Posology : מינונים

4.2     Posology and method of administration

Posology
Piperacillin/Tazobactam – Fresenius should be administered by intravenous infusion over 30 minutes. Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before results are available.

Adults and adolescents (over 12 years)
The usual dosage for adults and juveniles with normal renal function is 4 g piperacillin/ 0.5 g tazobactam given every eight 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.

Nosocomial pneumonia
Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin/Tazobactam – Fresenius at a dosage of 4 g piperacillin/ 0.5 g tazobactam every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/ 2.0 g tazobactam). Treatment with the aminoglycoside should be continued in patients from whom Pseudomonas aeruginosa is isolated. If Pseudomonas aeruginosa is not isolated, the aminoglycoside may be discontinued at the discretion of the treating physician.
Due to the in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, Piperacillin/Tazobactam – Fresenius and the aminoglycoside are recommended for separate administration. Piperacillin/Tazobactam – Fresenius and the aminoglycoside should be reconstituted, diluted and administered separately when concomitant therapy with aminoglycosides is indicated. (See interaction, section 4.5).
The dose and frequency of Piperacillin/Tazobactam depends on the severity and localization of the infection and expected pathogens.

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

Table 1
Treatment               Piperacillin/Tazobactam 4 g / 0.5 g frequency
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)


Renal Insufficiency: Adults
In patients with renal insufficiency (Creatinine clearance < 40 ml/min), the intravenous dose of Piperacillin/Tazobactam – Fresenius should be adjusted to the degree of actual renal function impairment and each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly.
In patients with nosocomial pneumonia receiving concomitant aminoglycoside therapy, the aminoglycoside dosage should be adjusted according to the recommendations of the manufacturer. The recommended daily doses of Piperacillin/Tazobactam – Fresenius for patients with renal insufficiency are as follows:

Recommended dosing of Piperacillin/Tazobactam – Fresenius in patients with normal renal function and renal insufficiency:

(As total grams Piperacillin/Tazobactam)

Table 2
Renal function (Creatinine clearance All indications (except              Nosocomial (ml/min))                            nosocomial pneumonia)                pneumonia > 40 ml/min                          No       dose  adjustment            4.5 q 6 h necessary
20-40 ml/min*                        Maximum dose suggested:              3.375 q 6 h
4.5 g q 8 h
< 20 ml/min*                         Maximum dose suggested:              2.25 q 6 h 4.5 g q 12 h
Hemodialysis**                       2.25 q 12 h                          2.25 q 8 h 
2.25 q 12 h                2.25 q 8 h
CAPD
* Creatinine clearance for patients not receiving hemodialysis
** 0.75 g should be administered following each hemodialysis session on hemodialysis days For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.
Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g Piperacillin/Tazobactam – Fresenius should be administered following each dialysis period on hemodialysis days. No additional dosage of Piperacillin/Tazobactam – Fresenius is necessary for CAPD patients.

Duration of Therapy
The usual duration of Piperacillin/Tazobactam – Fresenius treatment for most indications is in the range of 5-14 days. However, the recommended duration of Piperacillin/Tazobactam – Fresenius treatment of nosocomial pneumonia is 7 to 14 days.
In all conditions, the duration of treatment should be guided by the severity of the infection and the patient's clinical and bacteriological progress.

Patients with hepatic impairment
Dosage adjustment of Piperacillin/Tazobactam – Fresenius is not warranted in patients with hepatic cirrhosis (see section 5.2 Pharmacokinetic properties).

Elderly patients
Patients over 65 years are not an increased risk of developing adverse effects solely because of age.
However, dosage should be adjusted in the presence of renal impairment (see Posology, section 4.2).

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
One vial of Piperacillin/Tazobactam – Fresenius 2 g/0.25 g contains 4.9 mmol (112 mg) of sodium and one vial of Piperacillin/Tazobactam – Fresenius 4 g/0. 5 g contains 9.7 mmol (224 mg) of sodium.
The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.
This drug is known to be substantially excreted by the kidney, and the risk of the toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Pediatric patients (2-12 years of age)
For children with appendicitis older than 2 years and/or peritonitis, weighing up to 40 kg, and with normal renal function, the recommended Piperacillin/Tazobactam – Fresenius dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.

The following table summarizes the treatment frequency and the dose per body weight for pediatric patients 2-12 years of age by indication or condition:

Table 3
Dose per weight and treatment frequency       Indication / condition
80 mg Piperacillin / 10 mg Tazobactam per kg Neutropenic children with fever suspected to body weight / every 6 hours                   be due to bacterial infections* 100 mg Piperacillin / 12.5 mg Tazobactam per Complicated intra-abdominal infections* kg body weight / every 8 hours
* Not to exceed the maximum 4 g / 0.5 g per dose over 30 minutes.

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):

Table 4

Creatinine clearance Piperacillin/Tazobactam (recommended dose)
(ml/min)
> 50                 No dose adjustment needed
< 50                 70 mg piperacillin/ 8.75 mg tazobactam/ kg every 8 hours 
For children on hemodialysis, one additional dose of 40 mg piperacillin / 5 mg tazobactam / kg should be administered following each dialysis period.

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.


Method of Administration
Piperacillin/Tazobactam – Fresenius 2 g / 0.25 g is administered by intravenous infusion (over 30 minutes).
Piperacillin/Tazobactam – Fresenius 4 g / 0.5 g is administered by intravenous infusion (over 30 minutes).

Precautions to be taken before handling or administering the medicinal product For instructions on reconstitution/dilution of the medicinal product before administration, see section 6.6.