34%, respectively, when midazolam was administered in combination with 300 mg idebenone t.i.d. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving idebenone.

No data are available in these populations. Therefore, caution should be exercised when prescribing idebenone to patients with hepatic impairment.

No data are available in these populations. Therefore, caution should be exercised when prescribing idebenone to patients with renal impairment.

Idebenone may inhibit P-glycoprotein (P-gp) with possible exposure increases of, e.g., dabigatran etexilate, digoxin or aliskiren. These medicines should be administered with caution in patients receiving idebenone. Idebenone is not a substrate for P-gp in vitro.

The safety of idebenone in pregnant women has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Idebenone should only be administered to pregnant women or women of child-bearing potential likely to become pregnant if it is considered that the benefit of the therapeutic effect outweighs any potential risk.

Available pharmacodynamic/toxicological data in animals have shown excretion of idebenone in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from idebenone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data concerning the effect of exposure to idebenone on human fertility.

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

Summary of the safety profile

The most commonly reported adverse reactions to idebenone are mild to moderate diarrhoea (usually not requiring the discontinuation of the treatment), nasopharyngitis, cough and back pain.

List of adverse reactions

The following adverse reactions emerging from clinical trials in LHON patients or reported postmarketing in other indications are listed below. Frequency groupings are defined to the following convention: very common (≥1/10), common (≥1/100 to <1/10), not known (cannot be estimated from the available data).

Infections and Infestations

Very common: Nasopharyngitis

Not known: Bronchitis

Blood and lymphatic system disorders

Not known: Agranulocytosis, anaemia, leukocytopenia, thrombocytopenia, neutropenia

Metabolism and nutrition disorders

Not known: Blood cholesterol increased, blood triglycerides increased

Nervous system disorders

Not known: Seizure, delirium, hallucinations, agitation, dyskinesia, hyperkinesia, poriomania, dizziness, headache, restlessness, stupor

Respiratory, thoracic and mediastinal disorders

Very common: Cough

Gastrointestinal disorders

Common: Diarrhoea

Not known: Nausea, vomiting, anorexia, dyspepsia

Hepatobiliary disorders

Not known: Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gammalutamyltransferase increased, blood bilirubin increased, hepatitis

Skin and subcutaneous tissue disorders

Not known: Rash, pruritus

Musculoskeletal and connective tissue disorders

Common: Back pain

Not known: Pain in extremity

Renal and urinary disorders

Not known: Azotaemia, chromaturia

General disorders and administration site conditions

Not known: Malaise