Patient Information Leaflet

EXBLIFEP 2 g/0.5 g powder for concentrate for solution for infusion

cefepime/enmetazobactam

This medicine is subject to additional monitoring, which will speed up the detection of any new information about its safety. You can contribute by reporting any side effects you may experience. The final part of section 4 includes information on how to report these side effects.

Read this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor or nurse.
• If you experience side effects, consult your doctor or nurse, even if they are not listed in this leaflet. See section 4.

EXBLIFEP is an antibiotic, which contains two active principles:

• cefepima, which belongs to a group of antibiotics called fourth-generation cephalosporins and can destroy certain bacteria;
• enmetazobactam, which blocks the action of certain enzymes called beta-lactamases. These enzymes make bacteria resistant to cefepima, breaking down the antibiotic before it can exert its action. By blocking the action of beta-lactamases, enmetazobactam achieves that cefepima is more effective in destroying bacteria.

EXBLIFEP is used in adults for the treatment of:

• complicated severe urinary tract infections (bladder and kidneys)
• specific types of pneumonia (a lung infection) that occur during hospital stay

EXBLIFEP is also used to treat bacteremia (the presence of bacteria in the blood) due to or possibly due to one of the infections listed above.

Do not use EXBLIFEP:

• if you are allergic to cefepime, metazobactam, or any of the other components of this medication (listed in section 6).
• if you are allergic to cephalosporins, which are antibiotics used to treat a wide variety of infections.
• 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 beta-lactam antibiotics (such as penicillins, carbapenems, or monobactams).

Warnings and precautions

Consult your doctor or pharmacistbeforestarting to use EXBLIFEP, if:

• you are allergic to cephalosporins, penicillins, or other antibiotics (see “Do not use Exblifep”).
• you have or have had asthma or are prone to allergic reactions. The first time you are administered this medication, your doctor will monitor you for any signs of an allergic reaction (see section 4).
• you have kidney problems. Your doctor may need to change the dose of this medication.
• you need to have a blood or urine test. This medication may affect the results of some tests (see section 4).

Consult your doctor or pharmacistwhileusing EXBLIFEP, if:

• you have acute and persistent diarrhea during treatment or shortly after it. This could be a condition of intestinal inflammation that requires immediate medical intervention.
• you suspect that you have acquired an infection during prolonged use of EXBLIFEP. This could be due to microorganisms that are not sensitive to cefepime and may require discontinuation of treatment with Exblifep.

Children and adolescents

This medication should not be administered to children under 18 years of age because there is not enough information available about its use in this age group.

Other medications and EXBLIFEP

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

Specifically, inform your doctor if you are using any of the following medications:

• other antibiotics, especially aminoglycosides (such as gentamicin) or diuretics (such as furosemide). If you are using these medications, your doctor will need to monitor your kidney function.
• medications used to prevent blood clotting (anticoagulant coumarins, such as warfarin). The effect of these medications may be increased if you use Exblifep.
• certain types of antibiotics (bacteriostatic antibiotics). These antibiotics may affect the functioning of EXBLIFEP.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor before using this medication.

Your doctor will inform you if you can receive EXBLIFEP during pregnancy.

Exblifep may be excreted in breast milk. If you are breastfeeding, your doctor will inform you if you should stop breastfeeding or not use the treatment with EXBLIFEP, taking into account the benefits of breastfeeding for your child and the benefits of treatment for you.

Driving and operating machinery

This medication may cause dizziness, which may affect your ability to drive and operate machinery. Do not drive or use machinery until this effect has disappeared.

Your doctor or another healthcare professional will administer this medication through an infusion (IV) into a vein (directly into the bloodstream). Depending on the type of infection you have and your kidney function, the infusion will be administered for two or four hours.

The recommended dose is one vial (2 g of cefepime and 0.5 g of metazamide) every 8 hours.

Treatment usually lasts between 7 and 14 days, depending on the severity, location of the infection, and how your body responds to treatment.

If you have any kidney problems, your doctor may need to reduce the dose or modify the frequency at which EXBLIFEP is administered (see section 2. Warnings and precautions).

If you use more EXBLIFEP than you should

Since this medication will be administered by a doctor or another healthcare professional, it is unlikely that you will receive too much EXBLIFEP. However, if you have any doubts or concerns, inform your doctor, nurse, or pharmacist.

If you forgot to use EXBLIFEP

If you think you have not received a dose of EXBLIFEP, inform your doctor or another healthcare professional immediately.

If you have any other questions about using this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor immediately if you experience any of the following side effects because you may need urgent medical treatment:

Rare: may affect up to 1 in 1,000 people

• anaphylactic (allergic) and angioedema reaction. This reaction can be potentially fatal.

The signs and symptoms may be a sudden swelling of the lips, face, throat, or tongue, a severe rash, and difficulty swallowing or breathing.

Unknown frequency: the frequency cannot be estimated from the available data

• Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe and very intense skin reactions. The skin adverse reaction may present as a rash, accompanied or not by blisters. It may appear as skin irritation, sores, or inflammation in the mouth, throat, eyes, nose, and genital areas, as well as fever and flu-like symptoms. Skin rashes can become severe skin lesions of great extent (peeling of the epidermis and superficial mucous membranes) that can have potentially fatal consequences.

Other side effects

The other side effects that may appear after Exblifep treatment include the following:

Very common: may affect more than 1 in 10 people

Side effects identified through blood tests:

• positive Coombs test (a blood test to check for antibodies that attack red blood cells produced by the body)

Common: may affect up to 1 in 10 people

• phlebitis at the infusion site (inflammation at the infusion site that causes pain, swelling, and redness along a vein)
• reaction, pain, and inflammation at the infusion site
• diarrhea
• skin rash
• headache

Side effects identified through blood tests:

• increased concentrations of liver enzymes in the blood
• increased concentrations of bilirubin (a substance produced by the liver) in the blood
• increased concentrations of amylase (an enzyme that helps the body digest carbohydrates) in the blood
• increased concentrations of lipase (an enzyme that helps the body digest fats) in the blood
• increased concentrations of lactate dehydrogenase (a marker that indicates cellular and tissue damage in the body) in the blood
• changes in white blood cell counts (eosinophilia)
• low red blood cell counts (anemia)
• increased blood coagulation time (increased time for blood to clot)

Uncommon: may affect up to 1 in 100 people

• diarrhea associated withClostridioides difficile(DACD), a painful and intense diarrhea caused by a bacterium calledClostridioides difficile
• oral fungal infection
• vaginal infection
• inflammation of the large intestine that causes diarrhea, usually accompanied by blood and mucous
• dizziness, nausea, vomiting
• skin redness, hives, itching
• fever
• inflammation at the infusion site

Side effects identified through blood tests:

• low concentrations of certain blood cells (leucopenia, neutropenia, thrombocytopenia)
• increased concentrations of urea and creatinine (parameters that indicate a reduction in kidney function) in the blood

Rare: may affect up to 1 in 1,000 people

• difficulty breathing
• stomach pain, constipation
• fungus infection
• seizures (epileptic crises)
• alteration of taste
• sensation of tingling or numbness of the skin, muscle cramps
• itching around the vaginal area
• allergic dermatitis
• chills
• dilation of blood vessels in the body

Unknown frequency: the frequency cannot be estimated from the available data

• coma
• reduction of consciousness level
• encephalopathy (a cerebral disorder caused by harmful substances or an infection)
• altered state of consciousness
• muscle spasms

• confusion, hallucinations
• false positive glucose test in urine
• kidney problems (failure or any other physiological or functional change)
• hemorrhage
• erythema multiforme (a skin rash that can form blisters and appears as small dots (a central dark spot, surrounded by a lighter area, with a dark ring around the edge)

Side effects identified through blood tests:

• very low concentrations of granulocytes, which is a type of white blood cell (agranulocytosis)
• very rapid disintegration of red blood cells (hemolytic anemia)
• low red blood cell counts caused by the inability of the bone marrow to produce enough cells (aplastic anemia)

Reporting of side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the national notification system included in theAnexo V. By reporting side effects, you can contribute to providing more information about the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the box and vial after "CAD". The expiration date is the last day of the month indicated.

Unopened vial: Store in refrigerator (between 2 °C and 8 °C). Store the vial in the outer packaging to protect it from light.

After reconstitution and dilution: Store in refrigerator (between 2 °C and 8 °C) for a maximum period of 6 hours before use.

From a microbiological point of view, the medication should be used immediately after reconstitution.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. In this way, you will help protect the environment.

Composition of EXBLIFEP

• The active principles are cefepime and metazobactam.
• Each vial contains cefepime dihydrochloride monohydrate, equivalent to 2 g of cefepime and 0.5 g of metazobactam.
• The other components are L-arginine.

Appearance of the product and contents of the container

EXBLIFEP is a white to yellow powder for concentrate for solution for infusion (powder for concentrate) contained in glass vials of 20 ml, with bromobutyl rubber stopper and flip-off safety cap.

Container size: 10 vials.

Marketing Authorization Holder

Advanz Pharma Limited

Unit 17 Northwood House

Northwood Crescent

Dublin 9

D09 V504

Ireland

(+44) (0)208.588.9131

[email protected]

Responsible Person

Infosaúde - Instituto De Formação E Inovação Em Saúde S.A.

Rua Das Ferrarias Del Rei,

nº6 - Urbanização da Fábrica da Pólvora,

Barcarena,

2730-269,

Portugal

Last update date of this leaflet:

Other sources of information

The detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu.

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This information is intended solely for healthcare professionals:

Preparation of the solution

This medicine is for intravenous infusion, and each vial is exclusively for single use.

To prepare the infusion solution, aseptic techniques must be followed.

Preparation of the doses

Cefepime/metazobactam is compatible with 9 mg/ml sodium chloride injection solution, 5% glucose injection solution, and a combination of 5% glucose injection solution and 0.45% sodium chloride injection solution (containing 2.5% glucose and 0.45% sodium chloride).

EXBLIFEP is supplied as a dry powder contained in the interior of a single-dose vial that must be reconstituted and, subsequently, diluted before intravenous infusion, as indicated below.

To prepare the necessary dose for intravenous infusion, reconstitute the vial as indicated in theTable 1below:

1. Extract 10 ml from a 250 ml infusion bag (compatible with the injection solution) and reconstitute the cefepime/metazobactam vial.
2. Mix gently to dissolve. The reconstituted cefepime/metazobactam solution will have an approximate concentration of 0.20 g/ml cefepime and an approximate concentration of 0.05 g/ml metazobactam. The final volume is approximately 10 ml.

WARNING: THE RECONSTITUTED SOLUTION IS NOT INTENDED FOR DIRECT INJECTION.

Subsequently, the reconstituted solution must be dilutedimmediatelyin a 250 ml infusion bag (compatible with the injection solution) before intravenous infusion. To dilute the reconstituted solution, extract all or part of the contents of the reconstituted vial and return it to the infusion bag, according to theTable 1below.

1. The intravenous infusion of the diluted solution must be completed within 8 hours if it is stored in the refrigerator (i.e., between 2°C and 8°C; when refrigerated for less than 6 hours, before allowing it to reach room temperature and, subsequently, administering it at room temperature for a period of 2 or 4 hours).

Table 1. Preparation of cefepime/metazobactam doses

Examine the vial before use. Only use if the solution does not contain particulate matter in suspension. Use only clear solutions.

Like other cephalosporins, cefepime/metazobactam solutions may acquire a yellowish to amber color, depending on storage conditions. However, this does not negatively affect the product's effect.

The prepared solution must be administered by intravenous infusion.

The elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.