Swiss Summary of the Risk Management Plan (RMP) for (Bezlotoxumab 1000mg) Concentrate for solution for infusion Version 1.5 (November 2016) The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them. The RMP summary of is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation / Information sur le médicament approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorisation. Please note that the reference document which is valid and relevant for the effective and safe use of in Switzerland is the Arzneimittelinformation / Information sur le médicament (see www.swissmedicinfo.ch) approved and authorized by Swissmedic. MSD Merck Sharp & Dohme AG is fully responsible for the accuracy and correctness of the content of the published summary RMP of.
1 Elements for Summary Tables in the EPAR 1.1 Summary Table of Safety Concerns Table 1 Summary of Safety Concerns Important identified risks Important potential risks Missing information Infusion-related Reactions Including Hypersensitivity and Anaphylactic Reactions Potential for Immunogenicity Potential Lack of Efficacy if Bezlotoxumab is Administered Off-label as Monotherapy Impaired safety in patients with underlying CHF or with history of CHF Exposure in Patients <18 years of age Exposure in Pregnancy/Lactation Long Term Safety Repeated Administration of Bezlotoxumab
1.2 Table of Ongoing and Planned Studies in the Post-authorisation Pharmacovigilance Development Plan Table 2 Ongoing and Planned Additional Pharmacovigilance Studies / Activities in the Pharmacovigilance Plan: Imposed Activities, Specific Obligations and Required Activities (Categories 1-3) Study / Activity Objectives Safety Concerns Addressed Status Date for Submission of Interim / Final Reports (target dates) (MK-6072-PN001*): Trial in Paediatric Patients Aged 24 months to <18 years (Category 3) Randomised, doubleblind, single dose, placebo-controlled trial to evaluate efficacy, safety, and pharmacokinetics of Clostridium difficile toxin B human monoclonal antibody (MK-6072, bezlotoxumab) as add-on to standard of care antibiotic treatment in children from 2 to less than 18 years of age with Clostridium difficile infection (CDI). To provide information on safety and efficacy in patients with CDI who are 24 month to <18 years of age. In addition, anti-drug antibody (ADA) assessments will be conducted to assess the potential for immunogenicity. Planned Anticipated Final Report: MAR-2019 (MK-6072-PN002 ): Trial in Paediatric Patients Aged <24 months. (Category 3) Open label, single dose trial to evaluate safety, tolerability, and pharmacokinetics of Clostridium difficile toxin B human monoclonal antibody (MK-6072, bezlotoxumab) in children from birth to less than 2 years of age with suspected or documented Clostridium difficile Infection (CDI), or at risk for developing CDI. To provide information on safety and efficacy in patients with CDI who are <24 months of age. In addition, anti-drug antibody (ADA) assessments will be conducted to assess the potential for immunogenicity. Planned Anticipated Final Report: NOV-2020 * formerly MK-6072 Protocol 015 formerly MK-6072 Protocol 021
1.3 Summary of Post-authorisation Efficacy Development Plan Not applicable.
1.4 Summary Table of Risk Minimisation Measures Table 3 Summary of Safety Concerns and Risk Minimisation Activities Safety Concern Important Potential Risk: Infusion-related Reactions Including Hypersensitivity and Anaphylactic Reactions SmPC: Routine Risk Minimisation Measures Section 4.8 Undesirable effects Section for Tabulated list of adverse reactions within Table 1: Adverse Reactions with ZINPLAVA includes infusion related reactions occurring on the day of, or the day after infusion. Section for Description of selected adverse reactions under Infusion Related Reactions states that overall, 10% of subjects in the ZINPLAVA group experienced one or more infusion specific adverse reactions on the day of, or the day after, the infusion compared to 8% in the placebo group. Infusion specific adverse reactions reported in 0.5% of subjects receiving ZINPLAVA and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%), and hypertension (1%). Of the patients who experienced an infusion specific adverse reaction, the majority reported a reaction with a maximum intensity of mild (78%) or moderate (20%) and the majority of reactions resolved within 24 hours following onset. Additional Risk Minimisation Measures Package Leaflet: Section 4 Possible side effects Includes side effects reported in clinical trials as Common: diarrhoea, dizziness, feeling sick (nausea), fever, headache, high blood pressure, shortness of breath, tiredness. Tell your doctor or health care professional if you notice any of the side effects above.
Table 3 Summary of Safety Concerns and Risk Minimisation Activities Safety Concern Important Potential Risk: Potential for Immunogenicity SmPC: Routine Risk Minimisation Measures Section 4.2 Posology and method of administration The experience with ZINPLAVA in patients is limited to a single CDI episode and single administration. 4.4 Special Warnings and precautions for use There is no experience with repeat administration of ZINPLAVA in patients with CDI. In clinical trials, patients with CDI were only administered a single dose of ZINPLAVA. Section 4.8 Undesirable effects Section for Description of selected adverse reactions under Immune-related Adverse Reactions states that in a Phase 1 clinical trial, healthy subjects received two consecutive doses of 10 mg/kg of bezlotoxumab separated by 12 weeks. The adverse reactions after the second dose were not markedly different from those observed after the first dose, and are consistent with adverse reactions observed in the two Phase 3 trials (MODIFY I and MODIFY II) in which all patients received a single dose. Section 5.1 Pharmacodynamic properties Section 5.1 under Immunogenicity states that immunogenicity of ZINPLAVA was evaluated using an electrochemiluminescence (ECL) assay in MODIFY I and MODIFY II. Following treatment with ZINPLAVA in MODIFY I and MODIFY II, none of the 710 evaluable patients tested positive for treatmentemergent anti-bezlotoxumab antibodies. Although ZINPLAVA is intended for single dose administration, the immunogenicity of bezlotoxumab following a second administration of 10 mg/kg, 12 weeks after the first dose, was assessed in 29 healthy subjects. No antibezlotoxumab antibodies were detected after the second dose. There are no data on repeated administration of bezlotoxumab in patients with CDI. Additional Risk Minimisation Measures Package Leaflet: Not applicable Important Potential Risk: Potential Lack of Efficacy if Bezlotoxumab is Administered Offlabel as Monotherapy SmPC: Section 4. Clinical Particulars Section 4.1 under Therapeutic indications states that ZINPLAVA is indicated for the prevention of recurrence of Clostridium difficile infection (CDI) in adults at high risk for recurrence of CDI. Section 4.2 under Posology and method of administration states that ZINPLAVA should be administered during the course of antibacterial therapy for CDI. Section 4.4 under Special warnings and precautions for use states that ZINPLAVA is not
Table 3 Summary of Safety Concerns and Risk Minimisation Activities Safety Concern Routine Risk Minimisation Measures a treatment for CDI and has no effect on the current CDI episode. ZINPLAVA should be administered during the course of antibacterial therapy for CDI. There are no data regarding the efficacy of ZINPLAVA if given after the initial 10 to 14 days of antibacterial therapy for CDI. Additional Risk Minimisation Measures Package Leaflet: Section 1 What ZINPLAVA is and what is it used for? ZINPLAVA is a medicine that is given together with an antibiotic to prevent Clostridium difficile infection (CDI) from coming back in patients 18 years of age or older who have a high risk of CDI coming back. How ZINPLAVA works When people get CDI, they are usually given an antibiotic to get rid of the infection but CDI can often come back within weeks or months. The bacteria responsible for CDI produce a toxin that can inflame and damage your colon, causing stomach pain and severe diarrhoea. ZINPLAVA acts by attaching to the toxin and blocking it, thereby preventing the symptoms of CDI from coming back. Section 2 What you need to know before you are given ZINPLAVA under Warnings and precautions ZINPLAVA is not a treatment for CDI. ZINPLAVA has no effect on the CDI you have now. ZINPLAVA is given with the antibiotic therapy you are taking for CDI. Important Potential Risk: Impaired safety in patients with underlying CHF or with history of CHF Text in Local Swiss Labeling Warnings and Precautions Heart Failure Heart failure was reported more commonly in the two Phase 3 clinical trials in treated patients compared to placebo-treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of -treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period (see Adverse Reactions). Additionally, in patients with a history of CHF, there were more deaths in -treated patients, 19.5% (23/118) than in placebo-treated patients, 12.5% (13/104) during the 12-week study period. The causes of death varied and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, should
Table 3 Summary of Safety Concerns and Risk Minimisation Activities Safety Concern Routine Risk Minimisation Measures be reserved for use when the benefit outweighs the risk. Additional Risk Minimisation Measures Other Routine Risk Minimisation Measure(s) Use of a CHF Specific Targeted Follow-Up Questionnaire Missing Information: Exposure in Patients <18 years of age SmPC: Section 4.2 Posology and method of administration Section for Posology under Special Populations states that safety and efficacy of bezlotoxumab in patients below 18 years of age have not been established. No data are available. Package Leaflet: Section 2 What you need to know before you are given ZINPLAVA? Children and adolescents ZINPLAVA should not be used in children and adolescents below 18 years of age.
Table 3 Summary of Safety Concerns and Risk Minimisation Activities Safety Concern Missing Information: Exposure During Pregnancy/Lactation SmPC: Routine Risk Minimisation Measures Section 4.6 Fertility, pregnancy and lactation Section under Pregnancy states that there are limited data from the use of bezlotoxumab in pregnant women. Animal studies do not indicate reproductive toxicity. ZINPLAVA should not be used during pregnancy unless the clinical condition of the woman requires treatment with bezlotoxumab. Section under Breast Feeding states that it is unknown whether bezlotoxumab is secreted in human milk. Because monoclonal antibodies may be excreted in human milk, a decision should be made whether to discontinue breastfeeding or to not administer ZINPLAVA, taking into account the importance of ZINPLAVA to the mother. Additional Risk Minimisation Measures Missing Information: Long Term Safety Package Leaflet: Section 2 What you need to know before you are given ZINPLAVA? Pregnancy and breast-feeding If you are pregnant or trying to get pregnant, tell your doctor. We don t know if ZINPLAVA will harm your baby while you are pregnant. If you are breastfeeding or are planning to breastfeed, check with your doctor first. We don t know if ZINPLAVA gets in your breast milk and is passed to your baby. You and your doctor should decide together if you will use ZINPLAVA. SmPC: Not applicable Patient leaflet: Not applicable
Table 3 Summary of Safety Concerns and Risk Minimisation Activities Safety Concern Missing Information: Repeated Administration of Bezlotoxumab SmPC: Routine Risk Minimisation Measures Section 4.2 Posology and method of administration The experience with ZINPLAVA in patients is limited to a single CDI episode and single administration. 4.4 Special Warnings and precautions for use There is no experience with repeat administration of ZINPLAVA in patients with CDI. In clinical trials, patients with CDI were only administered a single dose of ZINPLAVA. Section 4.8 Undesirable effects Section c Description of selected adverse reactions under Immune-related Adverse Reactions states that in a Phase 1 clinical trial, healthy subjects received two consecutive doses of 10 mg/kg of bezlotoxumab separated by 12 weeks. The adverse reactions after the second dose were not markedly different from those observed after the first dose, and are consistent with adverse reactions observed in the two Phase 3 trials (MODIFY I and MODIFY II) in which all patients received a single dose. Section 5.1 Pharmacodynamic properties Section 5.1 under Immunogenicity states that immunogenicity of ZINPLAVA was evaluated using an electrochemiluminescence (ECL) assay in MODIFY I and MODIFY II. Following treatment with ZINPLAVA in MODIFY I and MODIFY II, none of the 710 evaluable patients tested positive for treatmentemergent anti-bezlotoxumab antibodies. Although ZINPLAVA is intended for single dose administration, the immunogenicity of bezlotoxumab following a second administration of 10 mg/kg, 12 weeks after the first dose, was assessed in 29 healthy subjects. No antibezlotoxumab antibodies were detected after the second dose. There are no data on repeated administration of bezlotoxumab in patients with CDI. Additional Risk Minimisation Measures Patient leaflet: Not applicable
2 Elements for a Public Summary 2.1 Overview of Disease Epidemiology Clostridium difficile infection (CDI), also known as C. difficile associated diarrhea (CDAD), is a type of infection caused by bacteria that affects the colon. C. difficile produces two exotoxins, toxin A and toxin B, that target the gut causing changes and disruption of the normal intestinal barrier that is essential for the gut to function normally. Antibiotic use disrupts the normal flora of the gut, leading to excessive growth of C. difficile and CDI. CDI can cause complications, including death (mortality). The death rate due to CDI ranges between 5 to 10 per 100 patients, and increases with age. After treatment, CDI frequently recurs. One of the greatest challenges in managing CDI is to prevent its recurrence. For every 100 patients with CDI who are initially successfully treated, 15-35% will develop a recurrent infection. Among the clinical risk factors for recurrence of CDI are advanced age, having had a CDI in the past, and severity of the patient s underlying comorbidities. 2.2 Summary of Treatment Benefits Bezlotoxumab is a fully human monoclonal antibody that binds and neutralizes C. difficile toxin B. In the two main studies, the medicine has been shown to be effective in the prevention of CDI recurrence relative to placebo in patients receiving concomitant standard of care (SoC) antibiotic therapy for the treatment of CDI. The two main studies included a total of 1563 adult patients with CDI who were receiving concomitant SoC antibiotics to treat CDI. The 1563 patients were then randomly assigned to receive either a single infusion of bezlotoxumab or an infusion without bezlotoxumab (placebo). All patients were observed for 12 weeks. At the end of the 12 week period 16.5% of patients treated with bezlotoxumab compared to 26.6% of patients treated with placebo experienced a recurrence of CDI. Bezlotoxumab significantly prevented CDI from recurring. 2.3 Unknowns Relating to Treatment Benefits Bezlotoxumab is indicated for the prevention of recurrence of Clostridium difficile infection in adults at high risk for recurrence of CDI. Bezlotoxumab has been studied in male and female patients 18 to 100 years of age and in patients with renal and hepatic impairment. Bezlotoxumab has not been studied in patients less than 18 years of age or in pregnant or breastfeeding women.
2.4 Summary of Safety Concerns Important Identified Risks Table 4 Summary of Important Identified Risks Risk What is Known Preventability Important Potential Risks Table 5 Summary of Important Potential Risks Risks Allergic reactions related to the infusion of medicine into the body (infusion-related hypersensitivity reactions hypersensitivity and anaphylactic reactions) What is Known The infusion related allergic reactions reported on the day of, or the day after, the infusion of medicine included: feeling sick (nausea); being sick (vomiting); fever (pyrexia); chills; tiredness (fatigue); dizziness; headache; difficulty in breathing (dyspnea); itching (pruritus); high blood pressure (hypertension); and low blood pressure (hypotension). The majority of these infusion-related allergic reactions reported in clinical studies were mild to moderate in intensity; the majority of reactions resolved within 24 hours following onset. Infusionrelated allergic reactions are frequently reported with other similar kinds of medicines called monoclonal antibodies. Possibility of provoking immune defensive response of the body against the medicine (potential for immunogenicity) Administration of any substance made from living organisms (biologics) has the ability to initiate formation of a protein (antibodies) against the medicine (antidrug antibodies). In clinical studies, no subjects tested positive for antibodies against the medicine. Possibility of not improving because of persistence of acute CDI if bezlotoxumab is administered off-label as a single therapy and without antibiotic therapy for CDI Bezlotoxumab is indicated for the prevention of recurrence of CDI in adults who are at high risk for CDI recurrence. Bezlotoxumab is not an antibiotic and has no effect on the current CDI episode. Antibiotic therapy is required for treatment of the acute CDI. In the two main clinical studies, all patients administrated bezlotoxumab or placebo received concomitant oral SoC antibiotic therapy. Not using antibiotic therapy during the course of an acute episode is likely to result in persistence of acute CDI. Impaired safety in patients with underlying CHF or with history of CHF Heart failure was reported more commonly in the two Phase 3 clinical trials in -treated patients compared to placebo-treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of -treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period (see Adverse Reactions). Additionally, in patients with a history of CHF, there were more deaths in -treated patients, 19.5% (23/118) than in placebo-treated patients, 12.5% (13/104) during the 12-week study period. The causes of death varied and included cardiac failure, infections, and respiratory failure.
Missing Information Table 6 Summary of Missing Information Missing Information Use in patients less than 18 years of age (exposure in patients <18 years of age) What is Known Safety and effectiveness of bezlotoxumab in patients less than 18 years of age have not been studied and proven. Use in pregnant/breastfeeding women (exposure in pregnancy/lactation) Sufficient studies with bezlotoxumab have not been done in pregnant or lactating women. As it is not known whether bezlotoxumab can cause harm to unborn babies or affect reproductive capacity in pregnant women, this medicine should be used during pregnancy only if clearly needed. It is not known whether bezlotoxumab gets into your breast milk and will pass to your baby. Because monoclonal antibodies may be excreted in human milk, a decision should be made whether to stop breastfeeding or to not give medicine, taking into account the importance of medicine to the mother. Long term safety >4 weeks after bezlotoxumab has been given During clinical trials adverse events were collected for 4 weeks and serious adverse events were collected for 12 weeks. Information on non-serious adverse events for bezlotoxumab 4 weeks after administration and serious adverse events 12 weeks after administration is not known. Use of bezlotoxumab for more than one episode of CDI Repeat doses of bezlotoxumab in patients with CDI have not been studied.
2.5 Summary of Risk Minimisation Measures by Safety Concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimizing them. The measures in these documents are known as routine risk minimisation measures. The current Information for Professionals for can be found on www.swissmedicinfo.ch. This medicine has no additional risk minimisation measures.
2.6 Planned Post-authorisation Development Plan 2.6.1 List of Studies in Post-authorisation Development Plan Table 7 List of Studies in Post-authorisation Development Plan Study/Activity (Including Study Number) Objectives Safety Concerns/Efficacy Issue Addressed Status Planned Date for Submission of (Interim and) Final Results (MK-6072-PN001*): Trial in Paediatric Patients Aged 24 months to <18 years Randomised, double-blind, single dose, placebocontrolled trial to evaluate efficacy, safety, and pharmacokinetics of Clostridium difficile toxin B human monoclonal antibody (MK-6072, bezlotoxumab) as add-on to standard of care antibiotic treatment in children from 2 to less than 18 years of age with Clostridium difficile infection (CDI). To provide information on safety and efficacy in patients with CDI who are 24 month to <18 years of age. In addition, anti-drug antibody (ADA) assessments will be conducted to assess the potential for immunogenicity. Planned Anticipated final report: MAR 2019 (MK-6072-PN002 ): Trial in Paediatric Patients Aged <24 months. Open label, single dose trial to evaluate safety, tolerability, and pharmacokinetics of Clostridium difficile toxin B human monoclonal antibody (MK-6072, bezlotoxumab) in children from birth to less than 2 years of age with suspected or documented Clostridium difficile Infection (CDI), or at risk for developing CDI. To provide information on safety and efficacy in patients with CDI who are <24 months of age. In addition, anti-drug antibody (ADA) assessments will be conducted to assess the potential for immunogenicity. Planned Anticipated Final Report: NOV 2020 * formerly MK-6072 Protocol 015 formerly MK-6072 Protocol 021 2.6.2 Studies which are a Condition of the Marketing Authorisation The above studies are conditions of the marketing authorisation.
2.7 Summary of Changes to the Risk Management Plan Over Time This is version 1.5 and the first RMP for bezlotoxumab. Table 8 Major Changes to the Risk Management Plan RMP Version Date Safety Concerns Comment 1.5 22-NOV-2016 (at the time of authorisation) Important identified risks Important potential risks Infusion-related Reactions Including Hypersensitivity and Anaphylactic Reactions Potential for Immunogenicity Potential Lack of Efficacy if Bezlotoxumab is Administered Off-label as Monotherapy Impaired safety in patients with underlying CHF or with history of CHF Missing information Exposure in patients <18 years of age Exposure in pregnancy/lactation Long Term Safety Repeated Administration of Bezlotoxumab Initial Version