Fidaxomicin

Fidaxomicin is a substrate of P-gp. Co-administration of single doses of the P-gp inhibitor cyclosporine A and fidaxomicin 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.

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

No dose adjustment is considered necessary. Due to the limited clinical data in this population, fidaxomicin should be used with caution in patients with severe renal impairment.

No dose adjustment is considered necessary. Due to the limited clinical data in this population, fidaxomicin should be used with caution in patients with moderate to severe hepatic impairment.

Hypersensitivity reactions including severe angioedema have been reported. If a severe allergic reaction occurs during treatment with fidaxomicin, 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.

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 fidaxomicin during pregnancy.

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 fidaxomicin 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 evaluated in rats.

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

Summary of the safety profile

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

List of adverse reactions

The list belwo 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.

Immune system disorders

Uncommon: rash, pruritus

Frequency not known: hypersensitivity reactions (angioedema, dyspnea)

Metabolism and nutrition disorders

Uncommon: decreased appetite

Nervous system disorders

Uncommon: dizziness, headache, dysgeusia

Gastrointestinal disorders

Common: vomiting, nausea, constipation

Uncommon: abdominal distention, flatulence, dry mouth

Description of selected adverse reactions

Acute hypersensitivity reactions, such as angioedema and dyspnea, have been reported during post-marketing.

Paediatric population

The safety and efficacy of fidaxomicin has been evaluated in 136 patients from birth to less than 18 years of age. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. In addition to the ADRs shown above, two cases of urticaria were reported.