RAXONE 150mg tablets medication leaflet

Raxone 150 mg film-coated tablets

Each film-coated tablet contains 150 mg idebenone.

Each film-coated tablet contains 46 mg of lactose (as monohydrate) and 0.23 mg of sunset yellow FCF(E110).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Orange, round, biconvex film-coated tablet of 10 mm diameter, engraved with ‘150’ on one side.

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).

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

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

Data regarding continuous treatment with idebenone for up to 24 months are available as part of a

Natural History controlled open label clinical trial (see section 5.1).

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 been investigated. However, no specific posologyrecommendations can be made. Caution is advised in treatment of patients with hepatic or renalimpairment, since adverse events have resulted in temporary interruption or discontinuation oftreatment (see section 4.4).

In the absence of sufficient clinical data, caution should be exercised in patients with renalimpairment.

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

Raxone film-coated tablets should be swallowed whole with water. The tablets should not be brokenor chewed. Raxone should be administered with food because food increases the bioavailability ofidebenone.

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

Patients should be regularly monitored according to local clinical practice.

Hepatic or renal impairment

Caution should be exercised when prescribing Raxone to patients with hepatic or renal impairment.

Adverse events have been reported in patients with hepatic impairment, which have resulted intemporary interruption or discontinuation of treatment.

Chromaturia

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

Raxone contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take Raxone.

Sunset yellow

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

Data from in vitro studies have demonstrated that idebenone and its metabolite QS10 do not exertsystemic inhibition of cytochrome P450 isoforms CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 atclinically 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 in32 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 productswere administered together. After repeated administration Cmax and AUC of midazolam were increasedby 28% and 34%, respectively, when midazolam was administered in combination with 300 mgidebenone t.i.d. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such asalfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus,tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution inpatients receiving idebenone.

Idebenone may inhibit P-glycoprotein (P-gp) with possible exposure increases of, e.g., dabigatranetexilate, digoxin or aliskiren. These medicines should be administered with caution in patientsreceiving 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 indicatedirect or indirect harmful effects with respect to reproductive toxicity. Idebenone should only beadministered to pregnant women or women of child-bearing potential likely to become pregnant if it isconsidered that the benefit of the therapeutic effect outweighs any potential risk.

Available pharmacodynamic/toxicological data in animals have shown excretion of idebenone in milk(for details see 5.3). A risk to the suckling child cannot be excluded. . A decision must be madewhether to discontinue breast-feeding or to discontinue/abstain from Raxone therapy taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

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

The most commonly reported adverse reactions to idebenone are mild to moderate diarrhoea (usuallynot requiring the discontinuation of the treatment), nasopharyngitis, cough and back pain.

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 followingconvention: very common (≥1/10), common (≥1/100 to <1/10), not known (cannot be estimated fromthe available data).

System Organ Class Preferred Term Frequency

Infections and Nasopharyngitis Very common

Infestations Bronchitis Not known

Blood and lymphatic Agranulocytosis, anaemia, leukocytopenia, Not knownsystem disorders thrombocytopenia, neutropenia

Metabolism and nutrition Blood cholesterol increased, blood Not knowndisorders triglycerides increased

System Organ Class Preferred Term Frequency

Nervous system disorders Seizure, delirium, hallucinations, agitation,dyskinesia, hyperkinesia, poriomania, Not knowndizziness, headache, restlessness, stupor

Respiratory, thoracic and Cough Very commonmediastinal disorders

Gastrointestinal disorders Diarrhoea Common

Nausea, vomiting, anorexia, dyspepsia Not known

Hepatobiliary disorders Alanine aminotransferase increased,aspartate aminotransferase increased, bloodalkaline phosphatase increased, blood Not knownlactate dehydrogenase increased, gamma-glutamyltransferase increased, bloodbilirubin increased, hepatitis

Skin and subcutaneous Rash, pruritus Not knowntissue disorders

Musculoskeletal and Back pain Commonconnective tissue Pain in extremity Not knowndisorders

Renal and urinary Azotaemia, chromaturia Not knowndisorders

General disorders and Malaise Not knownadministration siteconditions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No report of overdose has been received from the RHODOS, the LEROS and the PAROS studies.

Doses up to 2,250 mg/day have been administered in clinical studies showing a safety profileconsistent with that reported in section 4.8.

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

Pharmacotherapeutic group: Psychoanaleptics, Other psychostimulants and nootropics;

ATC code: N06BX13

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

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

Clinical safety and efficacy of idebenone in LHON have been assessed in one double-blind,randomised, placebo-controlled study (RHODOS). Long term efficacy and safety have been studied ina post-approval open-label study (LEROS). Long term safety has been studied in a non-interventionalpost-authorisation safety study (PAROS).

In RHODOS a total of 85 LHON patients, 14-66 years of age, with any of the 3 primary mtDNAmutations (G11778A, G3460A or T14484C) and disease duration of not more than 5 years wereenrolled. Patients received either 900 mg/day Raxone or placebo for a period of 24 weeks (6 months).

Raxone was given as 3 doses of 300 mg daily, each with meals.

The primary endpoint “best recovery of visual acuity (VA)” was defined as the result from the eyeexperiencing 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 VAin 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: logMAR* -0.135 ± 0.041 logMAR -0.071 ± 0.053

Best recovery of VA logMAR -0.064, 3 letters (-0.184; 0.055)(mean ± SE; 95%CI) p=0.291

Main secondary endpoint: logMAR -0.035 ± 0.046 logMAR 0.085 ± 0.060

Change in best VA logMAR -0.120, 6 letters (-0.255; 0.014)(mean ± SE; 95% CI) 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 patientyielded similar results as in the ITT population; as could be expected, the difference between idebenone and placebo arm wasslightly larger.

*logMAR - Logarithm of the Minimum Angle of Resolution

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 inthe placebo group showed such a deterioration.

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

A post-hoc responder analysis was performed in RHODOS evaluating the proportion of patients whohad 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 ETDRSchart; 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 frombaseline

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 62patients (30.6%) at 6 months to 17 out of 47 patients (36.2%) at 12 months.

In LEROS; a total of 199 LHON patients were enrolled in this open - label study. Over half (112[56.6%]) had the G11778A mutation, whereas 34 (17.2%) had the T14484C mutation and 35 (17.7%)had the G3460A mutation. The mean age at Baseline (BL) was 34.2 years. Patients received900 mg/day Raxone for a period of 24 months. Raxone was given as 3 doses of 300 mg daily, eachwith meals.

The primary endpoint in LEROS was the proportion of eyes that achieved a Clinically Relevant

Benefit (CRB) (that is, in which there was either a Clinically Relevant Recovery [CRR] of VA from

Baseline or a Clinically Relevant Stabilization [CRS]) at Month 12 in those patients that startedtreatment with Raxone ≤1 year after the onset of symptoms, compared to eyes of patients from anexternal Natural History (NH) control group. CRB was observed in 42.3% of eyes from LEROSpatients, in contrast to 20.7% eyes from NH patients. Clinically, this represents a relevant 104%relative improvement compared to spontaneous CRB that may occur in the control NH eyes. Theestimated difference between treatment and control was statistically significant (p-value 0.0020) infavor of Raxone presenting an Odds Ratio (OR) of 2.286 (95% confidence limits 1.352, 3.884).

One of the secondary endpoints in LEROS was the proportion of eyes with CRB in patients treatedwith Raxone >1 year after the onset of symptoms, with CRR of VA from Baseline or CRS in which

Baseline VA better than 1.0 logMAR was maintained at Month 12 compared to an external NHcontrol group. CRB was observed in 50.3% eyes of LEROS patients and 38.6% eyes of NH patients.

The difference between the two groups was statistically significant in favor of Raxone presenting ap-value of 0.0087 and OR [95% CI] of 1.925 [1.179, 3.173].

A total of 198 patients received treatment with Raxone and were included in the Safety Population.

The mean duration of treatment in the Safety Population was 589.17 days (range: 1 - 806 days), whichwas equivalent to a total exposure of 319.39 person-years. A total of 154 (77.8%) of the patientsundertook treatment for >12 months. A total of 149 (75.3%) patients underwent treatment at the>18-month timeframe; at the >24-month timeframe, this was 106 (53.5%). A total of 154 (77.8%)patients reported Treatment Emergent Adverse Events. The Adverse Events (AE) reported weremainly of mild or moderate severity; 13 (6.6%) patients who received Raxone treatment reportedsevere AEs. Forty-nine (24.7%) patients reported AEs that were considered by the Investigator to betreatment-related. Twenty-seven (13,6%) patients experienced Serious Adverse Events and ten (5.1%)had AEs that led to permanent discontinuation of study treatment. No new safety concerns haveemerged in patients with LHON enrolled in the LEROS study.

PAROS was a post-authorization non-interventional safety study designed to collect longitudinalsafety and effectiveness data in routine clinical settings in patients prescribed with Raxone for thetreatment of LHON. This study was conducted at 26 centres in 6 European countries (Austria, France,

Germany, Greece, Italy and The Netherlands).

In the long-term safety study PAROS, a total of 224 LHON patients with a median age of 32.2 years atbaseline received treatments with Raxone and were included in the Safety population. Over half of thepatients (52.2%) had the G11778A mutation; 17.9% had the T14484C mutation, 14.3% had the

G3460A mutation, and 12.1% had other mutations. Time in treatment of these patients is displayed inthe table 3 below.

Table 3: Time in treatment (Safety Population)

Time in treatment Idebenone-naïve at Idebenone non-naïve at baseline Allbaseline

N 39 185 224

Day 1 39 (100.0%) 185 (100.0%) 224 (100.0%)≥ 6 months 35 (89.7%) 173 (93.5%) 208 (92.9%)≥ 12 months 30 (76.9%) 156 (84.3%) 186 (83.0%)≥ 18 months 20 (51.3%) 118 (63.8%) 138 (61.6%)≥ 24 months 14 (35.9%) 93 (50.3%) 107 (47.8%)≥ 30 months 8 (20.5%) 68 (36.8%) 76 (33.9%)≥ 36 months 8 (20.5%) 54 (29.2%) 62 (27.7%)

The mean duration of exposure is of 765.4 days (SD 432.6 days)

The long-term safety profile of Raxone in the treatment of patients with LHON was evaluated whenused under conditions of routine clinical care.

A total of 130 patients (58.0% of the Safety population) reported 382 Treatment Emergent Adverse

Events (TEAEs). Eleven (4.9%) patients reported severe Adverse Events (AEs). Fifty (22.3%) patientsreported 82 TEAEs that were considered by the Investigator to be drug-related. Thirty-four (15.2%)patients had 39 TEAEs that led to discontinuation of Raxone treatment. Twenty-five (11.2%) patientsexperienced 31 serious TEAEs.

There was one death in the study, in an 81-year-old male patient who died of terminal prostatecarcinoma, which was assessed by the Investigator as unrelated to Raxone.

No new safety concerns have been identified with long-term treatment with Raxone in patients with

LHON when used under conditions of routine clinical care in the PAROS study. The safety profile of

Raxone observed in PAROS was similar to that from a previous open-label study (the LEROS study).

In clinical trials in Friedreich’s Ataxia, 32 patients between the ages of 8 and 11 years and 91 patientsbetween 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 27patients between the ages of 12 and 17 years received idebenone at 900 mg/day for up to 33 months.

In PAROS, only nine patients under 14 years of age were included and received Raxone at 900mg/day.

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 informationon this medicinal product.

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

Food increases the bioavailability of idebenone by approximately 5-7-fold and therefore, Raxoneshould 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, maximumplasma concentrations of idebenone are reached on average within 1 hour (median 0.67 h range:0.33-2.00 h).

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

Metabolism occurs by means of oxidative shortening of the side chain and by reduction of the quinonering and conjugation to glucuronides and sulphates. Idebenone shows a high first pass metabolismresulting 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.

Due to the high first-pass effect, the plasma concentrations of idebenone were generally onlymeasurable up to 6 hours after oral administration of 750 mg Raxone, given either as a single oral doseor after repeated (14 days) t.i.d dosing. The main route of elimination is metabolism, with the majorityof 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, representingon average between 49.3% and 68.3% of the total administered dose. QS6+QS6 represented 6.45% to9.46%, whereas QS10+QS10-C and IDE+IDE-C were close to 1% or below.

In phase I pharmacokinetic studies, proportional increases in plasma concentrations of idebenone wereobserved for doses from 150 mg to 1050 mg. Neither idebenone nor its metabolites showed time-dependent pharmacokinetics.

Hepatic or renal impairment

No data are available in these populations.

Whilst clinical trials experience in paediatrics with LHON is limited to patients of 14 years of age andabove, 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 thepharmacokinetics of idebenone.

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

Lactose monohydrate

Cellulose, microcrystalline

Croscarmellose sodium

Povidone (K25)

Magnesium stearate

Silica, colloidal anhydrous

Macrogol (3350)

Poly(vinyl alcohol)

Talc

Titanium dioxide

Sunset yellow FCF (E110)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

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

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

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

EU/1/15/1020/001

Date of first authorisation: 8 September 2015

Date of latest renewal: 6 August 2020

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu