fidaxomicin: prescribing information – dosing, contraindications, interactions, side effects

DIFICLIR film-coated tablets is indicated for the treatment of Clostridioides difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) in adult and paediatric patients with a body weight of at least 12.5 kg (see section 4.2 and 5.1).

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

DIFICLIR granules for oral suspension is indicated for the treatment of Clostridioides difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) in adults and paediatric patients from birth to < 18 years of age (see section 4.2 and 5.1).

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

Posology

Adults
Standard dosing
The recommended dose is 200 mg (one tablet) administered twice daily (once every 12 hours) for 10 days (see section 5.1).

DIFICLIR 40 mg/ml granules for oral suspension may be used in adult patients with difficulties in swallowing tablets.

Extended-pulsed dosing
Fidaxomicin 200 mg tablets administered twice daily for days 1-5 (no intake of a tablet on day 6) then once daily on alternate days for days 7-25 (see section 5.1).

If a dose has been forgotten, the missed dose should be taken as soon as possible or, if it's nearly time for the next dose, the tablet should be skipped altogether.

Special populations

Elderly population
No dose adjustment is considered necessary (see section 5.2).

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 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, fidaxomicin should be used with caution in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
The recommended dose in paediatric patients weighing at least 12.5 kg is 200 mg administered twice daily (once every 12 hours) for 10 days using the film-coated tablets or the granules for oral suspension.

Reduced doses are recommended for patients with a body weight of less than 12.5 kg. See the SmPC of DIFICLIR 40 mg/ml granules for oral suspension.

Method of administration

DIFICLIR is intended for oral use.
The film-coated tablets should be administered whole with water.
They can be taken with or without food.

Posology

Adults
Standard dosing
The recommended dose is 200 mg (5 ml) administered twice daily (once every 12 hours) for 10 days (see section 5.1).

Extended-pulsed dosing
Fidaxomicin 40 mg/ml granules for oral suspension (5 ml) administered twice daily for days 1-5 (no intake of suspension on day 6) then once daily on alternate days for days 7-25 (see section 5.1).

If a dose has been forgotten, the missed dose should be taken as soon as possible or, if it's nearly time for the next dose, the dose should be skipped altogether.

Special populations

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 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, fidaxomicin should be used with caution in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
For appropriate dosing in the paediatric population, granules for oral suspension or film-coated tablets may be used.

The recommended dose in paediatric patients weighing at least 12.5 kg is 200 mg (5 ml oral suspension) administered twice daily (once every 12 hours) for 10 days.

The recommended dose of the oral suspension in paediatric patients, by body weight, to be administered twice daily (once every 12 hours) for 10 days, is presented in the table below.

Table 1:
Dosing instruction for the oral suspension
Weight band of patient

Mg per dose
(every 12 hours)
Volume of fidaxomicin oral suspension
(every 12 hours)
< 4.0 kg
40 mg
1 ml

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

Summary of the safety profile

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

Tabulated list 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:
Adverse reactions
MedDRA system organ class
Common
Uncommon
Frequency not known
Immune system disorders

rash, pruritus hypersensitivity reactions
(angioedema, dyspnea)
Metabolism and nutrition disorders

decreased appetite

Nervous system disorders

dizziness, headache, dysgeusia

Gastrointestinal disorders vomiting, nausea, constipation abdominal distention, flatulence, dry mouth

Description of selected adverse reactions

Acute hypersensitivity reactions, such as angioedema and dyspnea, have been reported during post-marketing (see section 4.3 and 4.4).

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 in table 1, two cases of urticaria were reported.

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.

Summary of the safety profile

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

Tabulated list of adverse reactions

Table 2 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 2:
Adverse reactions
MedDRA system organ class
Common
Uncommon
Frequency not known
Immune system disorders

rash, pruritus hypersensitivity reactions
(angioedema, dyspnea)
Metabolism and nutrition disorders

decreased appetite

MedDRA system organ class
Common
Uncommon
Frequency not known
Nervous system disorders

dizziness, headache, dysgeusia

Gastrointestinal disorders vomiting, nausea, constipation abdominal distention, flatulence, dry mouth

Description of selected adverse reactions

Acute hypersensitivity reactions, such as angioedema and dyspnea, have been reported during post-marketing (see section 4.3 and 4.4).

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 in table 2, two cases of urticaria were reported.

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.

Hypersensitivity reactions

Hypersensitivity reactions including severe angioedema have been reported (see section 4.8). 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.

Renal and hepatic impairment

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).

Pseudomembranous colitis, fulminant or life threatening CDI

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

Co-administration of potent P-glycoprotein inhibitors

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). In case fidaxomicin is administered concomitantly with potent P-glycoprotein inhibitors, caution is advised.

Paediatric population

Only one paediatric patient below 6 months of age has been exposed to fidaxomicin in clinical trials.
Therefore, patients below 6 months of age should be treated with caution.

Testing for C. difficile colonization or toxin is not recommended in children younger than 1 year due to high rate of asymptomatic colonisation unless severe diarrhoea is present in infants with risk factors for stasis such as Hirschsprung disease, operated anal atresia or other severe motility disorders.
Alternative aetiologies should always be sought and C. difficile enterocolitis be proven.

Hypersensitivity reactions

Hypersensitivity reactions including severe angioedema have been reported (see section 4.8). 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.

Renal and hepatic impairment

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).

Pseudomembranous colitis, fulminant or life threatening CDI

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

Co-administration of potent P-glycoprotein inhibitors

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). In case fidaxomicin is administered concomitantly with potent P-glycoprotein inhibitors, caution is advised.

DIFICLIR contains sodium

DIFICLIR contains less than 1 mmol sodium (23 mg) per 5 ml suspension, that is to say essentially ‘sodium-free’.

Paediatric population

Only one paediatric patient below 6 months of age and no patients with a body weight below 4 kg have been exposed to fidaxomicin in clinical trials. Therefore, fidaxomicin should be used with caution in these patients.

Testing for C. difficile colonization or toxin is not recommended in children younger than 1 year due to high rate of asymptomatic colonisation unless severe diarrhoea is present in infants with risk factors for stasis such as Hirschsprung disease, operated anal atresia or other severe motility disorders.
Alternative aetiologies should always be sought and C. difficile enterocolitis be proven.

Sodium benzoate content
This medicine contains 2.5 mg sodium benzoate (E 211) in each ml oral suspension. Sodium benzoate (E 211) may increase jaundice in newborn babies (up to 4 weeks old).

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 fidaxomicin 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 is not recommended (see sections 4.4 and 5.2).

Effect of fidaxomicin on P-gp substrates

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.

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 a clinically significant effect on the AUCinf of rosuvastatin.

Paediatric population

Interaction studies have only been performed in adults.

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 fidaxomicin 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 is not recommended (see section 4.4 and 5.2).

Effect of fidaxomicin on P-gp substrates

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.

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 a clinically significant effect on the AUCinf of rosuvastatin.

Paediatric population

Interaction studies have only been performed in adults.

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 fidaxomicin 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 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 (see section 5.3).

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

No adverse reactions for acute overdose have been reported during clinical studies or from post-marketing data. However, the potential for adverse reactions cannot be ruled out and general supportive measures are recommended.

5.
PHARMACOLOGICAL PROPERTIES

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.

Pharmacokinetic/Pharmacodynamic (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 adults

The efficacy of fidaxomicin was evaluated in two pivotal, randomised, double-blind Phase 3 studies (Study 003 and 004). Fidaxomicin was compared with orally administered vancomycin. The primary endpoint was clinical cure assessed after 12 days.

Non-inferiority of fidaxomicin compared with vancomycin was demonstrated in both studies (see Table 2)

Table 2 Combined results of studies 003 and 004
Per Protocol (PP)
Fidaxomicin
(200mg bid for 10 days)
Vancomycin
(125mg qid for 10 days)
95% Confidence
Interval*
Clinical Cure
91.9%
(442/481 patients)
90.2%
(467/518 patients)
(-1.8, 5.3) modified Intent-to-
Treat (mITT)
Fidaxomicin
(200mg bid)
Vancomycin
(125mg qid)
95% Confidence
Interval*
Clinical Cure
87.9%
(474/539 patients)

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.

Pharmacokinetic/Pharmacodynamic (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 adults

The efficacy of fidaxomicin was evaluated in two pivotal, randomised, double-blind Phase 3 studies (Study 003 and 004). Fidaxomicin was compared with orally administered vancomycin. The primary endpoint was clinical cure assessed after 12 days.

Non-inferiority of fidaxomicin compared with vancomycin was demonstrated in both studies (see Table 3)

Table 3 Combined results of studies 003 and 004
Per Protocol (PP)
Fidaxomicin
(200mg bid for 10 days)
Vancomycin
(125mg qid for 10 days)
95% Confidence
Interval*
Clinical Cure
91.9%
(442/481 patients)
90.2%
(467/518 patients)
(-1.8, 5.3) modified Intent-to-
Treat (mITT)
Fidaxomicin
(200mg bid)
Vancomycin
(125mg qid)
95% Confidence
Interval*
Clinical Cure
87.9%
(474/539 patients)

Absorption

The bioavailability in humans is unknown. In healthy adults, Cmax is approximately 9.88 ng/ml and AUC0-t is 69.5 ng•hr/ml following administration of 200 mg fidaxomicin, with a Tmax 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.

Cmax for fidaxomicin and OP-1118 in plasma were 22% and 33% lower following a high fat meal vs fasting, but the extent of exposure (AUC0-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. 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.

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

Absorption

The bioavailability in humans is unknown. After administration of fidaxomicin film-coated tablets in healthy adults, Cmax is approximately 9.88 ng/ml and AUC0-t is 69.5 ng•hr/ml following administration of 200 mg fidaxomicin, with a Tmax 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.

Cmax for fidaxomicin and OP-1118 in plasma were 22% and 33% lower following a high fat meal vs fasting, but the extent of exposure (AUC0-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. 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.

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