DIFICLIR 200 mg film-coated tablets

Each tablet contains 200 mg of fidaxomicin .

For the full list of excipients, see section 6.1.

Film-coated tablet.

Capsule shaped tablets, white to off-white in colour, debossed with “FDX” on one side and “200” on the other side.

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.

Posology

Adults and 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.

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

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.

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.

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 is not recommended.

Effect of fidaxomicin on P-gp substrates

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

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.

Pregnancy

There are no data available from the use of fidaxomicin in pregnant women. Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of DIFICLIR during pregnancy.

Breast-feeding

It is unknown whether fidaxomicin and its metabolites are excreted in human milk. Although no effects on the breastfed newborns/infants are anticipated since the systemic exposure to fidaxomicin is low, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from DIFICLIR therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Fidaxomicin had no effects on fertility when eva luated in rats (see section 5.3).

DIFICLIR has no influence on the ability to drive and use machines.

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 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

No cases of acute overdose have been reported.

Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, antibiotics, ATC code: A07AA12

Mechanism of action

Fidaxomicin is an antibiotic belonging to the macrocyclic class of antibacterials.

Fidaxomicin is bactericidal and inhibits RNA synthesis by bacterial RNA polymerase. It interferes with RNA polymerase at a distinct site from that of rifamycins. Inhibition of the Clostridial RNA polymerase occurs at a concentration 20-fold lower than that for the E. coli enzyme (1 μM vs. 20 μM), partly explaining the significant specificity of fidaxomicin activity. Fidaxomicin has been shown to inhibit C. difficile sporulation in vitro.

PK/PD relationship

Fidaxomicin is a locally acting drug. As a topical agent, systemic PK/PD relationships cannot be established, however in vitro data show fidaxomicin to have time-dependent bactericidal activity and suggest time over MIC may be the parameter most predicative of clinical efficacy.

Breakpoints

Fidaxomicin is a topically acting drug that cannot be used to treat systemic infections; therefore the establishment of a clinical breakpoint is not relevant. The epidemiological cut-off value for fidaxomicin and C. difficile, distinguishing the wild-type population from isolates with acquired resistance traits, is ≥1.0 mg/L.

Antimicrobial spectrum

Fidaxomicin is a narrow spectrum antimicrobial drug with bactericidal activity against C. difficile. Fidaxomicin has an MIC₉₀ of 0.25 mg/L versus C. difficile, and its main metabolite, OP-1118, has an MIC₉₀ of 8 mg/L. Gram negative organisms are intrinsically not susceptible to fidaxomicin.

Effect on the intestinal flora

Studies have demonstrated that fidaxomicin treatment did not affect Bacteroides concentrations or other major components of the microbiota in the faeces of CDI patients.

Mechanism of resistance

There are no known transferable elements that confer resistance to fidaxomicin. Also no cross-resistance has been discovered with any other antibiotic class including β-lactams, macrolides, metronidazole, quinolones, rifampin, and vancomycin. Specific mutations of RNA polymerase are associated with reduced susceptibility to fidaxomicin.

Clinical efficacy

In the pivotal clinical trials the rate of recurrence in the 30 days following treatment was assessed as a secondary endpoint. The rate of recurrence (including relapses) was significantly lower with fidaxomicin (14.1% versus 26.0% with a 95% CI of [-16.8%, -6.8%]), however these trials were not prospectively designed to prove prevention of reinfection with a new strain.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with DIFICLIR in one or more subsets of the paediatric population in enterocolitis caused by C. difficile (see section 4.2 for information on paediatric use).

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.

Biotransformation

No extensive analysis of metabolites in plasma has been performed, due to low levels of systemic absorption of fidaxomicin. A main metabolite, OP-1118, is formed through hydrolysis of the isobutyryl ester. In vitro metabolism studies showed that the formation of OP-1118 is not dependent on CYP450 enzymes. This metabolite also shows antimicrobial activity (see section 5.1).

Fidaxomicin does not induce or inhibit CYP450 enzymes in vitro.

Elimination

Following a single dose of 200 mg fidaxomicin, the majority of the administered dose (over 92%) was recovered in the stool as fidaxomicin or its metabolite OP-1118 (66%). The main elimination pathways of systemically available fidaxomicin have not been characterized. Elimination through urine is negligible (<1%). Only very low levels of OP-1118 and no fidaxomicin was detectable in human urine. The half life of fidaxomicin is approximately 8-10 h.

Special populations

Plasma levels appear to be elevated in the elderly (age ≥ 65 years). Fidaxomicin and OP-1118 levels were approximately 2 times higher in patients ≥ 65 years compared to patients < 65 years. This difference is not considered clinically relevant.

Limited data from patients with an active history of chronic hepatic cirrhosis in the Phase 3 studies showed that median plasma levels of fidaxomicin and OP-1118 may be approximately 2- and 3-fold higher, respectively, than in non-cirrhotic patients.

Limited data suggest that there is no major difference in plasma concentration of fidaxomicin or OP-1118 between patients with reduced renal function (creatinine clearance < 50 ml/min) and patients with normal renal function (creatinine clearance ≥ 50 ml/min).

Limited data suggest that gender, weight and race do not have any major influence on the plasma concentration of fidaxomicin or OP-1118.

Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, and reproductive toxicity.

Reproductive and fertility parameters showed no statistically significant differences in rats treated with fidaxomicin at doses up to 6.3 mg/kg/day (i.v.).

Core tablets:

Microcrystalline cellulose

Pregelatinised starch

Hydroxypropyl cellulose

Butylated hydroxytoluene

Sodium starch glycolate

Magnesium stearate

Coating:

Polyvinyl alcohol

Titanium dioxide

Talc

Polyethylene glycol

Lecithin (Soy)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

30 ml HDPE bottles with induction-sealed, polypropylene child-resistant caps; 20 film-coated tablets per bottle.

60 ml HDPE bottles with induction-sealed, polypropylene child-resistant caps; 60 film-coated tablets per bottle.

100 x 1 film-coated tablet in alu/alu perforated unit dose blisters (10 film-coated tablets per blister card; 10 blister cards per carton).

20 x 1 film-coated tablet in alu/alu perforated unit dose blisters (10 film-coated tablets per blister card; 2 blister cards per carton).

Not all pack sizes may be marketed.

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

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

The Netherlands

EU/1/11/733/001-004

05/12/2011

23/01/2014

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