4.1. Therapeutic indications

Piperacillin/Tazobactam 2 g/0.25 g Powder for Solution for Infusion is indicated for treatment of the following infections in adults and children over 2 years of age (see sections 4.2 and 5.1):

Adults and adolescents

• Severe pneumonia including hospital-acquired and ventilator-associated pneumonia

• Complicated urinary tract infections (including pyelonephritis)

• Complicated intra-abdominal infections

• Complicated skin and soft tissue infections (including diabetic foot infections)

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with any of the infections listed above.

Piperacillin/Tazobactam may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection.

Note: Use for bacteraemia due to extended-beta-lactamase (ESBL) producing E. coli and K. pneumoniae (ceftriaxone non-susceptible), is not recommended in adult patients, see section 5.1.

Children aged 2-12 years

• Complicated intra-abdominal infections

Piperacillin/Tazobactam may be used in the management of neutropenic children with fever suspected to be due to a bacterial infection.

Consideration should be given to official guidance on the appropriate use of anti-bacterial agents.

4.2. Posology and method of administration

Posology

The dose and frequency of Piperacillin/Tazobactam depends on the severity and localisation of the infection and expected pathogens.

Adult and adolescent patients

Infections

The usual dose is 4 g piperacillin/0.5 g tazobactam given every 8 hours.

For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin/0.5 g tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe.

The following table summarises the treatment frequency and the recommended dose for adult and adolescent patients by indication or condition:

Treatment frequency

Piperacillin/Tazobactam 4 g/0.5 g

Every 6 hours

Severe pneumonia

Neutropenic adults with fever suspected to be due to a bacterial infection

Every 8 hours

Complicated urinary tract infections (including pyelonephritis)

Complicated intra-abdominal infections

Skin and soft tissue infections (including diabetic foot infections)

Patients with renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly).

Creatinine clearance (ml/min)

Piperacillin/Tazobactam (recommended dose)

> 40

No dose adjustment necessary

20-40

Maximum dose suggested: 4 g/0.5 g every 8 hours

< 20

Maximum dose suggested: 4 g/0.5 g every 12 hours

For patients on haemodialysis, one additional dose of piperacillin/tazobactam 2 g/0.25 g should be administered following each dialysis period, because haemodialysis removes 30%-50% of piperacillin in 4 hours.

Patients with hepatic impairment

No dose adjustment is necessary (see section 5.2).

Elderly patients

No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 40 ml/min.

Paediatric population (2-12 years of age)

Infections

The following table summarises the treatment frequency and the dose per body weight for paediatric patients 2-12 years of age by indication or condition.

Dose per weight and treatment frequency

Indication/condition

80 mg Piperacillin/10 mg Tazobactam per kg body weight/every 6 hours

Neutropenic children with fever suspected to be due to bacterial infections*

100 mg Piperacillin/12.5 mg Tazobactam per kg body weight/every 8 hours

Complicated intra-abdominal infections*

* Not to exceed the maximum 4 g/0.5 g per dose over 30 minutes.

Patients with renal impairment

The intravenous dose should be adjusted to the degree of actual renal impairment as follows (each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly):

Creatinine clearance

(ml/min)

Piperacillin/Tazobactam (recommended dose)

> 50

No dose adjustment necessary

≤ 50

70 mg piperacillin/8.75 mg tazobactam/kg every 8

hours

For children on haemodialysis, one additional dose of 40 mg piperacillin/5 mg tazobactam/kg should be administered following each dialysis period.

Use in children aged below 2 years

The safety and efficacy of Piperacillin/Tazobactam in children 0- 2 years of age has not been established. No data from controlled clinical studies are available.

Treatment duration

The usual duration of treatment for most indications is in the range of 5-14 days. However, the duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.

Method of administration

Piperacillin/Tazobactam 2 g/0.25 g is administered by intravenous infusion (over 30 minutes).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substances or any other penicillin-antibacterial agent.

History of acute severe allergic reaction to any other beta-lactam active substances (e.g. cephalosporin, monobactam or carbapenem).

4.4. Special warnings and precautions for use

The selection of piperacillin/tazobactam to treat an individual patient should take into account the appropriateness of using a broad-spectrum semi-synthetic penicillin based on factors such as the severity of the infection and the prevalence of resistance to other suitable antibacterial agents.

Before initiating therapy with Piperacillin/Tazobactam careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, other beta-lactam agents (e.g cephalosporins, monobactam or carbapenem) and other allergens. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins, including piperacillin/tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. Serious hypersensitivity reactions require the discontinuation of the antibiotic, and may require administration of epinephrine and other emergency measures.

Piperacillin/Tazobactam may cause severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis (see section 4.8). If patients develop a skin rash they should be monitored closely and Piperacillin/Tazobactam discontinued if lesions progress.

Antibiotic-induced pseudomembranous colitis may be manifested by severe, persistent diarrhoea which may be life-threatening. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. In these cases Piperacillin/Tazobactam, should be discontinued.

Therapy with Piperacillin/Tazobactam may result in the emergence of resistant organisms, which might cause superinfections.

Bleeding manifestations have occurred in some patients receiving beta-lactam antibiotics. These reactions sometimes have been associated with abnormalities of coagulation tests, such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.

Leukopenia and neutropenia may occur, especially during prolonged therapy, therefore, periodic assessment of haematopoietic function should be performed.

As with treatment with other penicillins, neurological complications in the form of convulsions (seizures) may occur when high doses are administered, especially in patients with impaired renal function (see section 4.8).

Hypokalaemia may occur in patients with low potassium reserves or those receiving concomitant medicinal products that may lower potassium levels; periodic electrolyte determinations may be advisable in such patients.

Haemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients treated with piperacillin/tazobactam often following treatment longer than 10 days. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, piperacillin/tazobactam treatment should be discontinued.

Renal Impairment

Due to its potential nephrotoxicity (see section 4.8), piperacillin/tazobactam should be used with care in patients with renal impairment or in hemodialysis patients. Intravenous dosages and administration intervals should be adjusted to the degree of renal function impairment (see section 4.2).

In a secondary analysis using data from a large multicenter, randomized-controlled trial when glomerular filtration rate (GFR) was examined after administration of frequently used antibiotics in critically ill patients, the use of piperacillin/tazobactam was associated with a lower rate of reversible GFR improvement compared with the other antibiotics. This secondary analysis concluded that piperacillin/tazobactam was a cause of delayed renal recovery in these patients.

Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury (see section 4.5).

Sodium content

This medicinal product contains 108 mg sodium per vial, equivalent to 5.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Non-depolarising muscle relaxants

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanisms of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising muscle relaxants could be prolonged in the presence of piperacillin.

Anticoagulants

During simultaneous administration of heparin, oral anticoagulants and other substances that may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.

Methotrexate

Piperacillin may reduce the excretion of methotrexate; therefore, serum levels of methotrexate should be monitored in patients to avoid substance toxicity.

Probenecid

As with other penicillins, concurrent administration of probenecid and piperacillin/tazobactam produces a longer half-life and lower renal clearance of piperacillin and tazobactam; however, peak plasma concentrations of either substances are unaffected.

Aminoglycosides

Piperacillin, either alone or with tazobactam, did not significantly alter the pharmacokinetics of tobramycin in subjects with normal renal function and with mild or moderate renal impairment. The pharmacokinetics of piperacillin, tazobactam, and the M1 metabolite were also not significantly altered by tobramycin administration.

The inactivation of tobramycin and gentamicin by piperacillin has been demonstrated in patients with severe renal impairment.

For information related to the administration of piperacillin/tazobactam with aminoglycosides please refer to sections 6.2 and 6.6.

Vancomycin

Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone (see section 4.4). Some of these studies have reported that the interaction is vancomycin dose dependent.

No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.

Effects on laboratory tests

Non-enzymatic methods of measuring urinary glucose may lead to false-positive results, as with other penicillins. Therefore, enzymatic urinary glucose measurement is required under Piperacillin/Tazobactam therapy.

A number of chemical urine protein measurement methods may lead to false-positive results. Protein measurement with dip sticks is not affected.

The direct Coombs test may be positive.

Bio-Rad Laboratories Platelia Aspergillus EIA tests may lead to false-positive results for patients receiving Piperacillin/Tazobactam. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.

Positive test results for the assays listed above in patients receiving Piperacillin/Tazobactam should be confirmed by other diagnostic methods.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or a limited amount of data from the use of Piperacillin/Tazobactam in pregnant women.

Studies in animals have shown developmental toxicity, but no evidence of teratogenicity, at doses that are maternally toxic (see section 5.3).

Piperacillin and tazobactam cross the placenta. Piperacillin/tazobactam should only be used during pregnancy if clearly indicated, i.e. only if the expected benefit outweighs the possible risks to the pregnant woman and foetus.

Breast-feeding

Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

Fertility

A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed.

4.8. Undesirable effects

The most commonly reported adverse reaction is diarrhoea (occurring in 1 patient out of 10).

Among the most serious adverse reactions, pseudo-membranous colitis and toxic epidermal necrolysis occur in 1 to 10 patients in 10,000. The frequencies for pancytopenia, anaphylactic shock and Stevens-Johnson syndrome cannot be estimated from the currently available data.

In the following table, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Rare

(≥ 1/10,000 to < 1/1,000)

Frequency not known (cannot be estimated from available data)

Infections and infestations

Candida infection*

Pseudo-membranous colitis

Blood and Lymphatic system disorders

Thrombocytopenia,anaemia*

Leukopenia

Agranulocytosis

Pancytopenia*, neutropenia, haemolytic anaemia*, thrombocytosis*, eosinophilia*

Immune system disorders

Anaphylactoid shock*, anaphylactic shock*, anaphylactoid reaction*, anaphylactic reaction*, hypersensitivity*

Metabolism and nutrition disorders

Hypokalaemia

Psychiatric disorders

Insomnia

Delirium*

Nervous system disorders

Headache

Seizure*

Vascular disorders

Hypotension, phlebitis, thrombophlebitis, flushing

Respiratory, thoracic and mediastinal disorders

Epistaxis

Eosinophilic pneumonia

Gastrointestinal disorders

Diarrhoea

Abdominal pain, vomiting, constipation, nausea, dyspepsia

Stomatitis

Hepatobiliary disorders

Hepatitis*, jaundice

Skin and subcutaneous tissue disorders

Rash, pruritus

Erythema multiforme*, urticaria, rash maculo-papular*

Toxic epidermal necrolysis*

Stevens-Johnson syndrome*, dermatitis exfoliative, drug reaction with eosinophilia and systemic symptoms (DRESS)*, acute generalised exanthematous pustulosis (AGEP)*, dermatitis bullous, purpura

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

Renal and urinary disorders

Renal failure, tubulointerstitial nephritis*

General disorders and administration site conditions

Pyrexia, injection site reaction

Chills

Investigations

Alanine aminotransferase increased, aspartate aminotransferase increased, protein total decreased, blood albumin decreased, Coombs direct test positive, blood creatinine increased, blood alkaline phosphatase increased, blood urea increased, activated partial thromboplastin time prolonged

Blood glucose decreased, blood bilirubin increased, prothrombin time prolonged

Bleeding time prolonged, gamma-glutamyltransferase increased

*ADR identified post marketing

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Beta-lactam antibiotic class effects

Beta-lactam antibiotics, including piperacillin tazobactam, may lead to manifestations of encephalopathy and convulsions (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced including nausea, vomiting, and diarrhoea, have also been reported with the usual recommended dose. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Treatment

In the event of an overdose, piperacillin/tazobactam treatment should be discontinued.

No specific antidote is known.

Treatment should be supportive and symptomatic according to the patient's clinical presentation.

Excessive serum concentrations of either piperacillin or tazobactam may be reduced by haemodialysis (see section 4.4).