4.4     Special warnings and precautions for use

Deletion of the following paragraph.

There are no data in patients with concomitant inflammatory bowel disease. Fidaxomicin should be used with caution in these patients due to the risk of enhanced absorption and potential risk of systemic adverse reactions.

5.2     Pharmacokinetic properties

New headings for special populations:

Elderly, Hepatic impariment, renal impairment, Gender, weight and race.

New paragraph as follows:

Inflammatory bowel disease
Data from an open label, single arm study in CDI patients with concomitant inflammatory bowel disease (IBD) indicated no major difference in plasma concentrations of fidaxomicin or its main metabolite OP-1118 in patients with IBD as compared with patients without IBD in other studies. The maximum fidaxomicin and OP‑1118 plasma levels in CDI patients with concomitant IBD were within the range of levels found in CDI patients without IBD.

The black triangle has been removed
The text of the SPC has been clarified throughout in connection with the renewal of the authorisation, the section Description of the patient population in clinical trials has been moved to section 5.1.
The bottle formulation has been removed (this was never marketed)
The impact of the effect of coadministration with  rosuvastatin has been clarified in section 4.5
Acute hypersensitivity reactions have been added to section 4.8. Section 4.8 has been updated to reflect data available from post-marketing experience as well as clinical trials.
The date of last renewal has been added.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Effect of fidaxomicin on other transporters

Fidaxomicin does not have a clinically significant effect on the exposure of rosuvastatin, a substrate for the transporters OATP2B1 and BCRP. Co-administration of 200 mg fidaxomicin twice daily with a single dose of 10 mg rosuvastatin to healthy subjects did not have an effect on the AUC_inf of rosuvastatin. The C_max of rosuvastatin increased by approx. 17%, indicating that an increase in the rate of absorption cannot be excluded.

 

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

 

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie.

 

5.2     Pharmacokinetic properties

 

Absorption

 

Fidaxomicin and the metabolite OP‑1118 are substrates of P‑gp.

In vitro studies showed that fidaxomicin and the metabolite OP-1118 are inhibitors of the transporters BCRP, MRP2 and OATP2B1, but were not found to be substrates. The clinical relevance is not yet

Known. Under conditions of clinical use, fidaxomicin has no clinically relevant effect on the exposure of rosuvastatin, a substrate for OATP2B1 and BCRP (see section 4.5). The clinical relevance of MRP2 inhibition is not yet known.

 

10.     DATE OF REVISION OF THE TEXT

 

JanuaryJune 2014

4.4     Special warnings and precautions for use

 

Hypersensitivity reactions including severe angioedema have been reported. If a severe allergic reaction occurs during treatment with Dificlir, the medicinal product should be discontinued and appropriate measures taken.

Some patients with hypersensitivity reactions reported a history of allergy to macrolides. Fidaxomicin should be used with caution in patients with a known macrolides allergy.

 

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:

 

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6767836

www.imb.ie

 

IMB Pharmacovigilance

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

10.     DATE OF REVISION OF THE TEXT

 

 June 2012January 2014

 

 

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

 

DIFICLIR 200 mg film-coated tablets

 

 

4.       CLINICAL PARTICULARS

 

4.1     Therapeutic indications

 

DIFICLIR is indicated in adults for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) (see section 5.1).

 

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

 

4.2     Posology and method of administration

 

Posology

Adults and elderly older people (≥ 65 years of age)

The recommended dose is 200 mg (one tablet) administered twice daily (once every 12 hours) for 10 days.

 

Paediatric population

The safety and efficacy of fidaxomicin in children aged below 18 years has not yet been established. No data are available.

 

Renal impairment

No dose adjustment is considered necessary. Due to the limited clinical data in this population, DIFICLIR should be used with caution in patients with severe renal impairment (see sections 4.4 and 5.2).

 

Hepatic impairment

No dose adjustment is considered necessary. Due to the limited clinical data in this population, DIFICLIR should be used with caution in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).

 

Method of administration

DIFICLIR is intended for oral administration.

DIFICLIR can be taken with or without food.

 

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

 

Hypersensitivity reactions including severe angioedema have been reported. If a severe allergic reaction occurs during treatment with Dificlir, the medicinal product should be discontinued and appropriate measures taken.

 

Due to limited clinical data, fidaxomicin should be used with caution in patients with severe renal impairment or moderate to severe hepatic impairment (see section 5.2).

 

Due to limited clinical data, fidaxomicin should be used with caution in patients with pseudomembranous colitis, fulminant or life threatening CDI.

 

There are no data in patients with concomitant inflammatory bowel disease. Fidaxomicin should be used with caution in these patients due to the risk of enhanced absorption and potential risk of systemic adverse reactions.

 

Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended (see sections 4.5 and 5.2).

 

Description of the patient population in clinical trials

 

In the two clinical trials of patients with CDI, 47.9% (479/999) of patients (per protocol population) were ≥ 65 years of age and 27.5% (275/999) of patients were treated with concomitant antibiotics during the study period. Twenty-four percent of patients met at least one of the following three criteria at baseline for scoring severity: body temperature > 38.5°C, leukocyte count > 15,000, or creatinine value ≥ 1.5 mg/dl. Patients with fulminant colitis and patients with multiple episodes (defined as more than one prior episode within the previous 3 months) of CDI were excluded in the studies.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Effect of P-gp inhibitors on fidaxomicin

Fidaxomicin is a substrate of P‑gp. Co-administration of single doses of the P‑gp inhibitor cyclosporine A and DIFICLIR in healthy volunteers, resulted in a 4‑ and 2‑fold increase in fidaxomicin C_max and AUC, respectively and in a 9.5 and 4‑fold increase in C_max and AUC, respectively, of  the main active metabolite OP‑1118. As the clinical relevance of this increase in exposure is unclear, co-administration of potent inhibitors of P‑gp, such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone are not recommended.

 

Effect of fidaxomicin on P-gp substrates

and Fidaxomicin may be a mild to moderate inhibitor of intestinal P‑gp.

 

Co-administration of single doses of the P-gp inhibitor cyclosporine A and DIFICLIR in healthy

volunteers, resulted in a 4- and 2-fold increase in fidaxomicin Cmax and AUC, respectively and in a 9.5

and 4-fold increase in Cmax and AUC, respectively, of the main active metabolite OP-1118. As the

clinical relevance of this increase in exposure is unclear, co-administration of potent inhibitors of

P-gp, such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and

amiodarone are not recommended.

 

DIFICLIR (200 mg twice daily) had a small but not clinically relevant effect on digoxin exposure. However, a larger effect on P‑gp substrates with lower bioavailability more sensitive to intestinal P‑gp inhibition such as dabigatran etexilat cannot be excluded.

 

 

4.8     Undesirable effects

 

Summary of the safety profile

The safety profile of DIFICLIR is based on data from 564 patients with CDI treated with fidaxomicin in Phase 3 studies.

 

The most common treatment related adverse reactions were vomiting (1.2%), nausea (2.7%) and constipation (1.2%).

 

Tabulated summary of adverse reactions

Table 1 Table 1 displays adverse reactions associated with twice daily administration of fidaxomicin in the treatment of C. difficile infection, reported in at least two patients, presented by system organ class.

 

The frequency of adverse reactions is defined 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Table 1 :           Summary of adverse reactions by MedDRA system organ class

 

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 listed in Appendix V.

 

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6767836

www.imb.ie

 

4.9     Overdose

 

No cases of acute overdose have been reported.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.2     Pharmacokinetic properties

 

Absorption

 

The bioavailability in humans is unknown. In healthy adults, C_max is approximately 9.88 ng/ml and AUC_0-t is 69.5 ng-hr/ml following administration of 200 mg fidaxomicin, with a T_max of 1.75 hours. In CDI patients, average peak plasma levels of fidaxomicin and its main metabolite OP‑1118 tend to be 2‑ to 6-fold higher than in healthy adults. There was very limited accumulation of fidaxomicin or OP‑1118 in plasma following administration of 200 mg fidaxomicin every 12 hours for 10 days.

 

C_max for fidaxomicin and OP‑1118 in plasma were 22% and 33% lower following a high fat meal vs fasting, but the extent of exposure (AUC_0-t) was equivalent.

 

Fidaxomicin and the metabolite OP‑1118 are substrates of P‑gp.

In vitro studies showed that fidaxomicin and the metabolite OP-1118 are inhibitors of the transporters BCRP, MRP2 and OATP2B1, but were not found to be substrates. The clinical relevance is not yet known.

 

Distribution

 

The volume of distribution in humans is unknown, due to very limited absorption of fidaxomicin.

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

June 2013

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

 

None provided