DIFICLIR 200 mg film-coated tablets
- Name:
DIFICLIR 200 mg film-coated tablets
- Company:
Astellas Pharma Co. Ltd
- Active Ingredients:
- Legal Category:
Product subject to medical prescription which may not be renewed (A)
Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 18/02/20

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Astellas Pharma Co. Ltd

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Updated on 18 February 2020 SPC
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 5.3 - Preclinical safety data
- Change to paediatric information
Legal category: Product subject to medical prescription which may not be renewed (A)
Updated on 18 February 2020 PIL
Reasons for updating
- Change to section 1 - what the product is used for
- Change to section 2 - what you need to know - warnings and precautions
- Change to section 2 - use in children and adolescents
- Change to section 2 - excipient warnings
- Change to section 3 - how to take/use
- Change to section 4 - possible side effects
- Change to section 6 - what the product looks like and pack contents
- Changes to therapeutic indications
Updated on 19 June 2019 SPC
Reasons for updating
- File format updated to PDF
Legal category: Product subject to medical prescription which may not be renewed (A)
Updated on 10 June 2019 PIL
Reasons for updating
- New individual PIL (was previously included in a combined PIL)
Updated on 29 May 2018 SPC
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 5.2 - Pharmacokinetic properties
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
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.
Updated on 29 May 2018 PIL
Reasons for updating
- Change to section 2 - what you need to know - warnings and precautions
Updated on 16 September 2016 PIL
Reasons for updating
- New PIL for new product
Updated on 16 September 2016 PIL
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to drug interactions
- Change to date of revision
- Deletion of a pack size
- Removal of black triangle
Updated on 15 September 2016 SPC
Reasons for updating
- New SPC for new product
Legal category: Product subject to medical prescription which may not be renewed (A)
Updated on 15 September 2016 SPC
Reasons for updating
- Removal of black triangle
- Change to section 3 - Pharmaceutical form
- Change to section 4.8 - Undesirable effects
- Change to section 5 - Pharmacological properties
- Change to section 6.5 - Nature and contents of container
- Change to section 9 - Date of renewal of authorisation
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
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.
Updated on 8 July 2014 PIL
Reasons for updating
- Change to further information section
- Change to date of revision
- Addition of information on reporting a side effect.
Updated on 8 July 2014 SPC
Reasons for updating
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
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 AUCinf of rosuvastatin. The Cmax 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
Updated on 19 March 2014 SPC
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
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
Updated on 19 March 2014 PIL
Reasons for updating
- Change to warnings or special precautions for use
- Change to date of revision
- Addition of information on reporting a side effect.
Updated on 28 August 2013 SPC
Reasons for updating
- Addition of black triangle
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.8 - Undesirable effects
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
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 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.
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
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 |
|
Hepatobiliary disorders |
|
alanine aminotransferase increased |
|
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, 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. 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.
Updated on 22 August 2013 PIL
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to further information section
- Change to date of revision
- Addition of black triangle
Updated on 15 March 2013 SPC
Reasons for updating
- New SPC for new product
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 11 March 2013 PIL
Reasons for updating
- New PIL for new product