Raxone 150 mg film-coated tablets

• To remove Santhera logo from one side of the tablet face, resulting in an update to the SmPC, package leaflet and finished product specifications (engraving on the other side of the tablet face ‘150’ is maintained)

• To remove Santhera logo from one side of the tablet face, resulting in an update to the SmPC, package leaflet and finished product specifications (engraving on the other side of the tablet face ‘150’ is maintained)

The Marketing Authorisation Holder in the EU for the product Raxone 150 mg film-coated tablets has now been transferred from Santhera Pharmaceuticals to ‘Chiesi Farmaceutici SpA’

The Marketing Authorisation Holder in the EU for the product Raxone 150 mg film-coated tablets has now been transferred from Santhera Pharmaceuticals to ‘Chiesi Farmaceutici SpA’

Fax number removed

4.2    Posology and method of administration

Posology

Added: 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)

Special populations

Hepatic or renal impairment

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

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

4.4       Special warnings and precautions for use

Hepatic or renal impairment

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

4.9    Overdose

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

 5.1    Pharmacodynamic properties

Clinical efficacy and safety

S). Long term efficacy and safety have been studied in a post-approval open-label study (LEROS).[SP1]  Long term safety has been studied in a non-interventional post-authorisation safety study (PAROS).

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 received 900 mg/day Raxone for a period of 24 months. Raxone was given as 3 doses of 300 mg daily, each with 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 started treatment with Raxone ≤1 year after the onset of symptoms, compared to eyes of patients from an external Natural History (NH) control group. CRB was observed in 42.3% of eyes from LEROS patients, 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. The estimated difference between treatment and control was statistically significant (p-value 0.0020) in favor 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 treated with 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 NH control 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 a p 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), which was equivalent to a total exposure of 319.39 person-years. A total of 154 (77.8%) of the patients undertook 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 were mainly of mild or moderate severity; 13 (6.6%) patients who received Raxone treatment reported severe AEs. Forty-nine (24.7%) patients reported AEs that were considered by the Investigator to be treatment-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 have emerged in patients with LHON enrolled in the LEROS study.

PAROS was a post-authorization non-interventional safety study designed to collect longitudinal safety and effectiveness data in routine clinical settings in patients prescribed with Raxone for the treatment 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 at baseline received treatments with Raxone and were included in the Safety population. Over half of the patients (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 in the table 3 below.

The long-term safety profile of Raxone in the treatment of patients with LHON was evaluated when used 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%) patients reported 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%) patients experienced 31 serious TEAEs.

There was one death in the study, in an 81-year-old male patient who died of terminal prostate carcinoma, 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).

Paediatric population

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

Renewal application for Raxone 150 mg film-coated tablets.

There are only minor updates to the SmPC and the following sections have been impacted: 4.4, 4.5, 4.6, 4.8 (ADR reporting only), 5.1, 5.2 & 6.1.

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 FCF (E110).

4.4          Special warnings and precautions for use

Lactose

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

4.5         Interaction with other medicinal products and other forms of interaction

Idebenone may inhibit P-glycoprotein (Pp-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 pP-gp in vitro.

4.6     Fertility, pregnancy and lactation

Breast-feeding

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

4.8     Undesirable effects

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:

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, Website: www.hpra.ie United Kingdom: Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax:

+353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

6.1     List of excipients

Core tTablet core

Lactose monohydrate

Microcrystalline cCellulose, microcrystalline

Croscarmellose sodium

Povidone (K25)

Magnesium stearate

Colloidal sSilica, colloidal anhydrous

Film-Ccoating

Macrogol (3350)

Poly(vinyl alcohol)

Talc

Titanium dioxide

Sunset yellow FCF (E110)

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 8 September 2015

Date of latest renewal: 6 August 2020

10.     DATE OF REVISION OF THE TEXT

6 August 2020

There was an error in the previous versions submitted they were missing local information under Section 4 which refers to reporting side effects using the "the national reporting system listed in Appendix V" these have now been completed with  information specific to Ireland 

Section 4 refers to reporting side effects using the "the national reporting system listed in Appendix V" which have now been updated to include information specific to Ireland