4.4 Special warnings and precautions for use

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.

4.8 Undesirable effects

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* Coombs direct test positive, activated partial thromboplastin time prolonged	leukopenia prothrombin time prolonged	agranulocytosis epistaxis	pancytopenia*, neutropenia, purpura, bleeding time prolonged,  haemolytic anaemia*, eosinophilia thrombocytosis*, eosinophilia,*
Immune system disorders					anaphylactoid reaction*, anaphylactic reaction*, anaphylactoid shock*, anaphylactic shock*, anaphylactoid reaction*, anaphylactic reaction*, hypersensitivity*
Metabolism and nutrition disorders		blood albumin decreased, protein total decreased	hypokalaemia blood glucose decreased
Psychiatric disorders		insomnia
Nervous system disorders		headache insomnia
Vascular disorders			hypotension, phlebitis, thrombophlebitis,  phlebitisflushing
Respiratory, thoracic and mediastinal disorders				epistaxis	eosinophilic pneumonia
Gastrointestinal disorders	diarrhoea	abdominal pain, vomiting, nausea, constipation, nausea, dyspepsia		pseudo-membranous colitis, stomatitis
Hepatobiliary disorders		alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased	blood bilirubin increased		hepatitis*, jaundice gamma-glutamyl-transferase increased
Skin and subcutaneous tissue disorders		rash, pruritus	erythema multiforme*, urticaria, rash maculopapular*	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		blood creatinine increased, blood urea increased			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

6.6 Special precautions for disposal and other handling

The reconstitution and dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discolouration prior to administration. The solution should only be used if the solution is clear and free from particles.
Intravenous use
Each injection vial of Piperacillin Tazobactam needs to be reconstituted by adding 50 ml to 150 ml of one of the following solutions:
• Sterile water for injection
• 0,9% (9 mg/ml) sodium chloride solution for injection
• Glucose 5%
In a first step, add the volume of solution indicated in the table below to each injection vial:

Content of the vial	Volume of solution to be added to the vial
2 g/0.25 g (2 g piperacillin and 0.25 g tazobactam)	10 ml
4 g/0.5 g (4 g piperacillin and 0.5 g tazobactam)	20 ml

Shake strongly the medicinal product during 1 to 2 minutes. The reconstituted solutions may be further diluted to the desired volume (e.g. 50 ml to 150 ml) with the same solvents. and following this step, add the same solution to make total volume to 50 ml.

Shake strongly the medicinal product again until it is completely dissolved.

10. DATE OF REVISION OF THE TEXT

December 2016July 2017

 

 

 

 

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. cephalosporin, 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.

Therapy with 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 generalised exanthematous pustulosis Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving piperacillin/tazobactam (see section 4.8).  If patients develop a skin rash they should be monitored closely and piperacillin/tazobactam discontinued if lesions progress.

4.5 Interaction with other medicinal products and other forms of interaction

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

However, a limited number of retrospective studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin / tazobactam and vancomycin as compared to vancomycin alone.

4.8 Undesirable effects

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		Candidiasiscandida infection*
Blood and lymphatic system disorders		thrombocytopenia, anaemia*, Coombs direct test positive, activated partial thromboplastin time prolonged	leukopenia, prothrombin time prolonged	agranulocytosis, epistaxis	pancytopenia*, neutropenia, purpura, bleeding time prolonged, haemolytic anaemia*, eosinophilia, thrombocytosis*
Immune system disorders					anaphylactoid reaction*, anaphylactic reaction*, anaphylactoid shock*, anaphylactic shock*, hypersensitivity*
Metabolism and nutrition disorders		blood albumin decreased, protein total decreased	hypokalaemia, blood glucose decreased
Nervous system disorders		headache, insomnia
Vascular disorders			hypotension, thrombophlebitis, phlebitis, flushing
Gastrointestinal disorders	diarrhoea	abdominal pain, vomiting, nausea, constipation, dyspepsia		pseudo-membranous colitis, stomatitis
Hepatobiliary disorders		alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased	blood bilirubin increased		hepatitis*, jaundice, gamma-glutamyl-transferase increased
Skin and subcutaneous tissue disorders		rash, pruritus	erythema multiforme*, urticaria, rash maculopapular*	toxic epidermal necrolysis*	Stevens-Johnson syndrome*,drug reaction with eosinophilia and systemic symptoms (DRESS)*, acute generalised exanthematous pustulosis (AGEP)*, dermatitis bullous
Musculoskeletal and connective tissue disorders			arthralgia, myalgia
Renal and urinary disorders		blood creatinine increased, blood urea increased			renal failure, tubulointerstitial nephritis*
General disorders and administration site conditions		pyrexia, injection-site reaction	chills

* ADR identified post marketing

4.2 Posology and method of administration

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

4.3 Contraindications

Hypersensitivity to the active substances, or any other penicillin-antibacterial agent or to any of the excipients listed in section 6.1.
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. cephalosporin, 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.

Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving piperacillin/tazobactam (see section 4.8).  If patients develop a skin rash they should be monitored closely and piperacillin/tazobactam discontinued if lesions progress.

4.8 Undesirable effects

The most commonly reported adverse reaction is diarrhoea (occurring in 1 patient out of 10)The most commonly reported adverse reactions (occurring in 1 to 10 patients in 100) are diarrhoea, vomiting, nausea and rash.

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.

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				candidiasis					candidal superinfection
Blood and lymphatic system disorders		thrombocytopenia, anaemia, Coombs direct test positive, activated partial thromboplastin time prolonged			leukopenia,   neutropenia, thrombocytopeniaprothrombin time prolonged		anaemia, haemolytic anaemia, purpura     agranulocytosis, epistaxis, bleeding time prolonged, eosinophilia			pancytopenia, neutropenia, purpura, bleeding time prolonged, haemolytic anaemia, eosinophilia, thrombocytosis

Immune system disorders		hypersensitivity			anaphylactic/ anaphylactoid reaction (including shock)			anaphylactoid reaction, anaphylactic reaction, anaphylactoid shock, anaphylactic shock, hypersensitivity
Metabolism and nutrition disorders			blood albumin decreased, protein total decreased				hypokalaemia, blood glucose decreased
Nervous system disorders			headache, insomnia				headache, insomnia
Vascular disorders			hypotension, thrombophlebitis, phlebitis   , flushing				flushing
Gastrointestinal disorders	diarrhoea			diarrhoea,     abdominal pain, vomiting, nausea, constipation, dyspepsia		jaundice, stomatitis, constipation, dyspepsia			pseudo-membranous colitis,   abdominal painstomatitis
Hepatobiliary disorders	alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased			alanine aminotransferase increased, aspartate aminotransferase increased     blood bilirubin increased		hepatitis, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltrans-ferase increased			hepatitis, jaundice, gamma-glutamyl-transferase increased
Skin and subcutaneous tissue disorders	rash,   pruritusincluding maculopapular rash			erythema multiforme,     urticaria, rash maculopapularpruritus		toxic epidermal necrolysis     erythema multiforme, dermatitis bullous, exanthema			Stevens-Johnson syndrome, dermatitis bullous
Musculoskeletal and connective tissue disorders			arthralgia, myalgia				arthralgia, myalgia
Renal and urinary disorders	blood creatinine increased, blood urea increased			blood creatinine increased		renal failure, tubulointerstitial nephritis			renal failure, tubulointerstitial nephritis
General disorders and administration site conditions		pyrexia, injection-site reaction			pyrexia, injection-site reaction     chills			chills

5.2 Pharmacokinetic properties

Elderly patients
The mean half-life for piperacillin and tazobactam were 32% and 55% longer, respectively, in the elderly compared with younger subjects. This difference may be due to age-related changes in creatinine clearance.

6.6 Special precautions for disposal and other handling

The reconstitution and dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discolouration prior to administration. The solution should only be used if the solution is clear and free from particles.

Intravenous use

Each injection vial of Piperacillin Tazobactam <Product Name> needs to be reconstituted by adding 50 ml of one of the following solutions:

• Sterile water for injection
• 0,9% (9 mg/ml) sodium chloride solution for injection
• Glucose 5%

In a first step, add the volume of solution indicated in the table below to each injection vial:

Reconstitute each vial with the volume of solvent shown in the table below, using one of the compatible solvents for reconstitution. Swirl until dissolved. When swirled constantly, reconstitution generally occurs within 2 to 3 minutes (for details on handling, please see below).

Content of the vial	Volume of solvent* solution to be added to the vial
2 g/0.25 g (2 g piperacillin and 0.25 g tazobactam)	10 ml
4 g/0.5 g (4 g piperacillin and 0.5 g tazobactam)	20 ml

* Compatible solvents for reconstitution:
- 0.9% (9 mg/ml) sodium chloride solution for injection
- Sterile water for injections(1)
- Glucose 5%
(1) Maximum recommended volume of sterile water for injection per dose is 50 ml.

Shake strongly the medicinal product during 1 to 2 minutes and following this step, add the same solution to make total volume to 50 ml.

Shake strongly the medicinal product again until it is completely dissolved.

The reconstituted solutions should be withdrawn from the vial by syringe. When reconstituted as directed, the vial contents withdrawn by syringe will provide the labelled amount of piperacillin and tazobactam.

The reconstituted solutions may be further diluted to the desired volume (e.g. 50 ml to 150 ml) with one of the following compatible solvents:
- 0.9% (9 mg/ml) sodium chloride solution for injection
- Glucose 5%
- Dextrose 5% in water

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains piperacillin (as sodium salt) equivalent to 2 g and tazobactam (as sodium salt)

equivalent to 0.25 g.

Each vial contains piperacillin (as sodium salt) equivalent to 4 g and tazobactam (as sodium salt)

equivalent to 0.5 g.

Each vial of Piperacillin Tazobactam 2 g/0.25 g contains 4.7 mmol (108 mg) of sodium.

Each vial of Piperacillin Tazobactam 4 g/0.5 g contains 9.4 mmol (216 mg) of sodium.

Excipients:

For a full list of excipients, see section 6.1.

4.2 Posology and Method of Administration

 

Route of administration

 

 

 

 

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

Piperacillin / tazobactam 4 g/0.5 g is administered by intravenous infusion (over 30 minutes).

For

 

instructions on reconstitution and dilution instructions of the medicinal product before

 

administration

 

 

, see section 6.6.


4.3 Contraindications

 

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

excipients

 

listed in section 6.1.

 

 

 

4.8 Undesirable Effects

 

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 HPRA Pharmacovigilance,

 

Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971 Fax: +353 1 6762517  Website:

www.hpra.ie; E-mail: medsafety@hpra.ie

6.4 Special Precautions for storage

 

 

 

For storage conditions

 

of the after reconstitutedreconstitution and dilutedion of the medicinal product,

 

see section 6.3.

6.5 Nature and Contents of the container

 

Not all the packs sizes may be marketed.

 

 

 

 

 

 

 

 

Section 9 & 10 updated to include date of last renewal 28 February 2013 & date of revision of text September 2014

SPC now individual (not combined) & includes updates following Article 30 referral.
Please note the method of administration has changed from injection to infusion only.
As a consequence the name has been revised from
'piperacillin tazobactam 2g/0.25g powder for solution for injection or infusion' to
'piperacillin tazobactum 4g/0.5g powder for solution for infusion' .