ZINPLAVA 25mg / ml perfusive solution concentrate medication leaflet

ZINPLAVA 25 mg/mL concentrate for solution for infusion

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 byrecombinant DNA technology. It binds to C. difficile toxin B.

Each mL of concentrate contains 0.2 mmol sodium, which is 4.57 mg sodium.

This corresponds to 182.8 mg of sodium per vial.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to moderately opalescent, colourless to pale yellow liquid.

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

ZINPLAVA should be administered during the course of antibacterial therapy for CDI (see sections4.4 and 5.1).

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

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

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

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

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

The safety and efficacy of ZINPLAVA in patients below 18 years of age have not been established.

No data are available.

- 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. ZINPLAVAshould 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 throughthe same infusion line.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

ZINPLAVA is not a treatment for CDI and has no effect on the current CDI episode. ZINPLAVAshould be administered during the course of antibacterial therapy for CDI. There is no data regardingthe 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 clinicaltrials, patients with CDI were only administered a single dose of ZINPLAVA (see section 5.1).

This medicinal product contains 182.8 mg sodium per vial, equivalent to 9.1 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No formal interactions studies with other medicinal products were conducted. Therapeutic monoclonalantibodies do not typically have significant drug-drug interaction potential, as they do not directlyaffect 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 anexogenous toxin.

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

ZINPLAVA.

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

It is unknown whether bezlotoxumab is secreted in human milk. Because monoclonal antibodies maybe excreted in human milk, a decision should be made whether to discontinue breast-feeding or to notadminister ZINPLAVA, taking into account the importance of ZINPLAVA to the mother.

No clinical data are available on the possible effects of bezlotoxumab on fertility. Fertility studies havenot been conducted in animals. There was no binding of bezlotoxumab to reproductive tissue in tissuecross-reactivity studies, and no notable effects in the male and female reproductive organs in repeatdose toxicity studies in mice (see section 5.3).

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

The safety profile of ZINPLAVA was assessed in two Phase 3 clinical studies. The most commonadverse reactions following treatment with ZINPLAVA (reported in ≥ 4 % of patients within the first4 weeks of infusion) were nausea, diarrhoea, pyrexia and headache. These adverse reactions werereported at a similar frequency in placebo treated patients compared with ZINPLAVA-treated patients.

Table 1 presents the adverse reactions reported within 4 weeks of infusion in ZINPLAVA-treatedpatients 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 availabledata). Within each frequency grouping, adverse reactions are presented in order of decreasingfrequency.

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 Common Pyrexiasite conditions

Injury, poisoning and procedural Common Infusion related reactions†complications† See Description of selected adverse reactions below.

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

Overall, 10 % of subjects in the ZINPLAVA group experienced one or more infusion specific adversereactions on the day of, or the day after, the infusion compared to 8 % in the placebo group. Infusionspecific adverse reactions reported in ≥ 0.5 % of subjects receiving ZINPLAVA and at a frequencygreater 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 adversereaction, 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.

In a Phase 1 clinical trial, healthy subjects received two consecutive doses of 10 mg/kg ofbezlotoxumab separated by 12 weeks. The adverse reactions after the second dose were not markedlydifferent from those observed after the first dose, and are consistent with adverse reactions observed inthe two Phase 3 trials (MODIFY I and MODIFY II; see section 5.1) in which all patients received asingle dose.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antiinfectives for systemic use, antibacterial monoclonal antibodies.

ATC code: J06BC03

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

The toxin B epitope to which bezlotoxumab binds is conserved, though not identical, across all knowntoxin sequences.

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 patientswere randomised to bezlotoxumab and 803 to placebo. The number of patients completing the studiesand included in the full analysis set (FAS) was 781 in the ZINPLAVA group versus 773 in the placebogroup. 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 wasdefined as diarrhoea (passage of 3 or more loose bowel movements as defined in the Bristol stool chartas types 5 through 7 in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from astool 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 oralfidaxomicin could have also received IV metronidazole.

A single infusion of ZINPLAVA or placebo was administered prior to completion of antibacterialtherapy 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 oftreatment, with a median on day 3.

The baseline characteristics of the 781 patients receiving ZINPLAVA and 773 receiving placebo weregenerally similar across treatment groups. The median age was 65 years, 85 % were white, 57 % werefemale, 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 treatmentfor 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 Placebo with SoC†

SoC† Percent (n/N)

Percent (n/N) Adjusted Difference (95% CI)‡ p-value16.5 (129/781) 26.6 (206/773) -10.0 (-14.0, -6.0) <0.0001n = 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 studymedication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol definedstandard of care therapy within a 1-day window of the infusion; (iv) 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 inpre-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 systemicantibacterial agents during the 12-week follow-up period. Of the total 28 % had one or more episodesof 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 patientswere 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 noknown risk factors for CDI.

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

ZINPLAVA Placebo withwith SoC† SoC†

Characteristic at study entry Percent (n/m) 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 25.0 (54/216) 41.1 (90/219) -16.1 (-24.7, -7.3)of CDI in past 6 months

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

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 endpointm = Number of patients within subgroup

* Full Analysis Set = a subset of all randomised patients with exclusions for: (i) did not receive infusion of studymedication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol definedstandard 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 thetreatment arms.

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 evaluablepatients tested positive for treatment-emergent anti-bezlotoxumab antibodies. Although ZINPLAVA isintended for single dose administration, the immunogenicity of bezlotoxumab following a secondadministration of 10 mg/kg, 12 weeks after the first dose, was assessed in 29 healthy subjects. Noanti-bezlotoxumab antibodies were detected after the second dose.

There are no data on repeated administration of bezlotoxumab in patients with CDI.

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).

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/mLand 185 mcg/mL, respectively, in patients with CDI. Bezlotoxumab exposures in healthy subjectsincreased in an approximately dose proportional manner across the 0.3 to 20 mg/kg dose range.

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

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

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

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

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

The effect of renal impairment on the pharmacokinetics of bezlotoxumab was evaluated in patientswith 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 ofbezlotoxumab were found between patients with renal impairment and patients with normal renalfunction.

The effect of hepatic impairment on the pharmacokinetics of bezlotoxumab was evaluated in patientswith hepatic impairment (defined as having two or more of the following: [1] albumin ≤ 3.1 g/dL;[2] ALT ≥ 2 X ULN; [3] total bilirubin ≥ 1.3 X ULN; or [4] mild, moderate or severe liver disease asreported 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 patientswith hepatic impairment and patients with normal hepatic function.

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

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

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 repeatdose toxicity studies and no binding to reproductive tissues was observed in tissue cross-reactivitystudies.

Citric acid monohydrate (E330)

Diethylenetriaminepentaacetic acid

Polysorbate 80 (E433)

Sodium chloride

Sodium citrate dihydrate (E331)

Water for injections

Sodium hydroxide (E524) (for pH adjustment).

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

Unopened vial: 3 years.

Solution for infusion: Chemical and physical in-use stability has been demonstrated for 24 hours at2°C - 8°C or 16 hours at room temperature (at or below 25°C). These time limits include storage ofthe infusion solution in the IV bag through the duration of infusion. From a microbiological point ofview, the product must be used immediately. If not used immediately, in-use storage times andconditions prior to use are the responsibility of the user and must not be longer than a total of 24 hoursat 2°C - 8°C or 16 hours at room temperature (at or below 25°C).

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

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

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

Each carton contains one vial.

- Prepare the diluted solution immediately after removal of the vial(s) from refrigerated storage, orthe vial(s) may be stored at room temperature protected from light for up to 24 hours prior topreparation of the diluted solution.

- Inspect vial contents for discoloration and particulate matter prior to dilution. ZINPLAVA is aclear to moderately opalescent, colourless to pale yellow liquid. Do not use the vial if the solutionis 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 transferinto an IV bag containing either 0.9 % Sodium Chloride Injection, or 5 % Dextrose Injection, toprepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix dilutedsolution 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 localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/16/1156/001

Date of first authorisation: 18 January 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.