ZERBAXA 1 g/0.5 g POWDER FOR CONCENTRATE FOR INFUSION SOLUTION

2. What you need to know before you use Zerbaxa

Do not use Zerbaxa

• if you are allergic to ceftolozane, tazobactam, or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to medicines called "cephalosporins".
• if you have had a severe allergic reaction (e.g., severe skin peeling; swelling of the face, hands, feet, lips, tongue, or throat; or difficulty swallowing or breathing) to other antibiotics (e.g., penicillins or carbapenems).

Warnings and precautions

Talk to your doctor or pharmacist before starting Zerbaxa if you know you are, or have been in the past, allergic to cephalosporins, penicillins, or other antibiotics.

Talk to your doctor or pharmacist if you get diarrhea while taking Zerbaxa.

Infections caused by bacteria that are not sensitive to Zerbaxa or caused by a fungus may occur during or after treatment with Zerbaxa. Tell your doctor if you think you may have another infection.

Sometimes treatment with Zerbaxa causes the production of antibodies that react with your red blood cells. If you are told you have an abnormal blood test (called a Coombs test), tell your doctor that you are using or have recently used Zerbaxa.

Children and adolescents

This medicine should not be given to children under 18 years of age to treat pneumonia, as there is not enough information available on the use of this medicine in this age group for the treatment of this infection.

Other medicines and Zerbaxa

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

Some medicines may interact with ceftolozane and tazobactam, including:

• Probenecid (a medicine for gout). This may increase the time it takes for tazobactam to leave your body.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine. Your doctor will advise you whether you should use Zerbaxa during pregnancy.

If you are breastfeeding, your doctor will advise you whether you should stop breastfeeding or stop using or avoid treatment with Zerbaxa, after considering the benefit of breastfeeding to the baby and the benefit of treatment to you.

Driving and using machines

Zerbaxa may cause dizziness, which may affect your ability to drive or use machines.

Zerbaxa contains sodium

This medicine contains 230 mg of sodium (the main component of cooking/table salt) per vial. This is equivalent to 11.5% of the maximum recommended daily intake of sodium for an adult. The reconstituted vial with 10 ml of 0.9% sodium chloride (physiological saline solution) for injectable preparations contains 265 mg of sodium per vial. This is equivalent to 13.3% of the maximum recommended daily intake of sodium for an adult.

3. How to use Zerbaxa

Your doctor or other healthcare professional will give you this medicine through a vein by infusion (drip) over 1 hour. The dose of medicine that you will be given depends on whether you have kidney problems or not.

The dose depends on the type of infection you have, where the infection is in your body, and the severity of the infection. Your doctor will decide the dose that you need.

Use in adults

The recommended dose of Zerbaxa is 1 g of ceftolozane and 0.5 g of tazobactam or 2 g of ceftolozane and 1 g of tazobactam every 8 hours, given into a vein (directly into the bloodstream).

Treatment with Zerbaxa usually lasts between 4 and 14 days, depending on the severity and location of the infection and how your body responds to treatment.

Use in children and adolescents

The recommended dose of Zerbaxa is 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam every 8 hours, given into a vein (directly into the bloodstream). The dose should not exceed 1 g of ceftolozane and 0.5 g of tazobactam.

Treatment with Zerbaxa usually lasts between 5 and 14 days, depending on the severity and location of the infection and how your body responds to treatment.

Patients with kidney problems

Your doctor may reduce your dose of Zerbaxa or decide on the frequency of administration of Zerbaxa. Your doctor may also perform blood tests to ensure that you receive an appropriate dose, especially if you need to receive this treatment for a long time.

If you use more Zerbaxa than you should

As this medicine is given by a doctor or other healthcare professional, it is unlikely that you will be given too much. However, if you have any concerns, you should tell your doctor, nurse, or pharmacist immediately.

If you miss a dose of Zerbaxa

If you think you have missed a dose of Zerbaxa, tell your doctor or healthcare professional immediately.

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

4. Possible side effects

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

Tell your doctor immediately if you get any of these symptoms, as you may need urgent medical treatment:

• Sudden swelling of your lips, face, throat, or tongue; a widespread rash; and problems swallowing or breathing. These may be signs of a severe allergic reaction (anaphylaxis) and can be life-threatening.
• Diarrhea that is severe or does not stop or stools that contain blood or mucus during or after treatment with Zerbaxa. In this situation, do not take medicines that stop or slow down bowel movements.

Adults treated for complicated infections within the abdomen and infections of the kidney and urinary tract

Common side effects(may affect up to 1 in 10 people):

Headache, stomach pain, constipation, diarrhea, nausea, vomiting, increased liver enzymes (in blood tests), rash, fever (high temperature), low blood pressure, low potassium levels (in blood tests), increased platelet count, dizziness, anxiety, difficulty sleeping, infusion site reactions.

Uncommon side effects(may affect up to 1 in 100 people):

Inflammation of the large intestine due to C. difficilebacteria, stomach inflammation, abdominal distension, indigestion, excessive gas in the stomach or intestines, intestinal obstruction, fungal infection of the mouth (candidiasis), fungal infection of the female genitals, fungal infection of the urinary tract, increased blood sugar levels (in blood tests), low magnesium levels (in blood tests), low phosphate levels (in blood tests), ischemic stroke (stroke caused by reduced blood flow to the brain), irritation or inflammation of a vein at the injection site, venous thrombosis (blood clot in a vein), low red blood cell count, atrial fibrillation (fast or irregular heartbeat), rapid heartbeat, angina (chest pain or feeling of tightness, pressure, or heaviness in the chest), itchy rash or skin swelling, hives, positive Coombs test (blood test that looks for antibodies against your red blood cells), kidney problems, kidney disease, difficulty breathing.

Additional side effects seen in children and adolescents treated for complicated infections within the abdomen and infections of the kidney and urinary tract

Common side effects(may affect up to 1 in 10 people):

Increased appetite, low white blood cell count, altered taste.

Adults treated for a lung infection called "pneumonia"

Common side effects(may affect up to 1 in 10 people):

Inflammation of the large intestine due to C. difficilebacteria, diarrhea, vomiting, increased liver enzymes (in blood tests).

Uncommon side effects(may affect up to 1 in 100 people):

C. difficileinfection, positive C. difficiletest (in stool tests), positive Coombs test (blood test that looks for antibodies against your red blood cells).

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Zerbaxa

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 after "EXP". The expiry date refers to the last day of the month shown.

Unopened vials: Store in a refrigerator (between 2°C and 8°C).

Store in the original package to protect from light.

Medicines should not be disposed of via wastewater or household waste. Disposal of unused medicine and all materials that have come into contact with it should be done in accordance with local regulations. This will help protect the environment.

6. Container Content and Additional Information

Zerbaxa Composition

• The active ingredients are ceftolozane and tazobactam.
• Each vial contains ceftolozane sulfate equivalent to 1 g of ceftolozane and sodium tazobactam equivalent to 0.5 g of tazobactam. Two vials are used for doses above 1 g of ceftolozane and 0.5 g of tazobactam.
• The other excipients are sodium chloride, arginine, and anhydrous citric acid.

Product Appearance and Container Content

Zerbaxa is a white to slightly yellow powder for concentrate for solution for infusion (powder for concentrate) presented in a vial.

Zerbaxa is available in packs containing 20 ml type I glass vials with a stopper (bromobutyl rubber) and a seal.

Packs containing 10 vials.

Marketing Authorisation Holder

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

Netherlands

Manufacturer

FAREVA Mirabel

Route de Marsat

Riom

63963, Clermont-Ferrand Cedex 9

France

You can request more information about this medicinal product by contacting the local representative of the marketing authorisation holder:

Date of Last Revision of this Leaflet:{month YYYY).

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency web site: https://www.ema.europa.eu.

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This information is intended only for healthcare professionals:

Preparation of Solutions

Each vial is for single use only.

An aseptic technique should be used to prepare the infusion solution.

Preparation of Doses

Each vial of powder for concentrate for solution for infusion is reconstituted with 10 ml of water for injections or 9 mg/ml sodium chloride solution for injections per vial; after reconstitution, the vial should be gently shaken to dissolve the powder. The final volume is approximately 11.4 ml per vial. The resulting concentration is approximately 132 mg/ml (88 mg/ml ceftolozane and 44 mg/ml tazobactam) per vial.

WARNING: THE RECONSTITUTED SOLUTION SHOULD NOT BE INJECTED DIRECTLY.

The Zerbaxa infusion solution is clear and colourless to slightly yellow.

The colour difference within this range does not affect the potency of the medicinal product.

After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 24 hours at room temperature or 4 days at a temperature of 2 to 8°C. The medicinal product is photosensitive and should be protected from light when not stored in the original packaging.

See section 4.2 of the Summary of Product Characteristics for recommended dosage guidelines for Zerbaxa according to indication and renal function. The preparation of each dose is shown below.

Instructions for Preparing Adult Doses in an INFUSION BAG:

Preparation of 2 g ceftolozane/1 g tazobactam dose: Withdraw all the contents of the two reconstituted vials (approximately 11.4 ml per vial) using a syringe and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Preparation of 1.5 g ceftolozane/0.75 g tazobactam dose: Withdraw all the contents of one reconstituted vial (approximately 11.4 ml per vial) and 5.7 ml of a second reconstituted vial using a syringe and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Preparation of 1 g ceftolozane/0.5 g tazobactam dose: Withdraw all the contents (approximately 11.4 ml) of the reconstituted vial using a syringe and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Preparation of 500 mg ceftolozane/250 mg tazobactam dose: Withdraw 5.7 ml of the contents of the reconstituted vial and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Preparation of 300 mg ceftolozane/150 mg tazobactam dose: Withdraw 3.5 ml of the contents of the reconstituted vial and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Preparation of 250 mg ceftolozane/125 mg tazobactam dose: Withdraw 2.9 ml of the contents of the reconstituted vial and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Preparation of 100 mg ceftolozane/50 mg tazobactam dose: Withdraw 1.2 ml of the contents of the reconstituted vial and add to an infusion bag containing 100 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.

Instructions for Preparing Paediatric Doses in an INFUSION BAG or INFUSION SYRINGE:

NOTE:The following procedure describes the steps to prepare 100 ml of a stock solution with a final concentration of 10 mg/ml ceftolozane / 5 mg/ml tazobactam. The volume to be administered to the paediatric patient will be based on the calculation of the appropriate dose based on the patient's weight (see section 4.2 of the Summary of Product Characteristics). Detailed steps and calculations are provided.

1. Preparation of the stock solution (100 ml of 10 mg/ml ceftolozane / 5 mg/ml tazobactam): Withdraw all the contents (approximately 11.4 ml) of the reconstituted vial using a syringe and add to an infusion bag containing 89 ml of 0.9% sodium chloride solution for injections (physiological saline solution) or 5% glucose solution for injections.
2. Preparation of the required volume of stock solution for infusion solution:
   1. Calculate the appropriate amount of Zerbaxa (in mg) to administer the required dose to the paediatric patient. Based on this dose in mg, calculate the appropriate volume of the 10 mg/ml ceftolozane / 5 mg/ml tazobactam stock solution to administer. Refer to Table 1 below to confirm calculations. Note that the table does not include all possible calculated doses but can be used to calculate the approximate volume for verification.
   2. Transfer the calculated volume of stock solution to an infusion bag or an infusion syringe of suitable size. The values shown in Table 1 are approximate and may need to be rounded to the nearest graduation mark of a suitable-sized syringe for smaller volumes.

Table 1: Preparation of Zerbaxa for Paediatric Patients (from birth* to 18 years of age) from 100 ml Stock Solution of 10 mg/ml Ceftolozane / 5 mg/ml Tazobactam

*Defined as > 32 weeks of gestational age and ≥ 7 days after birth.

**Children who weigh > 50 kg and have an eGFR > 50 ml/min/1.73 m2 should not exceed the maximum dose of 1 g ceftolozane / 0.5 g tazobactam.

From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

One of the active substances, ceftolozane, may have harmful effects if it reaches the aquatic environment. The unused medicinal product and all materials that have come into contact with it should not be disposed of via wastewater. The disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local requirements. By doing so, you will help protect the environment.