Zinplava

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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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

ZINPLAVA 25 mg/mL concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of concentrate contains 25 mg bezlotoxumab.
One 40 mL vial contains 1,000 mg of bezlotoxumab.

Bezlotoxumab is a human monoclonal antibody produced in Chinese hamster ovary cells by 
recombinant DNA technology. It binds to C. difficile toxin B.

Excipient with known effect

Each mL of concentrate contains 0.2 mmol sodium, which is 4.57 mg sodium.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.
Clear to moderately opalescent, colourless to pale yellow liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

ZINPLAVA is indicated for the prevention of recurrence of Clostridium difficile infection (CDI) in 
adults at high risk for recurrence of CDI (see sections 4.2, 4.4 and 5.1). 

4.2 Posology and method of administration

Posology

ZINPLAVA should be administered during the course of antibacterial therapy for CDI (see sections 
4.4 and 5.1).

ZINPLAVA should be administered as a single intravenous infusion of 10 mg/kg (see below and 
section 6.6).

The experience with ZINPLAVA in patients is limited to a single CDI episode and single 
administration (see section 4.4).

Special populations

Elderly
No dose adjustment is necessary in patients ≥ 65 years of age (see section 5.2).

Renal impairment
No dose adjustment is necessary for patients with renal impairment (see section 5.2).

 



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Hepatic impairment
No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

Paediatric population
The safety and efficacy of ZINPLAVA in patients below 18 years of age have not been established. 
No data are available.

Method of administration

 Administer the diluted solution for infusion intravenously over 60 minutes using a sterile, 
non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. ZINPLAVA 
should not be administered as an intravenous push or bolus.

 The diluted solution can be infused via a central line or peripheral catheter. 
 ZINPLAVA must not be co-administered with other medicinal products simultaneously through 

the same infusion line.

For instructions on dilution of the medicinal product before administration, see section 6.6.

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

ZINPLAVA is not 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 is no data regarding 
the efficacy of ZINPLAVA if given after the initial 10- to 14-days of antibacterial therapy for CDI.

ZINPLAVA should not be administered as an intravenous push or bolus.

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 (see section 5.1).

4.5 Interaction with other medicinal products and other forms of interaction

No formal interactions studies with other medicinal products were conducted. Therapeutic monoclonal 
antibodies do not typically have significant drug-drug interaction potential, as they do not directly 
affect cytochrome P450 enzymes and are not substrates of hepatic or renal transporters.

Bezlotoxumab-mediated drug-drug interactions are unlikely as the target of bezlotoxumab is an 
exogenous toxin.

Concomitant oral standard of care (SoC) antibacterial therapy for CDI was given together with 
ZINPLAVA.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of bezlotoxumab in pregnant women. Animal studies do not 
indicate reproductive toxicity (see section 5.3). ZINPLAVA should not be used during pregnancy 
unless the clinical condition of the woman requires treatment with bezlotoxumab.

 



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Breast-feeding

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 breast-feeding or to not 
administer ZINPLAVA, taking into account the importance of ZINPLAVA to the mother.

Fertility

No clinical data are available on the possible effects of bezlotoxumab on fertility. Fertility studies have 
not been conducted in animals. There was no binding of bezlotoxumab to reproductive tissue in tissue 
cross reactivity studies, and no notable effects in the male and female reproductive organs in repeat 
dose toxicity studies in mice (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety profile of ZINPLAVA was assessed in two Phase 3 clinical studies. The most common 
adverse reactions following treatment with ZINPLAVA (reported in ≥ 4 % of patients within the first 
4 weeks of infusion) were nausea, diarrhoea, pyrexia and headache. These adverse reactions were 
reported at a similar frequency in placebo treated patients compared with ZINPLAVA treated patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions reported within 4 weeks of infusion in ZINPLAVA-treated 
patients and listed 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 
frequency.

Table 1: Adverse Reactions with ZINPLAVA 

MedDRA System Organ Class Frequency Adverse Reaction(s)

Nervous system disorders Common Headache

Gastrointestinal disorders Common Nausea, diarrhoea

General disorders and administration 
site conditions

Common Pyrexia

Injury, poisoning and procedural 
complications

Common Infusion related reactions†

† See Description of selected adverse reactions below.

Description of selected adverse reactions

Serious adverse reactions
In clinical studies, serious adverse reactions occurring within 12 weeks following infusion were 
reported in 29 % of ZINPLAVA-treated patients and 33 % in patients receiving placebo.

Infusion related reactions
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

 



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greater than placebo were nausea (3 %), fatigue (1 %), pyrexia (1 %), dizziness (1 %), headache (2 %), 
dyspnoea (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.

Immune-related adverse reactions
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; see section 5.1) in which all patients received a 
single dose.

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.

4.9 Overdose

There is no clinical experience with overdosage of ZINPLAVA. In clinical trials, healthy subjects 
received up to 20 mg/kg, which was generally well tolerated. In case of overdose, patients should be 
closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment 
should be instituted.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiinfectives for systemic use, specific immunoglobulins. ATC code: 
J06BB21

Mechanism of action

Bezlotoxumab is a human monoclonal antitoxin antibody that binds with high affinity to C. difficile
toxin B and neutralizes its activity. Bezlotoxumab prevents CDI recurrence by providing passive 
immunity against toxin produced by the outgrowth of persistent or newly-acquired C. difficile spores.

Pharmacodynamic effects

Microbiology

Activity in vitro and in vivo
The toxin B epitope to which bezlotoxumab binds is conserved, though not identical, across all known 
toxin sequences.

Clinical trials

The efficacy of ZINPLAVA (bezlotoxumab) was investigated in two randomised, double-blind, 
placebo-controlled, multicentre, Phase 3 studies (MODIFY I and MODIFY II) where 810 patients 
were randomised to bezlotoxumab and 803 to placebo. The number of patients completing the studies 
and included in the full analysis set (FAS) was 781 in the ZINPLAVA group versus 773 in the placebo 
group. All patients received concomitant standard of care antibacterial therapy for CDI. 
Randomisation was stratified by the antibacterial agent and hospitalisation status (inpatient vs. 
outpatient) at the time of study entry. Adult patients had a confirmed diagnosis of CDI, which was 

 

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defined as diarrhoea (passage of 3 or more loose bowel movements as defined in the Bristol stool chart 
as types 5 through 7 in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a 
stool sample collected no more than 7 days before study entry.

Patients received a 10- to 14-day course of oral antibacterial therapy for CDI (metronidazole, 
vancomycin or fidaxomicin, chosen by the investigator). Patients on oral vancomycin or oral 
fidaxomicin could have also received IV metronidazole. 

A single infusion of ZINPLAVA or placebo was administered prior to completion of antibacterial 
therapy and patients were followed for 12 weeks following the infusion. The day of the infusion of 
ZINPLAVA or placebo ranged from prior to the start of antibacterial therapy up to day 14 of
treatment, with a median on day 3.

The baseline characteristics of the 781 patients receiving ZINPLAVA and 773 receiving placebo were 
generally similar across treatment groups. The median age was 65 years, 85 % were white, 57 % were 
female, and 68 % were inpatients. A similar proportion of patients were receiving oral metronidazole 
(48 %) or oral vancomycin (48 %) and only 4 % were receiving fidaxomicin as antibacterial treatment 
for CDI.

The CDI recurrence rates are shown in Table 2.

Table 2: CDI Recurrence Rate Through 12 Weeks After Infusion
(MODIFY I and MODIFY II, Full Analysis Set*)

ZINPLAVA with 
SoC†

Percent (n/N)

Placebo with SoC†

Percent (n/N)
Adjusted Difference (95% CI)‡ p-value

16.5 (129/781) 26.6 (206/773) -10.0 (-14.0, -6.0) <0.0001

n = Number of patients in the analysis population meeting the criteria for endpoint
N = Number of patients included in the analysis population
* Full Analysis Set = a subset of all randomised patients with exclusions for: (i) did not receive infusion of study 

medication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined 
standard of care therapy within a 1 day window of the infusion; (iiii) GCP non-compliance

† SoC = Standard of Care antibacterial (metronidazole or vancomycin or fidaxomicin) 
‡ One sided p-value based on the Miettinen and Nurminen method stratified by protocol (MODIFY I and MODIFY II), 

SoC antibacterial (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)

Table 3 shows the results of a prospectively planned combined analysis of the CDI recurrence rates in 
pre-specified subgroups of patients at high risk for CDI recurrence across the two Phase 3 Trials. 
Overall, 51 % were ≥ 65 years, 29% were ≥ 75 years and 39 % received one or more systemic 
antibacterial agents during the 12 week follow-up period. Of the total 28 % had one or more episodes 
of CDI within the six months prior to the episode under treatment (18 % of the patients had one, 7 % 
had two and a few patients had 3 or more prior episodes). Twenty one (21) percent of the patients were 
immunocompromised and 16 % presented with clinically severe CDI. Among the 976/1554 (62 %) 
patients who had a positive baseline stool culture for C. difficile a hypervirulent strain (ribotypes 027, 
078 or 244) was isolated in 22 % (217 of 976 patients), of which the majority (87 %, 189 of 
217 strains) were ribotype 027.

These patients presented with risk factors primarily but not exclusively associated with higher risk of 
CDI recurrence. Efficacy results did not point towards a benefit of ZINPLAVA in patients with no 
known risk factors for CDI.

 



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Table 3: CDI Recurrence Rate by Risk Factor Subgroup
(MODIFY I and MODIFY II, Full Analysis Set*)

Characteristic at study entry

ZINPLAVA
with SoC†

Percent (n/m)

Placebo with 
SoC†

Percent (n/m) Difference (95% CI)‡

Age ≥ 65 years 15.4 (60/390) 31.4 (127/405) -16.0 (-21.7, -10.2)

History of one or more episodes of 
CDI in past 6 months 

25.0 (54/216) 41.1 (90/219) -16.1 (-24.7, -7.3)

Immunocompromised§ 14.6 (26/178) 27.5 (42/153) -12.8 (-21.7, -4.1)

Severe CDI¶ 10.7 (13/122) 22.4 (28/125) -11.7 (-21.1, -2.5)

Infected with a hypervirulent 
strain#

21.6 (22/102) 32.2 (37/115) -10.6 (-22.1, 1.3)

Infected with 027 ribotype 23.6 (21/89) 34.0 (34/100) -10.4 (-23.0, 2.6)
n = Number of patients within subgroup that met the criteria for endpoint
m = Number of patients within subgroup
* Full Analysis Set = a subset of all randomised patients with exclusions for: (i) did not receive infusion of study 

medication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined 
standard of care therapy within a 1 day window of the infusion

† SoC = Standard of Care antibacterial (metronidazole or vancomycin or fidaxomicin)
‡ Based on the Miettinen and Nurminen method without stratification
§ Based on medical conditions or medications received that may result in immunosuppression
¶ Zar score ≥ 2
# Hypervirulent strain included the following: 027, 078, or 244 ribotypes

In the studies, the clinical cure rates of the presenting CDI episode were comparable between the 
treatment arms.

Immunogenicity

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.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with
ZINPLAVA in one or more subsets of the paediatric populations for the prevention of recurrence of
Clostridium difficile infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Bezlotoxumab is dosed via the IV route and therefore is immediately and completely bioavailable. 
After a single IV dose of 10 mg/kg bezlotoxumab, mean AUC(0-∞) and Cmax were 53,000 mcg.h/mL
and 185 mcg/mL, respectively, in patients with CDI. Bezlotoxumab exposures in healthy subjects 
increased in an approximately dose proportional manner across the 0.3 to 20 mg/kg dose range.

 



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Distribution

Bezlotoxumab has limited extravascular distribution. The mean volume of distribution of 
bezlotoxumab was 7.33 L (CV: 16 %).

Biotransformation

Bezlotoxumab is catabolized through protein degradation processes; metabolism does not contribute to 
its clearance.

Elimination

Bezlotoxumab is eliminated from the body primarily by protein degradation. The mean clearance of 
bezlotoxumab was 0.317 L/day (CV: 41 %) and the terminal half-life (t½) was approximately 19 days 
(28 %).

Special populations

The effects of various covariates on the pharmacokinetics of bezlotoxumab were assessed in a 
population pharmacokinetic analysis. The clearance of bezlotoxumab increased with increasing body 
weight; the resulting exposure differences are adequately addressed by the administration of a 
weight-based dose.

The following factors had no clinically meaningful effect on the exposure of bezlotoxumab and no 
dose adjustment is required: age (range 18 to 100 years), gender, race, ethnicity, renal impairment, 
hepatic impairment, and presence of co-morbid conditions.

Renal impairment

The effect of renal impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients 
with mild (eGFR 60 to < 90 mL/min/1.73 m2), moderate (eGFR 30 to < 60 mL/min/1.73 m2), or severe 
(eGFR 15 to < 30 mL/min/1.73 m2) renal impairment, or with end stage renal disease 
(eGFR < 15 mL/min/1.73 m2), as compared to patients demonstrating normal (eGFR 
≥ 90 mL/min/1.73 m2) renal function. No clinically meaningful differences in the exposure of 
bezlotoxumab were found between patients with renal impairment and patients with normal renal 
function.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients 
with hepatic impairment (defined as having two or more of the following: [1] albumin ≤ 3.1 g/dL; 
[2] ALT ≥ 2X ULN; [3] total bilirubin ≥ 1.3X ULN; or [4] mild, moderate or severe liver disease as 
reported by the Charlson Co-morbidity Index), as compared to patients with normal hepatic function. 
No clinically meaningful differences in the exposure of bezlotoxumab were found between patients 
with hepatic impairment and patients with normal hepatic function.

Elderly

The effect of age on the pharmacokinetics of bezlotoxumab was evaluated in patients ranging from 18 
to 100 years of age. No clinically meaningful differences in the exposure of bezlotoxumab were found 
between elderly patients 65 years and older and patients under 65 years of age.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose 
toxicity. Genotoxicity and carcinogenic potential have not been evaluated.

 



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Animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab. 
There were no notable effects in the male and female reproductive organs in mice based on repeat 
dose toxicity studies and no binding to reproductive tissues was observed in tissue cross-reactivity 
studies.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid monohydrate (E330)
Diethylenetriaminepentaacetic acid
Polysorbate 80 (E433)
Sodium chloride
Sodium citrate dihydrate (E331)
Water for injections
Sodium hydroxide (E524) (for pH adjustment).

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial: 3 years.

Solution for infusion: Chemical and physical in-use stability has been demonstrated for 24 hours at 
2°C – 8°C or 16 hours at room temperature (at or below 25°C). These time limits include storage of 
the infusion solution in the IV bag through the duration of infusion. From a microbiological point of 
view, the product must be used immediately. If not used immediately, in-use storage times and 
conditions prior to use are the responsibility of the user and must not be longer than a total of 24 hours 
at 2°C – 8°C or 16 hours at room temperature (at or below 25°C).

6.4 Special precautions for storage

Store in a refrigerator 2 °C to 8 °C. Do not freeze. Keep vial in the outer carton in order to protect 
from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vial containing 40 mL solution, with a chlorobutyl stopper, and a flip-off cap seal.

Each carton contains one vial.

6.6 Special precautions for disposal and other handling

Preparation of diluted solution
 Prepare the diluted solution immediately after removal of the vial(s) from refrigerated storage, 

or the vial(s) may be stored at room temperature protected from light for up to 24 hours prior to 
preparation of the diluted solution.

 Inspect vial contents for discoloration and particulate matter prior to dilution. ZINPLAVA is a 
clear to moderately opalescent, colourless to pale yellow liquid. Do not use the vial if the 
solution is discoloured or contains visible particles.

 Do not shake the vial.

 



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 Withdraw the required volume from the vial(s) based on the patient’s weight (in kg) and transfer 
into an IV bag containing either 0.9 % Sodium Chloride Injection, or 5 % Dextrose Injection, to 
prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted 
solution by gentle inversion.

 Discard vial(s) and all unused contents.
 If the diluted solution is refrigerated, allow the IV bag to come to room temperature prior to use.
 Do not freeze the diluted solution.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1156/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 January 2017

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



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ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

Lonza Biologics Inc.
101 International Drive
Portsmouth
New Hampshire
03801
United States

Name and address of the manufacturer responsible for batch release

SP Labo N.V.
Industriepark 30 - Zone A
2220 Heist-op-den-Berg
Belgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP.

An updated RMP should be submitted:

 At the request of the European Medicines Agency;

 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.

 



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ANNEX III

LABELLING AND PACKAGE LEAFLET

 



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A. LABELLING

 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

ZINPLAVA 25 mg/mL concentrate for solution for infusion
bezlotoxumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each 40 mL vial contains 1,000 mg bezlotoxumab.
Each mL contains 25 mg bezlotoxumab.

3. LIST OF EXCIPIENTS

Excipients: Citric acid monohydrate, diethylenetriaminepentaacetic acid, polysorbate 80, sodium 
chloride, sodium citrate dihydrate, water for injections, sodium hydroxide.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion
1 vial
1,000 mg/40 mL

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Intravenous use after dilution
Single dose vial

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Keep the vial in the outer carton in order to protect from light.

 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1156/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:

 



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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT

ZINPLAVA 25 mg/mL concentrate for solution for infusion
bezlotoxumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 1,000 mg bezlotoxumab.
Each mL contains 25 mg bezlotoxumab.

3. LIST OF EXCIPIENTS

Excipients: Citric acid monohydrate, diethylenetriaminepentaacetic acid, polysorbate 80, sodium 
chloride, sodium citrate dihydrate, water for injections, sodium hydroxide.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion
1 vial
1,000 mg/40 mL

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
See leaflet.
Intravenous use after dilution
Single dose vial

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

 



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9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Keep the vial in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

MSD

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1156/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

 



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B. PACKAGE LEAFLET

 



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Package leaflet: Information for the patient

ZINPLAVA 25 mg/mL concentrate for solution for infusion
bezlotoxumab

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you.
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor.
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4.

What is in this leaflet

1. What ZINPLAVA is and what it is used for
2. What you need to know before you are given ZINPLAVA
3. How you are given ZINPLAVA
4. Possible side effects
5. How to store ZINPLAVA
6. Contents of the pack and other information

1. What ZINPLAVA is and what it is used for

ZINPLAVA contains the active substance bezlotoxumab.

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.

2. What you need to know before you are given ZINPLAVA

Talk to your doctor before you are given ZINPLAVA.

You should not be given ZINPLAVA if:
 you are allergic to bezlotoxumab or any of the other ingredients of this medicine (listed in 

section 6).

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.

Children and adolescents
ZINPLAVA should not be used in children and adolescents below 18 years of age.

 



21

Other medicines and ZINPLAVA
Tell your doctor if you are taking, have recently taken or might take any other medicines.

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 breast-feeding or are planning to breast-feed, 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.

Driving and using machines
ZINPLAVA has no or very little effect on the ability to drive and use machines.

3. How you are given ZINPLAVA
 You will get ZINPLAVA as an infusion (drip) into a vein.
 You will get ZINPLAVA in one dose and it will take about 1 hour. Your dose will be calculated 

using your body weight.
 You should keep taking your antibiotic for CDI as directed by your doctor.

If you miss an appointment to get ZINPLAVA
 Call your doctor or health care professional right away to reschedule your appointment.
 It is very important that you do not miss the dose of this medicine.

If you have any further questions on the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects have been reported in clinical trials:

Common (may affect up to 1 in 10 people)
 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.

Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly the national reporting system listed in Appendix V. By 
reporting side effects you can help provide more information on the safety of this medicine.

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


22

5. How to store ZINPLAVA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP. 
The expiry date refers to the last day of that month.

Store in a refrigerator 2 °C to 8 °C. Do not freeze. Keep vial in the outer carton in order to protect 
from light.

The diluted solution of ZINPLAVA may be stored either at room temperature for up to 16 hours or 
under refrigeration at 2 °C to 8 °C for up to 24 hours. If refrigerated, allow the IV bag to come to room 
temperature prior to use.

Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste
material should be disposed of in accordance with local requirements.

6. Contents of the pack and other information

What ZINPLAVA contains
- The active substance is bezlotoxumab. Each mL of concentrate contains 25 mg of 

bezlotoxumab.
- The other ingredients are citric acid monohydrate (E330), diethylenetriaminepentaacetic acid, 

polysorbate 80 (E433), sodium chloride, sodium citrate dihydrate (E331), water for injections, 
and sodium hydroxide (E524) (for pH adjustment).

What ZINPLAVA looks like and contents of the pack
The concentrate for solution for infusion is a clear to moderately opalescent, colourless to pale yellow 
liquid.
It is available in cartons containing one glass vial.

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
SP Labo NV
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: 0800 38 693 (+32(0)27766211)
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. + 370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

 



23

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme BV
Tel: 0800 9999000 
(+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
clic@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

 



24

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in {month YYYY}.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

------------------------------------------------------------------------------------------------------------------------
The following information is intended for healthcare professionals only:

Preparation of diluted solution
 Prepare the diluted solution immediately after removal of the vial(s) from refrigerated storage, 

or the vial(s) may be stored at room temperature protected from light for up to 24 hours prior to 
preparation of the diluted solution.

 Inspect vial contents for discoloration and particulate matter prior to dilution. ZINPLAVA is a 
clear to moderately opalescent, colourless to pale yellow liquid. Do not use the vial if the 
solution is discoloured or contains visible particles.

 Do not shake the vial.
 Withdraw the required volume from the vial(s) based on the patient’s weight (in kg) and transfer 

into an IV bag containing either 0.9 % Sodium Chloride Injection, or 5 % Dextrose Injection, to 
prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted 
solution by gentle inversion.

 Discard vial(s) and all unused contents.
 If the diluted solution is refrigerated, allow the IV bag to come to room temperature prior to use.
 Do not freeze the diluted solution.

Method of administration
 Administer the diluted solution for infusion intravenously over 60 minutes using a sterile, 

non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. ZINPLAVA 
should not be administered as an intravenous push or bolus.

 The diluted solution can be infused via a central line or peripheral catheter. 
 ZINPLAVA must not be co-administered with other medicinal products simultaneously through 

the same infusion line.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET