This information is intended for use by health professionals

  This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Raxone 150 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 150 mg idebenone.

Excipients with known effect: Each film-coated tablet contains 46 mg of lactose (as monohydrate) and 0.23 mg of sunset yellow (E110).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Orange, round, biconvex film-coated tablet of 10 mm diameter, engraved with the Santhera logo on one side and '150' on the other side.

4. Clinical particulars
4.1 Therapeutic indications

Raxone is indicated for the treatment of visual impairment in adolescent and adult patients with Leber's Hereditary Optic Neuropathy (LHON) (see section 5.1).

4.2 Posology and method of administration

Treatment should be initiated and supervised by a physician with experience in LHON.

Posology

The recommended dose is 900 mg/day idebenone (300 mg, 3 times a day).

No data regarding a continuous treatment with idebenone beyond 6 months is available from controlled clinical trials.

Special populations

Elderly

No specific dose adjustment is required for the treatment of LHON in elderly patients.

Hepatic or renal impairment

Patients with hepatic or renal impairment have not been investigated. Caution is advised in treatment of patients with hepatic or renal impairment (see section 4.4).

Paediatric population

The safety and efficacy of Raxone in LHON patients under 12 years of age have not yet been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on posology can be made.

Method of administration

Raxone film-coated tablets should be swallowed whole with water. The tablets should not be broken or chewed. Raxone should be administered with food because food increases the bioavailability of idebenone.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Monitoring

Patients should be regularly monitored according to local clinical practice.

Hepatic or renal impairment

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

Chromaturia

The metabolites of idebenone are coloured and may cause chromaturia, i.e. a reddish-brown discoloration of the urine. This effect is harmless, not associated with haematuria, and does not require any adaptation of dose or discontinuation of treatment. Caution should be exercised to ensure that the chromaturia does not mask changes of colour due to other reasons (e.g. renal or blood disorders).

Lactose

Raxone contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Raxone.

Sunset yellow

Raxone contains sunset yellow (E110) which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Data from in vitro studies have demonstrated that idebenone and its metabolite QS10 do not exert systemic inhibition of cytochrome P450 isoforms CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations of idebenone or QS10. In addition, no induction of CYP1A2, CYP2B6 or CYP3A4 was observed.

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 drugs were administered together. After repeated administration Cmax 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.

Idebenone may inhibit P-glycoprotein (p-gp) with possible exposure increases of e.g. dabigatran etexilate, digoxin or aliskiren. Idebenone is not a substrate for p-gp in vitro.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 age likely to become pregnant if it is considered that the benefit of the therapeutic effect outweighs any potential risk.

Breast-feeding

Studies in rats have shown that idebenone is excreted into maternal milk. Therefore, a decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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.

Tabulated list of adverse reactions

The following adverse reactions emerging from clinical trials in LHON patients or reported post-marketing in other indications are tabulated 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).

System Organ Class

Preferred Term

Frequency

Infections and Infestations

Nasopharyngitis

Very common

Bronchitis

Not known

Blood and lymphatic system disorders

Agranulocytosis, anaemia, leukocytopenia, thrombocytopenia, neutropenia

Not known

Metabolism and nutrition disorders

Blood cholesterol increased, blood triglycerides increased

Not known

Nervous system disorders

Seizure, delirium, hallucinations, agitation, dyskinesia, hyperkinesia, poriomania, dizziness, headache, restlessness, stupor

Not known

Respiratory, thoracic and mediastinal disorders

Cough

Very common

Gastrointestinal disorders

Diarrhoea

Common

Nausea, vomiting, anorexia, dyspepsia

Not known

Hepatobiliary disorders

Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gamma- lutamyltransferase increased, blood bilirubin increased, hepatitis

Not known

Skin and subcutaneous tissue disorders

Rash, pruritus

Not known

Musculoskeletal and connective tissue disorders

Back pain

Common

Pain in extremity

Not known

Renal and urinary disorders

Azotaemia, chromaturia

Not known

General disorders and administration site conditions

Malaise

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 the national reporting system:

United Kingdom

Yellow Card Scheme

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

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

4.9 Overdose

No report of overdose has been received from the RHODOS study. Doses up to 2250 mg/day have been administered in clinical studies showing a safety profile consistent with that reported in section 4.8.

There is no specific antidote for idebenone. When needed, supportive symptomatic treatment should be given.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics, Other psychostimulants and nootropics;

ATC code: N06BX13

Idebenone, a short-chain benzoquinone, is an anti-oxidant assumed to be capable of transferring electrons directly to complex III of the mitochondrial electron transport chain, thereby circumventing complex I and restoring cellular energy (ATP) generation under experimental conditions of complex I deficiency. Similarly, in LHON idebenone can transfer electrons directly to complex III of the electron transport chain, thereby bypassing complex I which is affected by all three primary mtDNA mutations causing LHON, and restoring cellular ATP generation.

According to this biochemical mode of action, idebenone may re-activate viable-but-inactive retinal ganglion cells (RGCs) in LHON patients. Depending on the time since symptom onset and the proportion of RGCs already affected, idebenone can promote recovery of vision in patients who experience vision loss.

Clinical safety and efficacy of idebenone in LHON have been assessed in one double-blind, randomised, placebo-controlled study (RHODOS).

In RHODOS a total of 85 LHON patients, 14-66 years of age, with any of the 3 primary mtDNA mutations (G11778A, G3460A or T14484C) and disease duration of not more than 5 years were enrolled. Patients received either 900 mg/day Raxone or placebo for a period of 24 weeks (6 months). Raxone was given as 3 daily doses of 300 mg each with meals.

The primary endpoint “best recovery of visual acuity (VA)” was defined as the result from the eye experiencing the most positive improvement in VA from baseline to week 24 using ETDRS charts. The main secondary endpoint “change in best VA” was measured as the difference between best VA in either the left or right eye at 24 weeks compared to baseline (Table 1).

Table 1: RHODOS: Best recovery of VA and change in best VA from baseline to week 24

Endpoint (ITT)

Raxone (N=53)

Placebo (N=29)

Primary endpoint:

Best recovery of VA

(mean ± SE; 95%CI)

logMAR –0.135 ± 0.041

logMAR –0.071 ± 0.053

logMAR –0.064, 3 letters (–0.184; 0.055)

p=0.291

Main secondary endpoint:

Change in best VA

(mean ± SE; 95% CI)

logMAR –0.035 ± 0.046

logMAR 0.085 ± 0.060

logMAR –0.120, 6 letters (–0.255; 0.014)

p=0.078

Analysis according to Mixed Model of Repeated Measures

One patient in the placebo group presented with ongoing spontaneous recovery of vision at baseline. Exclusion of this patient yielded similar results as in the ITT population; as could be expected, the difference between idebenone and placebo arm was slightly larger.

A pre-specified analysis in RHODOS determined the proportion of patients with an eye with baseline VA of ≤0.5 logMAR in whom the VA deteriorated to ≥1.0 logMAR. In this small subgroup of patients (n=8), 0 of 6 patients in the idebenone group deteriorated to ≥1.0 logMAR whereas 2 of 2 patients in the placebo group showed such a deterioration.

In a single-visit observational follow-up study of RHODOS VA assessments from 58 patients obtained on average 131 weeks after discontinuation of treatment indicates that the effect of Raxone may be maintained.

A post-hoc responder analysis was performed in RHODOS evaluating the proportion of patients who had a clinically relevant recovery of VA from baseline in at least one eye, defined as either: (i) improvement in VA from unable to read a single letter to able to read at least 5 letters on the ETDRS chart; or (ii) improvement in VA by at least 10 letters on the ETDRS chart. Results are shown in Table 2 including supporting data from 62 LHON patients using Raxone in an Expanded Access Programme (EAP) and from 94 untreated patients in a Case Record Survey (CRS).

Table 2: Proportion of patients with clinically relevant recovery of VA after 6 months from baseline

RHODOS (ITT)

RHODOS Raxone (N=53)

RHODOS Placebo (N=29)

Responders (N, %)

16 (30.2 %)

3 (10.3 %)

EAP and CRS

EAP-Raxone (N=62)

CRS-untreated (N=94)

Responders (N, %)

19 (30.6 %)

18 (19.1 %)

In the EAP the number of responders increased with longer treatment duration, from 19 out of 62 patients (30.6%) at 6 months to 17 out of 47 patients (36.2%) at 12 months.

Paediatric population

In clinical trials in Friedreich's Ataxia, 32 patients between the ages of 8 and 11 years and 91 patients between the ages of 12 and 17 years received idebenone at ≥ 900 mg/day for up to 42 months.

In RHODOS and the EAP in LHON, a total of 3 patients between the ages of 9 and 11 years and 27 patients between the ages of 12 and 17 years received idebenone at 900 mg/day for up to 33 months.

This medicinal product has been authorised under 'exceptional circumstances'.

This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Absorption

Food increases the bioavailability of idebenone by approximately 5-7-fold and therefore, Raxone should always be administered with food. The tablets should not be broken or chewed.

After oral administration of Raxone, idebenone is rapidly absorbed. On repeat dosing, maximum plasma concentrations of idebenone are reached on average within 1 hour (median 0.67 h range: 0.33-2.00 h). In phase I pharmacokinetic studies, proportional increases in plasma concentrations of idebenone were observed for doses from 150 mg to 1050 mg. Neither idebenone nor its metabolites showed time-dependent pharmacokinetics.

Distribution

Experimental data have shown that idebenone passes the blood-brain barrier and is distributed at significant concentrations in cerebral tissue. Following oral administration pharmacologically relevant concentrations of idebenone are detectable in the aqueous humor of the eye.

Biotransformation

Metabolism occurs by means of oxidative shortening of the side chain and by reduction of the quinone ring and conjugation to glucuronides and sulphates. Idebenone shows a high first pass metabolism resulting in conjugates of idebenone (glucuronides and sulphates (IDE-C)) and the Phase I metabolites QS10, QS6, and QS4 as well as their corresponding Phase II metabolites (glucuronides and sulphates (QS10+QS10-C, QS6+QS6-C, QS4+QS4-C)). The main metabolites in plasma are IDE-C and QS4+QS4-C.

Elimination

Due to the high first-pass effect, the plasma concentrations of idebenone were generally only measurable up to 6 hours after oral administration of 750 mg Raxone, given either as a single oral dose or after repeated (14 days) t.i.d dosing. The main route of elimination is metabolism, with the majority of dose excreted via the kidneys as metabolites. After a single or repeated oral dose of 750 mg Raxone, QS4+QS4-C were the most prominent idebenone-derived metabolites in urine, representing on average between 49.3% and 68.3% of the total administered dose. QS6+QS6 represented 6.45% to 9.46%, whereas QS10+QS10-C and IDE+IDE-C were close to 1% or below.

Hepatic or renal impairment

No data are available in these populations.

Paediatric population

Whilst clinical trials experience in paediatrics with LHON is limited to patients of 14 years of age and above, pharmacokinetic data from population pharmacokinetic studies, which included paediatric Friedreich's Ataxia patients of age 8 years and above, did not reveal any significant differences in the pharmacokinetics of idebenone.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

6. Pharmaceutical particulars
6.1 List of excipients

Core tablet

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Povidone K25

Magnesium stearate

Colloidal silica

Coating

Macrogol 3350

Poly(vinyl alcohol)

Talc

Titanium dioxide

Sunset yellow FCF (E110)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

White high-density polyethylene bottles with white polypropylene child-resistant tamper-evident twist-off caps containing 180 film-coated tablets.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Santhera Pharmaceuticals (Deutschland) GmbH

Marie-Curie Strasse 8

79539 Lörrach

Germany

Tel: +49 (0) 7621 1690 200

Fax: +49 (0) 7621 1690 201

Email: [email protected]

8. Marketing authorisation number(s)

EU/1/15/1020/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 8 September 2015

10. Date of revision of the text

03/2018