Consumer medicine information

Zinplava

Bezlotoxumab

BRAND INFORMATION

Brand name

Zinplava

Active ingredient

Bezlotoxumab

Schedule

SUMMARY CMI

ZINPLAVA^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given ZINPLAVA?

ZINPLAVA contains the active ingredient bezlotoxumab. ZINPLAVA is used to prevent Clostridium difficile infection (CDI) from coming back in adults who are taking an antibiotic for CDI and have a high risk of CDI coming back.

For more information, see Section 1. Why am I being given ZINPLAVA? in the full CMI.

2. What should I know before I am given ZINPLAVA?

Do not use if you have ever had an allergic reaction to bezlotoxumab or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given ZINPLAVA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZINPLAVA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given ZINPLAVA?

ZINPLAVA is given as an infusion or "drip" injection into your vein (intravenously) for about 1 hour.
You do not need to do anything to prepare for getting ZINPLAVA.
ZINPLAVA will be given once during a course of antibiotic therapy for Clostridium difficile infection (CDI).

More instructions can be found in Section 4. How am I given ZINPLAVA? in the full CMI.

5. What should I know while being given ZINPLAVA?

Things you should do

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given ZINPLAVA.
If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given ZINPLAVA.
Keep taking your antibiotic for CDI as directed by your doctor. ZINPLAVA works with your antibiotic that you are taking for CDI. ZINPLAVA is not an antibiotic. It does not replace it.

Looking after your medicine

It is unlikely that you will be asked to store ZINPLAVA yourself. It will usually be stored in the pharmacy or on the ward.

For more information, see Section 5. What should I know while being given ZINPLAVA? in the full CMI.

6. Are there any side effects?

Common side effects of ZINPLAVA that can occur within 24 hours: tiredness, headache, fever, feeling sick (nausea), shortness of breath, dizziness, high blood pressure.

Common side effects of ZINPLAVA that can occur up to 4 weeks: feeling sick (nausea), diarrhoea, fever, headache.

ZINPLAVA may cause serious side effects, including: heart failure (symptoms include shortness of breath, tiredness, swollen legs and rapid heartbeat).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

ZINPLAVA^®

Active ingredient: Bezolotoxumab

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZINPLAVA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZINPLAVA.

Where to find information in this leaflet:

1. Why am I being given ZINPLAVA?
2. What should I know before I am given ZINPLAVA?
3. What if I am taking other medicines?
4. How am I given ZINPLAVA?
5. What should I know while being given ZINPLAVA?
6. Are there any side effects?
7. Product details

1. Why am I being given ZINPLAVA?

ZINPLAVA contains the active ingredient bezlotoxumab.

ZINPLAVA is a medicine to prevent Clostridium difficile infection (CDI) from coming back in adults who are taking an antibiotic for CDI and have a high risk of CDI coming back.

CDI is a bacterial infection that can damage your colon and cause stomach pain and severe diarrhoea.

When people get CDI, they often take an antibiotic to get rid of the infection. Even when treated with antibiotics, CDI can come back within weeks to months.

ZINPLAVA prevents the infection coming back. It works when given along with your antibiotic that you are taking for CDI.

Ask your doctor if you have any questions about why ZINPLAVA has been prescribed for you.

2. What should I know before I am given ZINPLAVA?

Warnings

Do not use ZINPLAVA if:

you are allergic to bezlotoxumab, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any allergies to any other medicines, or any other substances such as foods, preservatives or dyes.
have or have had congestive heart failure (CHF)
are pregnant, think you may be pregnant or trying to become pregnant.
are breastfeeding.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy

Check with your doctor if you are pregnant or intend to become pregnant.

It is unknown if ZINPLAVA will harm your baby while you are pregnant. Your doctor can discuss with you the risks and benefits involved.

Breastfeeding

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor can discuss the risks and benefits involved.

Children

ZINPLAVA should not be used in children below 18 years of age until more information becomes available.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZINPLAVA.

4. How am I given ZINPLAVA?

How ZINPLAVA is given

ZINPLAVA is given as an infusion or "drip" injection into your vein (intravenously) for about 1 hour.

You do not need to do anything to prepare for getting ZINPLAVA.

ZINPLAVA will be given once during a course of antibiotic therapy for Clostridium difficile infection (CDI).

If you are given too much ZINPLAVA

If you think that you have been given too much ZINPLAVA, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while being given ZINPLAVA?

Things you should do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given ZINPLAVA.

Keep taking your antibiotic for CDI as directed by your doctor.

ZINPLAVA works with your antibiotic that you are taking for CDI. ZINPLAVA is not an antibiotic. It does not replace it.

Remind any doctor, dentist or pharmacist you visit that you are using ZINPLAVA.

Looking after your medicine

It is unlikely that you will be asked to store ZINPLAVA yourself. It will usually be stored in the pharmacy or on the ward.

Getting rid of any unwanted medicine

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effects

What to do

The following side effects have been reported in clinical trials in adults:

Side effects of ZINPLAVA that can occur within 24 hours:

tiredness
headache
fever
feeling sick (nausea)
shortness of breath
dizziness
high blood pressure

Side effects of ZINPLAVA that can occur up to 4 weeks:

feeling sick (nausea)
diarrhoea
fever
headache

Speak to your doctor if you have any of these common side effects and they worry you.

Serious side effects

Serious side effects

What to do

ZINPLAVA may cause serious side effects, including:

heart failure (symptoms include shortness of breath, tiredness, swollen legs and rapid heartbeat)

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ZINPLAVA contains

Active ingredient
(main ingredient)

bezlotoxumab

Other ingredients
(inactive ingredients)

citric acid monohydrate

pentetic acid

polysorbate 80

sodium chloride

sodium citrate dihydrate

Water for Injections

May contain sodium hydroxide to adjust the pH to 6.0

Do not take this medicine if you are allergic to any of these ingredients.

What ZINPLAVA looks like

ZINPLAVA is a clear to moderately opalescent, colourless to pale yellow liquid in a glass vial (AUST R 281878).

Who distributes ZINPLAVA

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park NSW 2113 Australia

This leaflet was prepared in April 2022.

CCPI-MK6072-IV-122017

RCN000023367 - AU

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Zinplava

Active ingredient

Bezlotoxumab

Schedule

1 Name of Medicine

Bezlotoxumab.

2 Qualitative and Quantitative Composition

One vial contains bezlotoxumab 1,000 mg/40 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zinplava concentrated injection is a sterile, preservative-free, clear to moderately opalescent, colourless to pale yellow liquid that requires dilution for intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Zinplava (bezlotoxumab) is indicated for the prevention of recurrence of Clostridium difficile infection (CDI) in adult patients 18 years or older at high risk for recurrence of CDI who are receiving antibacterial therapy for CDI (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Zinplava is not indicated for the treatment of CDI. Zinplava is not an antibacterial drug. Zinplava should only be used in conjunction with antibacterial drug treatment of CDI.
The safety and efficacy of repeat administration of Zinplava in patients with CDI have not been studied.

4.2 Dose and Method of Administration

Zinplava (bezlotoxumab) should be administered during a course of antibacterial therapy for CDI (see Section 4.4 Special Warnings and Precautions for Use).

Dose recommendations in adults.

The recommended dose of Zinplava is 10 mg/kg based on patient body weight administered as an intravenous (IV) infusion over 60 minutes as a single dose.

Preparation and administration.

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% Glucose 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.

Storage of diluted solution.

The product does not contain preservative. 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. Product is for single use in one patient only. Discard any residue. If refrigerated, allow the IV bag to come to room temperature prior to use.
These time limits include storage of the infusion solution in the IV bag through the duration of infusion.
Do not freeze the diluted solution.

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.
The diluted solution can be infused via a central line or peripheral catheter. Do not administer Zinplava as an intravenous push or bolus.
Do not co-administer other drugs simultaneously through the same infusion line.

Paediatric patients.

Safety and efficacy of Zinplava in patients below 18 years of age have not been established.

Geriatric patients.

No dose adjustment is necessary in geriatric patients.

Renal impairment.

No dose adjustment is necessary for patients with renal impairment.

Hepatic impairment.

No dose adjustment is necessary for patients with hepatic impairment.

4.3 Contraindications

Zinplava is contraindicated in patients with hypersensitivity to bezlotoxumab or to any of the inactive ingredients.

4.4 Special Warnings and Precautions for Use

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 Section 4.8 Adverse Effects (Undesirable Effects)). 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 be reserved for use when the benefit outweighs the risk.

Treatment of acute CDI episode.

Zinplava is not an antibacterial therapy, and is not indicated for the treatment of an acute episode of CDI.
Zinplava should be administered during a course of antibacterial therapy for CDI (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

No dose adjustment is needed for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dose adjustment is needed for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Of the 786 patients treated with Zinplava, 50% were 65 years of age and over. Safety and efficacy were demonstrated in these patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials). No dose adjustment is necessary in this population (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Safety and efficacy of Zinplava in patients below 18 years of age have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal pharmacokinetic drug interaction studies have been conducted with bezlotoxumab. Since bezlotoxumab is eliminated by catabolism, no metabolic drug-drug interactions are expected.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal reproduction 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.
(Category B2)
Bezlotoxumab targets a non-endogenous microbial toxin antigen and lacks toxicologically relevant cross-reactivity to human tissues including reproductive tissues. Animal reproduction studies have not been conducted with bezlotoxumab. Adequate and well controlled studies with Zinplava have not been conducted in pregnant women. As it is not known whether Zinplava can cause foetal harm or affect reproductive capacity in pregnant women, this drug should be used during pregnancy only if clearly needed.
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 nursing or to not administer Zinplava, taking into account the importance of Zinplava to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine in a person’s ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

The safety of Zinplava was evaluated in two placebo-controlled, Phase 3 studies (MODIFY I and MODIFY II) in patients receiving a single dose of Zinplava of 10 mg/kg and concomitant standard of care (SoC) antibacterial therapy (metronidazole, vancomycin or fidaxomicin) for CDI.
Adverse reactions (adverse events regardless of causality or severity) reported within the first 4 weeks after Zinplava was administered are described for the pooled Phase 3 trial population of 786 patients. The median age of patients receiving Zinplava was 65 years (range 18 to 100), 50% were age 65 years or older, 56% were female, and 83% were white.
The type and severity of adverse reactions in patients treated with Zinplava was comparable to that in patients treated with placebo. 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. Adverse reactions reported in at least 4% of Zinplava treated patients, with a frequency greater than placebo are shown in Table 1.

Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of Zinplava-treated patients and 33% in patients receiving placebo. Four of 786 patients treated with Zinplava had serious adverse reactions that were considered to be drug-related (one report each of diarrhoea, ventricular tachyarrhythmia, haematuria, sepsis, and cerebral haemorrhage); all occurred within 4 weeks of receiving Zinplava. Of these four patients, one patient discontinued the Zinplava infusion due to the event (ventricular tachyarrhythmia).
There were no other Zinplava-treated patients who discontinued therapy due to adverse reactions.
Heart failure was reported as a serious adverse reaction in 2.3% of the Zinplava-treated patients and 1.0% of the placebo-treated patients (see Section 4.4 Special Warnings and Precautions for Use).
Mortality rates were similar across treatment arms (7% in Zinplava treatment arm and 8% in the placebo treatment arm) during the 12-week follow-up period.
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 MODIFY I and MODIFY II during which all patients received a single dose.

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 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.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity following administration of Zinplava. 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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

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.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ATC code: J06BB21.

Mechanism of action.

Clostridium difficile colonises and infects the large intestine. The bacterium expresses two exotoxins, toxin A and toxin B. In preclinical studies, the toxins have been shown to target host colonic epithelial cells, leading to tissue injury that disrupts the normal gut barrier function. In addition to their cytopathic/cytotoxic effects on cells, the toxins cause the release of pro-inflammatory mediators leading to the recruitment of neutrophils and other immune cells to the site of infection, which contributes to the persistence of tissue damage that underlies the symptoms of Clostridium difficile infection (CDI). CDI is generally treated with antibacterial therapy to kill the growing C. difficile bacteria that are expressing the toxins. Recurrence of CDI occurs due to persistent or newly-acquired C. difficile spores, whose outgrowth (leading to new toxin expression) is facilitated by the gut dysbiosis caused by antibacterial therapy. In patients, endogenous antibody titres against C. difficile toxins have been reported to correlate with reduced recurrence of C. difficile infection. Bezlotoxumab is an antitoxin antibody that binds with high affinity (Kd < 1 x 10^-9M) to C. difficile toxin B and neutralises its activity by preventing it from binding to host cells. Bezlotoxumab does not bind to C. difficile toxin A. In MODIFY I and MODIFY II, Zinplava prevented the recurrence of CDI when administered in combination with Standard of Care (SoC) antibacterial therapy during an active episode of CDI. Zinplava prevents CDI recurrence by providing enhanced 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 epitope of bezlotoxumab is conserved, though not identical, across all known toxin sequences. Bezlotoxumab neutralises the cytotoxic activities of toxin B from all clinical isolates of C. difficile tested (ribotypes 001, 002, 003, 012, 014, 017, 018, 023, 027, 053, 063, 077, 078, 081, 087, 106, 198, and 369).
In a gnotobiotic piglet model of CDI, bezlotoxumab reduced mortality and protected against intestinal damage and inflammation. Similar results were obtained in mice and hamster models of CDI, including recurrent CDI, although full protection in these models required co-administration of a toxin A-neutralising antibody.

Clinical trials.

The safety and efficacy of Zinplava (bezlotoxumab) were investigated in two randomised, double-blind, placebo-controlled, multicentre, Phase 3 studies (MODIFY I and MODIFY II) in 2,655 patients receiving concomitant oral Standard of Care (SoC) antibacterial therapy for CDI.
Randomisation was stratified by SoC antibacterial therapy and hospitalisation status (inpatient vs. outpatient) at the time of study entry. In MODIFY I, subjects were randomised in a 1:1:1:1 ratio to receive Zinplava, anti-toxin A, Zinplava plus anti-toxin A, or placebo. In MODIFY II, subjects were randomised in a 1:1:1 ratio to receive Zinplava, Zinplava plus anti-toxin A, or placebo. Anti-toxin A when given alone was not shown to prevent CDI recurrence compared to placebo, and Zinplava plus anti-toxin A was not superior to Zinplava in preventing CDI recurrence. Therefore, the anti-toxin A and Zinplava plus anti-toxin A arms are not described.
Enrolled patients were 18 years of age or older and had a confirmed diagnosis of CDI, which was defined as diarrhoea (passage of 3 or more loose bowel movements 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 were excluded if surgery for CDI was planned, or if they had uncontrolled chronic diarrhoeal illness. Patients received a 10- to 14-day course of oral SoC antibacterial therapy for CDI (metronidazole, vancomycin or fidaxomicin) and a single infusion of Zinplava or placebo was administered prior to completion of the SoC antibacterial therapy; patients were followed for 12-weeks following the infusion. Patients on oral vancomycin or oral fidaxomicin could have also received IV metronidazole. Choice of SoC antibacterial therapy was at the discretion of the health care provider.
The baseline characteristics of the 1,554 patients receiving Zinplava or placebo were similar across treatment groups and in MODIFY I and MODIFY II. 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%) as their SoC antibacterial therapy. A small proportion of patients received oral fidaxomicin (4%) as the SoC antibacterial therapy. The following risk factors associated with an increased risk of CDI recurrence or CDI-related adverse outcomes were present in the study population at entry: 51% were ≥ 65 years of age, 39% received one or more systemic antibacterial therapies (during the 12-week follow-up period), 28% had one or more episodes of CDI within the six months prior to the episode under treatment (15% had two or more episodes prior to the episode under treatment), 21% were immunocompromised and 16% presented with clinically severe CDI. A hypervirulent strain (ribotypes 027, 078 or 244) was isolated in 22% of patients who had a positive baseline culture, of which the majority (87%, 189 of 217 strains) were ribotype 027.
The primary efficacy endpoint was the proportion of patients with recurrence of CDI through 12 weeks following administration of the study infusion. CDI recurrence was defined as the development of a new episode of diarrhoea associated with a positive stool test for toxigenic C. difficile following clinical cure of the baseline CDI episode. Clinical cure was defined as no diarrhoea for 2 consecutive days following a ≤ 14 day regimen of SoC antibacterial therapy. In a prospectively planned combined analysis of MODIFY I and MODIFY II, Zinplava was superior to placebo in the prevention of CDI recurrence (see Table 2).

In a prospectively planned combined analysis of MODIFY I and MODIFY II, the CDI recurrence rates in pre-specified subgroups of patients predisposed to CDI recurrence and/or at risk for severe outcomes are presented in Table 3. In the subgroups studied, the proportion of patients with CDI recurrence in the Zinplava treatment group was consistently lower than the proportion of patients with CDI recurrence in the placebo group.

A secondary endpoint was global cure, defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion. In the combined data across MODIFY I and MODIFY II, Zinplava was superior to placebo in achieving global cure (64% for Zinplava vs. 54% for placebo, one-sided p < 0.0001).

5.2 Pharmacokinetic Properties

The pharmacokinetics of bezlotoxumab were studied in 1,515 patients in MODIFY I and MODIFY II. After a single IV dose of 10 mg/kg bezlotoxumab, mean AUC_(0-∞) and C_max were 53,000 microgram.h/mL and 185 microgram/mL, respectively. Bezlotoxumab exposures in healthy subjects increased in an approximately dose proportional manner across the 0.3 to 20 mg/kg dose range.

Absorption.

Bezlotoxumab is dosed via the IV route and therefore is immediately and completely bioavailable.

Distribution.

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

Metabolism.

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

Excretion.

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 (t_1/2) 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.

Geriatric.

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

Genotoxicity.

The genotoxic potential of bezlotoxumab has not been evaluated.

Carcinogenicity.

The carcinogenic potential of bezlotoxumab has not been evaluated in long-term animal studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each vial contains the following inactive ingredients: sodium chloride, sodium citrate dihydrate, citric acid monohydrate, polysorbate 80, pentetic acid, and water for injections. The vial may contain sodium hydroxide to adjust the pH to 6.0.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze). Store in original carton. Protect from light.
For storage of diluted solution, see Section 4.2 Dose and Method of Administration.

6.5 Nature and Contents of Container

Zinplava concentrated injection: carton containing one 1,000 mg/40 mL (25 mg/mL) single-dose vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Zinplava (bezlotoxumab) is a specific fully human monoclonal antibody that binds with high affinity to C. difficile toxin B. Bezlotoxumab is produced in Chinese hamster ovary cells by recombinant DNA technology.
Bezlotoxumab is an IgG₁ immunoglobulin with an approximate molecular weight of 148.2 kDa.

CAS number.

The CAS Registry Number is 1246264-45-8.

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Zinplava

Bezlotoxumab

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