Zevtera

Package leaflet: Information for the user

Zevtera, 500 mg, powder for solution for infusion
ceftobiprole
Please read all of this leaflet carefully before using 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, please ask your doctor or nurse.
• If you experience any side effects, including any not listed in this leaflet, please tell your doctor or nurse. See section 4.

Contents of the leaflet

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

1. What Zevtera is and what it is used for

Zevtera is an antibiotic that contains as its active substance the sodium salt of medocaril
ceftobiprole. The medicine belongs to a group of antibiotics called "cephalosporins".
Zevtera is used in full-term newborns, infants, children, adolescents, and adults with lung infections,
known as "pneumonia".
Zevtera works by killing certain strains of bacteria that may cause severe lung infections.

2. Important information before using Zevtera

When not to use Zevtera

• if the patient is allergic to ceftobiprole medocaril sodium or any of the other ingredients of this medicine (listed in section 6),
• if the patient is allergic to other cephalosporins or beta-lactam antibiotics,
• if the patient has previously experienced severe allergic reactions to other antibiotics, e.g. penicillin or carbapenems.

Do not use Zevtera if any of the above apply to the patient. If in doubt, consult a doctor or nurse before taking Zevtera.

Warnings and precautions

Before starting treatment with Zevtera, consult a doctor or nurse:

• if the patient has kidney disease (the doctor may reduce the dose),
• if the patient has ever had any allergic reactions to other antibiotics, e.g. penicillin or carbapenems,
• if the patient has seizures (seizure attacks),
• if the patient has previously had diarrhoea during or after treatment with this medicine (the patient may have inflammation of the intestine, so-called colitis). Do not take anti-diarrhoeal medicines before contacting a doctor.
• if the patient has tested positive for HIV,
• if the patient's immune system is severely weakened,
• if the patient has a very low white blood cell count or bone marrow suppression,
• if the lung infection occurred more than 48 hours after initiation of mechanical ventilation, Zevtera is not appropriate for the patient (the doctor will prescribe a suitable antibiotic),
• if the patient requires (or it is anticipated that the patient will require) simultaneous administration of calcium-containing solutions, except for injection solution of Ringer's lactate, via the same intravenous infusion set, due to the risk of precipitate formation.

If the doctor considers that the patient requires additional fluids, the patient may be asked to drink large amounts of fluid or may require fluid administration via intravenous infusion during treatment with Zevtera.

If the patient started treatment with Zevtera and subsequently required mechanical ventilation, the doctor will assess whether continued administration of Zevtera is appropriate for the patient.

Laboratory tests

The patient may have abnormal laboratory test results (Coombs test) related to the presence of certain antibodies against red blood cells in the patient's body. In addition, Zevtera may interfere with serum creatinine assays (Jaffé reaction) or certain urine glucose tests. Results of these tests may be falsely altered.

If any of the above apply to the patient (or the patient is unsure), discuss with a doctor or nurse before starting treatment with Zevtera.

Children

There are no available data on the use of Zevtera in premature neonates (preterm infants).

Zevtera with other medicines

Inform the doctor or nurse about all medicines the patient is currently taking or has recently taken, including medicines the patient plans to take.

Pregnancy and breastfeeding

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor before using this medicine.

Driving and operating machinery

Zevtera may cause adverse effects such as dizziness. This may impair the patient's ability to drive or operate machinery.

Zevtera contains sodium

This medicine contains approximately 22 mg of sodium (the main component of table salt) per vial. This corresponds to 1.1% of the maximum recommended daily intake of sodium in the diet for adults.

3. How to use Zevtera

Zevtera will be administered to the patient by a doctor or nurse.
The recommended dose for adults is 500 mg of ceftobiprole every 8 hours given as an intravenous infusion lasting 2 hours.
The recommended dose for term newborns, infants, children, and adolescents depends on the child's age and body weight and is administered every 8 hours (infants aged 3 months or older, children and adolescents) or every 12 hours (term newborns and infants under 3 months of age) as an intravenous infusion lasting 2 hours.
In adults and adolescents, an infusion solution with a ceftobiprole concentration of 2 mg/mL is used. In infants and term newborns, an infusion solution with a ceftobiprole concentration of 4 mg/mL is used.
Patients with kidney disease
If the patient has kidney disease, a lower dose of Zevtera may be required.
Administration of a higher than recommended dose of Zevtera
If the patient thinks that a higher than recommended dose of Zevtera has been administered, the doctor should be informed immediately.
Missed dose of Zevtera
If the patient thinks that a dose of Zevtera has been missed, the doctor should be informed immediately.
If there are any further doubts concerning the use of this medicine, consult the doctor or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
This medicine may cause the following adverse reactions:
Contact a doctor immediately if the patient experiences any of the following symptoms, as
the patient may require immediate medical attention:

• Sudden swelling of the lips, face, throat or tongue; severe rash and problems with swallowing or breathing. These may be symptoms of a severe allergic reaction (anaphylaxis), which may be life-threatening.
• Diarrhoea that becomes severe and does not resolve, or stools containing blood or mucus during or after treatment with Zevtera. In this case, do not take medicines that stop or slow down bowel movements.

Common: may affect up to 1 in 10 patients

• Nausea
• Headache, drowsiness
• Dizziness
• Rash, itching or hives
• Diarrhoea; if diarrhoea occurs, inform the doctor immediately
• Vomiting
• Stomach pain (abdominal pain), indigestion or heartburn (dyspepsia)
• Taste disturbances
• Fungal infections in various parts of the body
• Redness, pain or swelling at the injection site
• Low blood sodium levels
• Increased activity of certain liver enzymes in the blood
• Hypersensitivity, including skin redness

Uncommon: may affect up to 1 in 100 patients

• Seizures, convulsions or fits
• Transient decrease or increase in the number of certain blood cells
• Blood tests showing decreased potassium levels
• Insomnia and sleep disturbances, sometimes including anxiety, panic attacks and nightmares
• Shortness of breath or difficulty breathing, asthma
• Muscle spasms
• Kidney disorders
• Swelling, particularly of the ankles and legs
• Blood tests showing transient increased levels of triglycerides, blood glucose or creatinine

Frequency not known: frequency cannot be estimated from the available data

• Marked decrease in the number of a specific type of white blood cells (agranulocytosis)

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed
in this leaflet, inform the doctor or nurse. Adverse reactions can be
reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products;
Al. Jerozolimskie 181C; PL-02 222 Warsaw;
Tel.: + 48 22 49 21 301
Faks: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
By reporting adverse reactions, additional information on the safety of the medicine can be collected.

5. How to store Zevtera

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial after EXP.
The expiry date refers to the last day of the stated month.
Store in a refrigerator (2 °C–8 °C).
Keep the vial in the outer packaging to protect it from light.
Information on the storage of reconstituted and diluted Zevtera infusion solutions is provided in the package leaflet intended for healthcare professionals.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the packaging and other information

What Zevtera contains

• The active substance is ceftobiprole. Each vial contains 500 mg of ceftobiprole (as 666.6 mg of ceftobiprole medocaril sodium). After reconstitution, 1 mL of concentrate contains 50 mg of ceftobiprole (as 66.7 mg of ceftobiprole medocaril sodium).
• The other ingredients are citric acid monohydrate and sodium hydroxide (to adjust pH); see also section 2.

What Zevtera looks like and contents of the pack
Zevtera is a white, yellowish or slightly brownish tablet or crushed tablet of compressed
powder or a powder for preparing a concentrate solution for infusion in a 20 mL vial. The medicine is
available in packs containing 10 vials.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Advanz Pharma Limited
Unit 17, Northwood House
Northwood Crescent
Dublin 9
D09 V504
Ireland
e-mail: medicalinformation@advanzpharma
Manufacturer:
ACS Dobfar S.p.A.
Via A. Fleming, 2
37135 Verona (VR)
Italy
This medicinal product is authorised in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:
Austria: Zevtera 500 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Denmark: Zevtera
Finland: Zevtera 500 mg, kuiva-aine välikonsentraatiksi infuusionestettä varten, liuos
France: Mabelio 500 mg, poudre pour solution à diluer pour solution pour perfusion
Ireland: Adaluzis 500 mg powder for concentrate for solution for infusion
Germany: Zevtera 500 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Italy: Mabelio 500 mg, polvere per concentrato per soluzione per infusione
Luxembourg: Mabelio 500 mg, poudre pour solution à diluer pour solution pour perfusion
Norway: Zevtera 500 mg, pulver til konsentrat til infusjonsvæske, oppløsning
Poland: Zevtera 500 mg, proszek do sporządzania koncentratu roztworu do infuzji
Portugal: Zevtera 500 mg pó para concentrado para solução para perfusão
Spain: Zevtera 500 mg, polvo para concentrado para solución para perfusión
Sweden: Zevtera 500 mg pulver till koncentrat till infusionsvätska, lösning
United Kingdom (Northern Ireland): Zevtera 500 mg powder for concentrate for solution for
infusion.
Detailed information about this medicinal product is available on the website of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: www.urpl.gov.pl
__________________________________________________________________________________

Information intended exclusively for healthcare professionals:

Each vial is for single use only.
Preparation of infusion solutions of the medicinal product Zevtera
The medicinal product Zevtera must be reconstituted and then diluted prior to infusion administration.

Step 1: Reconstitution
For adults and adolescents aged ≥ 12 years requiring an infusion solution with a ceftobiprole concentration of 2 mg/mL, the lyophilized powder should be reconstituted with 10 mL of sterile water for injections or 50 mg/mL (5%) glucose solution for injections.

For children aged < 12 years requiring an infusion solution with a ceftobiprole concentration of 4 mg/mL, the lyophilized powder should be reconstituted with 10 mL of 50 mg/mL (5%) glucose solution for injections, sterile water for injections, or 50 mg/mL (5%) glucose solution for injections if the same diluent (i.e., 50 mg/mL (5%) glucose solution for injections) will be used for further dilution, or with 10 mL of water for injections if 9 mg/mL (0.9%) sodium chloride solution for injections will be used for further dilution (see tables below).

Vigorously shake the vial until complete dissolution. In some cases, this may take up to 10 minutes. The volume of the resulting concentrate is approximately 10.6 mL. If foam appears, allow it to dissipate and visually inspect the reconstituted solution to confirm complete dissolution and absence of particulate matter. The reconstituted concentrate contains 50 mg/mL ceftobiprole (as 66.7 mg medocaril sodium salt) and must be further diluted before administration. Immediate further dilution of the reconstituted solution is recommended. If this is not possible, the reconstituted solution may be stored at room temperature for up to 1 hour or refrigerated at 2°C–8°C for up to 24 hours.

Step 2: Dilution (infusion solution)
Use in adults and adolescents aged ≥ 12 years
Preparation of a 500 mg infusion dose of Zevtera product (2 mg/mL ceftobiprole)
Withdraw 10 mL of the reconstituted solution from the vial and transfer it into a suitable container (e.g., PVC or PE infusion bag, glass bottle) containing 250 mL of 9 mg/mL (0.9%) sodium chloride solution for injections, 50 mg/mL (5%) glucose solution for injections, or Ringer's lactate solution for injections. Gently invert the infusion container 5–10 times to obtain a homogeneous solution. Avoid vigorous shaking, as this may cause foaming.

For adults, the entire contents of the infusion bag should be administered to deliver a 500 mg dose of ceftobiprole.

For adolescents aged ≥ 12 years, the volume to be administered should be calculated based on body weight, and the maximum volume of 250 mL (500 mg dose) must not be exceeded.

Preparation of a 250 mg infusion dose of Zevtera product for adult patients with severe renal impairment
Withdraw 5 mL of the reconstituted solution from the vial and transfer it into a suitable container (e.g., PVC or PE infusion bag, glass bottle) containing 125 mL of 9 mg/mL (0.9%) sodium chloride solution for injections, 50 mg/mL (5%) glucose solution for injections, or Ringer's lactate solution for injections. Gently invert the infusion container 5–10 times to obtain a homogeneous solution. Avoid vigorous shaking, as this may cause foaming. The entire contents of the infusion bag should be administered to deliver a 250 mg dose of ceftobiprole.

Use in children aged < 12 years
Preparation of an infusion solution of the medicinal product Zevtera with a ceftobiprole concentration of 4 mg/mL
Administration via infusion bags, bottles, or syringes:
A reconstituted solution prepared with 10 mL of 50 mg/mL (5%) glucose solution for injections should be diluted with the same diluent (i.e., 50 mg/mL (5%) glucose solution for injections). A reconstituted solution prepared with 10 mL of water for injections should be diluted with 9 mg/mL (0.9%) sodium chloride solution for injections.

Remove 10 mL of diluent from an infusion container (e.g., PVC or PE infusion bag, glass bottle) containing 125 mL of diluent and replace it with 10 mL of reconstituted solution withdrawn from the vial. Gently invert the infusion container 5–10 times to obtain a homogeneous solution. Avoid vigorous shaking, as this may cause foaming. The volume to be administered should be calculated based on the patient's body weight, and the maximum volume of 125 mL (500 mg dose) must not be exceeded.

If the calculated dose does not exceed 200 mg, for administration via a 50 mL syringe, withdraw 4 mL of solution (corresponding to 200 mg ceftobiprole) reconstituted in 50 mg/mL (5%) glucose solution for injections or water for injections, and dilute with 46 mL of the appropriate infusion diluent (see section 6.3). Gently invert the syringe 5–10 times to obtain a homogeneous solution. Avoid vigorous shaking, as this may cause foaming. The volume to be administered should be calculated based on the patient's body weight, and the maximum volume of 50 mL (200 mg dose) must not be exceeded.

Appearance of the diluted solution
The infusion solution should be clear or slightly opalescent and yellowish. Before administration, visually inspect the infusion solution for particulate matter and discard the solution if any particles are present.

Additional information is also provided in section 3.

Storage of reconstituted and diluted Zevtera infusion solutions
Chemical and physical stability have been demonstrated for the reconstituted solution when stored for 1 hour at 25°C and for up to 24 hours at 2°C–8°C.

Data on chemical and physical stability during storage confirm the total time for reconstitution and infusion of diluted ceftobiprole solutions at concentrations of 2 mg/mL or 4 mg/mL, as described in the tables below:

Use in adults and adolescents aged ≥ 12 years (2 mg/mL ceftobiprole): Total time allowed for completion of reconstitution and infusion (including infusion duration)

Use in children, infants, and neonates (aged < 12 years) (4 mg/mL ceftobiprole):
Total time within which reconstitution and infusion must be completed (including infusion time)

From a microbiological standpoint, unless the reconstitution/dilution method eliminates the risk of microbiological contamination, the product should be used immediately. If the product is not used immediately, the user is responsible for the subsequent storage period and storage conditions. Do not freeze or expose reconstituted solutions and infusion solutions to direct sunlight.
If the infusion solution is stored in a refrigerator, it should be brought to room temperature before administration. During infusion, the infusion solution does not need to be protected from light.
Additional information is also provided in section 5.