Bezlotoxumab (Zinplava®) : RMP summary · underlying CHF or with history of CHF Text in Local Swiss Labeling Warnings and Precautions Heart Failure Heart failure was reported more

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®.

http://www.swissmedicinfo.ch/

Zinplava


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


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


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


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.


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


1.3 Summary of Post-authorisation Efficacy Development Plan

Not applicable.

Zinplava


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





Measures



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 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


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





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.


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





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:


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:


are given ZINPLAVA?

Children and adolescents

ZINPLAVA should not be used in children and

adolescents below 18 years of age.

None

Zinplava





Measures


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:


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


Long Term Safety

SmPC:

Not applicable

Patient leaflet:

Not applicable

None

Zinplava





Measures


Repeated Administration of

Bezlotoxumab

SmPC:


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 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


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


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


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


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.

http://www.swissmedicinfo.ch/

Zinplava


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.


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.


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


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 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

Documents

Bezlotoxumab (Zinplava®) : RMP summary · underlying CHF or with history of CHF Text in Local Swiss Labeling Warnings and Precautions Heart Failure Heart failure was reported more