Piperacillin/tazobactam Tillomed

Package leaflet: Information for the user

Piperacillin/Tazobactam Tillomed 2 g/0.25 g powder for solution for infusion, 4 g/0.5 g powder for solution for infusion

Generic medicine
Read 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 questions, ask your doctor, pharmacist or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

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

1. What Piperacillin/Tazobactam Tillomed is and what it is used for

Piperacillin/Tazobactam Tillomed contains the active substances piperacillin and tazobactam.
Piperacillin belongs to a group of medicines known as "broad-spectrum penicillin antibiotics". It is capable of killing many types of bacteria. Tazobactam can prevent certain resistant bacteria from surviving the effects of piperacillin. This means that when piperacillin and tazobactam are administered together, they can kill a greater number of bacterial types.
Piperacillin/Tazobactam Tillomed is used in adults and adolescents for the treatment of bacterial infections, such as those affecting the lower respiratory tract (lungs), urinary tract (kidneys and bladder), abdomen, skin or blood. Piperacillin/Tazobactam Tillomed may be used to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).
Piperacillin/Tazobactam Tillomed is used in children aged between 2 and 12 years for the treatment of abdominal infections, such as appendicitis, peritonitis (infection of the fluid and lining of abdominal organs), and gallbladder (biliary) infections.
Piperacillin/Tazobactam Tillomed may be used to treat bacterial infections in patients with low white blood cell counts (reduced resistance to infections).
In certain severe infections, the doctor may consider using Piperacillin/Tazobactam Tillomed in combination with other antibiotics.

2. What you need to know before using Piperacillin/Tazobactam Tillomed

Do not use Piperacillin/Tazobactam Tillomed:

• If you are allergic to sodium piperacillin or sodium tazobactam.
• If you are allergic to antibiotics known as penicillins, cephalosporins, or other beta-lactamase inhibitors, as you may also be allergic to piperacillin/tazobactam.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Piperacillin/Tazobactam Tillomed.

• If you have allergies. If you suffer from multiple allergies, inform your doctor or healthcare provider before receiving this medicine.
• If you have diarrhoea before treatment or develop diarrhoea during or after treatment. In this case, you must inform your doctor or healthcare provider immediately. Do not take anti-diarrhoeal medicines without first consulting your doctor.
• If you are taking another antibiotic called vancomycin. Taking Piperacillin/Tazobactam Tillomed together with vancomycin may increase the risk of kidney damage (see also section “Other medicines and Piperacillin/Tazobactam Tillomed” in this leaflet).
• If you have low levels of potassium in your blood. Your doctor will need to check your kidney function before administering this medicine and may perform periodic blood tests during treatment.
• If you have kidney or liver problems or are undergoing haemodialysis. Your doctor may wish to monitor your kidney function before administering this medicine and may carry out regular blood tests during treatment.
• If you are taking certain medicines (called anticoagulants) to prevent excessive blood clotting (see also section “Other medicines and Piperacillin/Tazobactam Tillomed”), or if unexpected bleeding occurs during treatment. In this case, you must inform your doctor or healthcare provider immediately.
• If you develop seizures during treatment. In this case, you must inform your doctor or healthcare provider immediately.
• If you suspect you have developed a new infection or if your infection worsens. In this case, you must inform your doctor or healthcare provider immediately.

Haemophagocytic lymphohistiocytosis
Cases of a condition in which the immune system produces abnormally high numbers of white blood cells called histiocytes and lymphocytes, leading to inflammation (haemophagocytic lymphohistiocytosis), have been reported. This condition can be life-threatening if not diagnosed and treated early. If you develop several symptoms such as fever, swollen lymph nodes, feeling of weakness, mental confusion, shortness of breath, bruising, or skin rash, contact your doctor immediately.

Children
The use of Piperacillin/Tazobactam Tillomed is not recommended in children under 2 years of age due to insufficient data on safety and efficacy.

Other medicines and Piperacillin/Tazobactam Tillomed
Tell your doctor, pharmacist, or healthcare provider if you are taking, have recently taken, or might take any other medicines, including those without a prescription. Some medicines may interact with piperacillin and tazobactam.

These include:

• Medicines for gout (probenecid), which may increase the time required for elimination of piperacillin and tazobactam from the body;
• Medicines to thin the blood or treat blood clots (e.g. heparin, warfarin, or aspirin);
• Medicines used to relax muscles during surgery. Inform your doctor if you are undergoing general anaesthesia;
• Methotrexate (a medicine used to treat cancer, arthritis, or psoriasis). Piperacillin and tazobactam may increase the time required for elimination of methotrexate from the body;
• Medicines that may reduce potassium levels in the blood (e.g. tablets that increase urine production or certain anticancer medicines);
• Medicines containing other antibiotics such as tobramycin, gentamicin, or vancomycin. Inform your doctor if you have kidney problems. Taking Piperacillin/Tazobactam Tillomed and vancomycin at the same time may increase the risk of kidney damage, even if you do not have kidney problems.

Effect on laboratory test results
Inform your doctor or laboratory staff that you are taking piperacillin/tazobactam if you need to provide a blood or urine sample.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or healthcare provider before using this medicine. Your doctor will decide whether piperacillin/tazobactam is appropriate for you.
Piperacillin and tazobactam may pass to the unborn child through the placenta or to the infant through breast milk. If you are breastfeeding, your doctor will decide whether piperacillin/tazobactam is suitable for you.

Driving and using machines
Piperacillin/tazobactam is not expected to affect the ability to drive vehicles or operate machinery.

Piperacillin/Tazobactam Tillomed contains sodium
Piperacillin/Tazobactam 2 g/0.25 g
This medicine contains 108.05 mg of sodium (the main component of table salt) per vial. This corresponds to 5.4% of the maximum daily dietary intake recommended for an adult.
Piperacillin/Tazobactam 4 g/0.5 g
This medicine contains 215.88 mg of sodium (the main component of table salt) per vial. This corresponds to 10.79% of the maximum daily dietary intake recommended for an adult.
This should be taken into account if you are on a low-sodium diet.

3. How to use Piperacillin/Tazobactam Tillomed

This medicine will be administered to you by infusion (an intravenous drip for at least 30 minutes) by a doctor or healthcare professional.
Dosage
The dose of medicine given depends on the reason for treatment, your age, and whether or not you have kidney problems.

Adults and adolescents over 12 years of age
The usual dose is 4 g/0.5 g of piperacillin/tazobactam every 6–8 hours, administered into a vein (directly into the bloodstream).

Children aged 2 to 12 years
The usual dose for children with abdominal infections is 100 mg/12.5 mg per kg of body weight of piperacillin/tazobactam every 8 hours, administered into a vein (directly into the bloodstream).
The usual dose for children with low white blood cell counts is 80 mg/10 mg per kg of body weight of piperacillin/tazobactam every 6 hours, administered into a vein (directly into the bloodstream).
The doctor will calculate the dose based on the child's body weight; however, no single dose will exceed 4 g/0.5 g of piperacillin/tazobactam.

Piperacillin/tazobactam will be administered to you until all signs of infection have completely disappeared (5–14 days).

Patients with kidney problems
Your doctor may need to reduce the dose of Piperacillin/Tazobactam Tillomed or the frequency of administration. Your doctor may also perform blood tests to ensure that the prescribed dose is appropriate, especially if you are to receive this medicine for a prolonged period.

If you receive more Piperacillin/Tazobactam Tillomed than you should
Since Piperacillin/Tazobactam Tillomed will be administered by a doctor or healthcare professional, it is unlikely that you will receive an incorrect dose. However, if you experience side effects such as seizures, or if you think you have been given too high a dose, inform your doctor immediately.

If you miss a dose of Piperacillin/Tazobactam Tillomed
If you think a dose of Piperacillin/Tazobactam Tillomed has not been administered, inform your doctor or healthcare professional immediately.

If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Contact a doctor immediately if you experience any of the following potentially serious side effects of piperacillin/tazobactam.
The serious side effects (with frequency indicated in brackets) of piperacillin/tazobactam are:

• severe skin reactions [Stevens-Johnson syndrome, bullous dermatitis (Not known), exfoliative dermatitis (Not known), toxic epidermal necrolysis (Rare), which initially present as red spots or circular raised areas often with central blisters on the trunk. Further symptoms include ulcers in the mouth, throat, nose, extremities, genitals and conjunctivitis (red and swollen eyes). The rash may progress to widespread blistering or peeling of the skin, which can potentially be life-threatening
• severe, potentially fatal allergic condition (drug reaction with eosinophilia and systemic symptoms), which may affect the skin and, particularly, other organs beneath the skin, such as the kidneys and liver
• a skin condition (acute generalized exanthematous pustulosis) accompanied by fever, characterised by numerous small fluid-filled blisters appearing within large areas of swollen and reddened skin
• swelling of the face, lips, tongue and other body parts (Not known)
• shortness of breath, wheezing or difficulty breathing (Not known)
• severe rash or hives (Uncommon), itching or skin rash (Common)
• yellowing of the eyes and skin (Not known)
• damage to blood cells [signs include: unexpected breathlessness, red or brown urine (Not known), nosebleeds (Rare), and small bruises (Not known)], severe reduction in white blood cells (Rare)
• severe or persistent diarrhoea accompanied by fever or weakness (Rare)

If any of the following side effects become severe, or if you notice any side effects not listed in this leaflet, inform your doctor or other healthcare professional.

Very common side effects (may affect more than 1 in 10 people):

• diarrhoea

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

• fungal infections
• reduction in platelets, reduction in red blood cells or blood pigment/hemoglobin, abnormal laboratory tests (positive direct Coombs test), prolonged blood clotting time (prolonged activated partial thromboplastin time)
• decreased blood proteins
• headache, insomnia
• abdominal pain, vomiting, nausea, constipation, stomach discomfort
• increased liver enzymes in blood
• rash, itching
• abnormal blood tests for kidney function
• fever, injection site reaction

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

• reduction in white blood cells (leucopenia), prolonged clotting time (prolonged prothrombin time)
• decreased potassium in blood, decreased blood sugar
• seizures (convulsions), observed in patients treated with high doses or with kidney problems
• low blood pressure, inflammation of veins (felt as tenderness or redness in the affected area), skin redness
• increase in a breakdown product of blood pigments (bilirubin)
• skin reactions with redness, skin lesion formation, hives
• joint and muscle pain
• chills

Rare side effects (may affect up to 1 in 1,000 people):

• severe reduction in white blood cells (agranulocytosis), nosebleeds
• severe colon infection, inflammation of the mucous membrane in the mouth
• detachment of the upper layer of skin over the entire body (toxic epidermal necrolysis)

Side effects with unknown frequency (frequency cannot be estimated from available data):

• severe reduction in red blood cells, white blood cells and platelets (pancytopenia), reduction in white blood cells (neutropenia), reduction in red blood cells due to breakdown or premature destruction, appearance of bruises with small spots, prolonged bleeding time, increased platelets, increase in a specific type of white blood cell (eosinophilia)
• allergic reaction and severe allergic reaction
• liver inflammation, yellowing of the skin or whites of the eyes
• severe, widespread allergic reaction affecting the whole body, with skin rash and blisters (Stevens-Johnson syndrome), severe allergic condition involving both the skin and other organs such as the kidneys and liver (drug reaction with eosinophilia and systemic symptoms), numerous small fluid-filled blisters appearing within large areas of swollen and reddened skin, accompanied by fever (acute generalized exanthematous pustulosis), skin reactions with blisters (bullous dermatitis)
• reduced kidney function and kidney problems
• a form of lung disease in which eosinophils (a type of white blood cell) appear in increased numbers in the lung
• acute disorientation and confusion (delirium)

Treatment with piperacillin has been associated with an increased incidence of fever and skin rash in patients with cystic fibrosis.
Beta-lactam antibiotics, including piperacillin-tazobactam, may lead to manifestations of encephalopathy and seizures.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Piperacillin/Tazobactam Tillomed

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the
packaging following "Exp". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Reconstituted/diluted infusion solution
Chemical and physical in-use stability has been demonstrated for 12 hours at 25°C and 48 hours at 2-8°C.
From a microbiological standpoint, the product should be used immediately. If not used
immediately, the duration and conditions of in-use storage are the responsibility of the user and normally should not exceed 24 hours at 2-8°C, unless reconstitution/dilution has taken place under controlled and validated aseptic conditions.
Vials must not be frozen after reconstitution.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Piperacillin/Tazobactam Tillomed contains
Piperacillin/Tazobactam 2 g/0.25 g

• The active substances are piperacillin and tazobactam. Each vial contains 2 g of piperacillin (as sodium piperacillin) and 0.25 g of tazobactam (as sodium tazobactam).
• There are no other ingredients.

Piperacillin/Tazobactam 4 g/0.5 g

• The active substances are piperacillin and tazobactam. Each vial contains 4 g of piperacillin (as sodium piperacillin) and 0.5 g of tazobactam (as sodium tazobactam).
• There are no other ingredients.

Description of the appearance of Piperacillin/Tazobactam Tillomed and contents of the pack
Piperacillin/Tazobactam 2 g/0.25 g
This medicinal product is a white to off-white powder for solution for infusion.
The medicine is available in 30 ml Type I glass vials with a bromobutyl rubber stopper and a grey plastic and aluminium flip-off cap.
Pack sizes: 1 or 10 vials.

Piperacillin/Tazobactam 4 g/0.5 g
This medicinal product is a white to off-white powder for solution for infusion.
The medicine is available in 50 ml Type I glass vials with a bromobutyl rubber stopper and a blue plastic and aluminium flip-off cap.
Pack sizes: 1 or 10 vials.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Tillomed Italia s.r.l.
Viale Giulio Richard 1, Torre A
20143 Milano (MI), Italy

Manufacturer
KYMOS, S.L.
Ronda de Can Fatjó, 7B (Parque Tecnológico del Vallès),
Cerdanyola del Vallès, 08290, Barcelona, Spain
Pharmadox Healthcare Ltd.
KW20A Kordin Industrial Park
Paola PLA 3000, Malta
Tillomed Malta Limited,
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta

This medicinal product has been authorised in the Member States of the European Economic Area under the following names:

Germany
Piperacillin/Tazobactam Tillomed 2 g/0.25 g Powder for solution for infusion
Piperacillin/Tazobactam Tillomed 4 g/0.5 g Powder for solution for infusion

France
Piperacilline/Tazobactam Tillomed 2 g/0.25 g, poudre pour solution pour perfusion
Piperacilline/Tazobactam Tillomed 4 g/0.5 g, poudre pour solution pour perfusion

Italy
Piperacillina/Tazobactam Tillomed

Netherlands
Piperacilline/Tazobactam Tillomed 2 g/0.25 g poeder voor oplossing voor infusie
Piperacilline/Tazobactam Tillomed 4 g/0.5 g poeder voor oplossing voor infusie

Spain
Piperacilina/Tazobactam Tillomed 2 g/0.25 g polvo para solución para perfusión de EFG
Piperacilina/Tazobactam Tillomed 4 g/0.5 g polvo para solución para perfusión de EFG

The following information is intended exclusively for healthcare professionals

Instructions for use

Piperacillin/Tazobactam Tillomed is administered by intravenous infusion (an intravenous infusion over 30 minutes).
Instructions for reconstitution and dilution
Reconstitute each vial with the volume of solvent indicated in the table below, using one of the compatible solvents for reconstitution. Shake until dissolved. Under constant agitation, reconstitution should be completed within 5–10 minutes (for details on handling, see below).
*Compatible solvents for reconstitution:

• Sodium chloride 9 mg/ml (0.9%) solution for injection
• Sterile water for injections
• Glucose 50 mg/ml (5%) solution for injection
  The maximum recommended volume of sterile water for injections per dose is 50 ml.

The reconstituted solutions must be withdrawn from the vial using a syringe. When reconstituted as indicated, the vial contents withdrawn with a syringe will provide the amount of piperacillin and tazobactam stated on the label.
The reconstituted solution may be further diluted to the desired volume (e.g. 50–150 ml) with one of the following compatible diluents:

• Sodium chloride 9 mg/ml (0.9%) solution for injection
• Glucose 50 mg/ml (5%)
• Dextran 60 mg/ml (6%) in sodium chloride 9 mg/ml (0.9%)

Incompatibilities
When Piperacillin/Tazobactam Tillomed is used concomitantly with another antibiotic (e.g. aminoglycosides), the substances must be administered separately. Mixing beta-lactam antibiotics with aminoglycosides in vitro may cause substantial inactivation of the aminoglycoside.
Piperacillin/Tazobactam Tillomed must not be mixed with other substances in a syringe or in an infusion vial, as compatibility has not been demonstrated.
Due to chemical instability, the piperacillin/tazobactam combination must not be used in solutions containing only sodium bicarbonate.
Piperacillin/Tazobactam Tillomed must not be added to blood derivatives or hydrolysed albumins.
Piperacillin/Tazobactam Tillomed must not be used with Ringer's lactate solutions, Ringer's acetate solutions, Ringer's acetate/maleate solutions, or Hartmann's solution.