Post on 24-Feb-2020
Zinplava
Swiss Risk Management Plan Summary V1.5
Swiss Summary of the Risk Management Plan (RMP)
for
Zinplava®
(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 Zinplava® 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
Zinplava® 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 Zinplava®.
Zinplava
Swiss Risk Management Plan Summary V1.5
1 Elements for Summary Tables in the EPAR
1.1 Summary Table of Safety Concerns
Table 1 Summary of Safety Concerns
Important identified risks None
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
Zinplava
Swiss Risk Management Plan Summary V1.5
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, double-
blind, 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
Zinplava
Swiss Risk Management Plan Summary V1.5
1.3 Summary of Post-authorisation Efficacy Development Plan
Not applicable.
Zinplava
Swiss Risk Management Plan Summary V1.5
1.4 Summary Table of Risk Minimisation Measures
Table 3 Summary of Safety Concerns and Risk Minimisation Activities
Safety Concern Routine Risk Minimisation Measures
Additional Risk Minimisation
Measures
Important Potential Risk:
Infusion-related Reactions Including
Hypersensitivity and Anaphylactic
Reactions
SmPC:
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.
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.
None
Zinplava
Swiss Risk Management Plan Summary V1.5
Table 3 Summary of Safety Concerns and Risk Minimisation Activities
Safety Concern Routine Risk Minimisation Measures
Additional Risk Minimisation
Measures
Important Potential Risk:
Potential for Immunogenicity
SmPC:
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 treatment-
emergent 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 anti-
bezlotoxumab antibodies were detected after the
second dose.
There are no data on repeated administration of
bezlotoxumab in patients with CDI.
Package Leaflet:
Not applicable
None
Important Potential Risk:
Potential Lack of Efficacy if
Bezlotoxumab is Administered Off-
label 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
None
Zinplava
Swiss Risk Management Plan Summary V1.5
Table 3 Summary of Safety Concerns and Risk Minimisation Activities
Safety Concern Routine Risk Minimisation Measures
Additional 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.
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 Zinplava-
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 Zinplava-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 Zinplava-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, Zinplava should
None
Zinplava
Swiss Risk Management Plan Summary V1.5
Table 3 Summary of Safety Concerns and Risk Minimisation Activities
Safety Concern Routine Risk Minimisation Measures
Additional Risk Minimisation
Measures
be reserved for use when the benefit outweighs
the risk.
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.
None
Zinplava
Swiss Risk Management Plan Summary V1.5
Table 3 Summary of Safety Concerns and Risk Minimisation Activities
Safety Concern Routine Risk Minimisation Measures
Additional Risk Minimisation
Measures
Missing Information:
Exposure During Pregnancy/Lactation
SmPC:
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.
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.
None
Missing Information:
Long Term Safety
SmPC:
Not applicable
Patient leaflet:
Not applicable
None
Zinplava
Swiss Risk Management Plan Summary V1.5
Table 3 Summary of Safety Concerns and Risk Minimisation Activities
Safety Concern Routine Risk Minimisation Measures
Additional Risk Minimisation
Measures
Missing Information:
Repeated Administration of
Bezlotoxumab
SmPC:
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 treatment-
emergent 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 anti-
bezlotoxumab antibodies were detected after the
second dose.
There are no data on repeated administration of
bezlotoxumab in patients with CDI.
Patient leaflet:
Not applicable
None
Zinplava
Swiss Risk Management Plan Summary V1.5
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.
Zinplava
Swiss Risk Management Plan Summary V1.5
2.4 Summary of Safety Concerns
Important Identified Risks
Table 4 Summary of Important Identified Risks
Risk What is Known Preventability
None
Important Potential Risks
Table 5 Summary of Important Potential Risks
Risks What is Known
Allergic reactions related to the
infusion of medicine into the body
(infusion-related hypersensitivity
reactions hypersensitivity and
anaphylactic reactions)
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. Infusion-
related 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 (anti-
drug 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
Zinplava-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 Zinplava-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 Zinplava-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.
Zinplava
Swiss Risk Management Plan Summary V1.5
Missing Information
Table 6 Summary of Missing Information
Missing Information What is Known
Use in patients less than 18 years of age
(exposure in patients <18 years of age)
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.
Zinplava
Swiss Risk Management Plan Summary V1.5
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 Zinplava can be found on
www.swissmedicinfo.ch.
This medicine has no additional risk minimisation measures.
Zinplava
Swiss Risk Management Plan Summary V1.5
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, 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.
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.
Zinplava
Swiss Risk Management Plan Summary V1.5
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
None
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