ZEVTERA Powder for concentrate for solution for infusion Ref.[7669] Active ingredients: Ceftobiprole medocaril

Posology

The recommended dose of Zevtera is 500 mg administered as a 2-hour intravenous infusion every 8 hours. For CAP, a switch to an appropriate oral antibiotic may be considered after completion of at least 3 days of intravenous ceftobiprole medocaril sodium treatment, depending on the patient’s clinical response.

Paediatric population

The safety and efficacy of Zevtera in children aged birth to <18 years have not yet been established. Zevtera is not recommended for use in children or adolescents below 18 years of age.

Elderly patients

No dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal impairment (see below and section 5.2).

Renal impairment

In patients with mild renal impairment (i.e. creatinine clearance [CLCR] 50 to 80 mL/min), no dosage adjustment is necessary. In patients with moderate renal impairment (CLCR 30 to <50 mL/min), the recommended dose of Zevtera is 500 mg administered every 12 hours as a 2-hour intravenous infusion. In patients with severe renal impairment (CLCR <30 mL/min), the recommended dose of Zevtera is 250 mg administered every 12 hours as a 2-hour intravenous infusion. Due to limited clinical data and an expected increased exposure of Zevtera and its metabolite, Zevtera should be used with caution in patients with severe renal impairment (see section 5.2).

End-stage renal disease requiring dialysis

Ceftobiprole medocaril sodium is haemodialysable. The recommended dose for patients with end-stage renal disease with or without intermittent haemodialysis is 250 mg once every 24 hours.

Patients with creatinine clearance >150 mL/min

At start of treatment the prescribing physician should assess the renal function of the patient based on creatinine clearance expressed in mL/minute.

In patients with a supra-normal creatinine clearance (>150 mL/min), based on pharmcokinetic/pharmacodynamic considerations, prolongation of the infusion duration to 4 hours is recommended (see section 5.2).

Hepatic impairment

There is no experience in patients with hepatic impairment. However, as ceftobiprole undergoes minimal hepatic metabolism and is eliminated predominantly by the kidneys, no dosage adjustment is considered necessary in patients with hepatic impairment.

Method of administration

Zevtera must to be reconstituted and then further diluted (see section 6.6) prior to administration by intravenous infusion over a period of 2 hours.

Precipitation can occur when Zevtera is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, Zevtera and calcium-containing solutions, except Lactated Ringer’s solution for injection, must not be mixed or administered simultaneously in the same intravenous line (see sections 4.4, 6.2).

Information on overdosage with Zevtera in humans is not available. The highest total daily dose administered in Phase 1 trials was 3 g (1 g every 8 hours). If overdosage should occur, it should be treated symptomatically. Ceftobiprole plasma concentrations can be reduced by haemodialysis.

Powder vial: 4 years.

After reconstitution: Chemical, and physical in-use stability of the reconstituted solution (50 mg/mL) has been demonstrated for 1 hour at 25°C and up to 24 hours at 2°C–8°C.

After dilution: Chemical, and physical in-use stability data support the total times for reconstitution and infusion (2.67 mg/mL) described in the table below:

Total time by which reconstitution and infusion (including a 2-hour period of infusion, see Section 4.2) must be completed:

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Infusion solutions stored at 2°C–8°C (refrigerator)|

From a microbiological point of view, unless the method of reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

The reconstituted and infusion solutions should not be frozen or exposed to direct sunlight.

If the infusion solution is stored in the refrigerator, it should be equilibrated to room temperature prior to administration. The infusion solution does not need to be protected from light during administration.

The infusion solution should be prepared and used as defined in section 6.6.

Store in a refrigerator (2°C–8°C). Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted and/or diluted medicinal product, see section 6.3.

20 mL clear type I glass vials fitted with a grey bromobutyl elastomeric closure and an aluminium seal with a blue plastic flip-off cap.

Pack size: 10 vials.

Each vial is for single use only.

Zevtera must be reconstituted and then further diluted prior to infusion.

Step 1. Reconstitution:

10 mL of sterile water for injections or dextrose 50 mg/mL (5%) solution for injection should be added to the vial and the vial should be shaken vigorously until complete dissolution, which in some cases may take up to 10 minutes. The volume of the resulting concentrate is approximately 10.6 mL. Any foam should be allowed to dissipate and the reconstituted solution should be inspected visually to ensure the product is in solution and particulate matter is absent. The reconstituted concentrate contains 50 mg/mL of ceftobiprole and must be further diluted prior to administration. It is recommended that the reconstituted solution be further diluted immediately. However, if this is not possible the reconstituted solution can be stored at room temperature for up to one hour, or in a refrigerator for up to 24 hours.

Step 2. Dilution:

Preparation of 500 mg dose of Zevtera solution for infusion: 10 mL of the reconstituted solution should be withdrawn from the vial and injected into a suitable container (e.g. PVC or PE infusion bags, glass bottles) containing 250 mL of sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer’s solution for injection. The infusion solution should be gently inverted 5-10 times to form a homogenous solution. Vigorous agitation should be avoided to prevent foaming. The entire contents of the infusion bag should be infused to administer a 500 mg dose of Zevtera.

Preparation of 250 mg dose of Zevtera solution for infusion for patients with severe renal impairment: 5 mL of the reconstituted solution should be withdrawn from the vial and injected into a suitable container (e.g. PVC or PE infusion bags, glass bottles) containing 125 mL of sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer’s solution for injection. The infusion solution should be gently inverted 5-10 times to form a homogenous solution. Vigorous agitation should be avoided to prevent foaming. The entire contents of the infusion bag should be infused to administer a 250 mg dose of Zevtera.

The solution for infusion should be clear to slightly opalescent and yellowish in colour. The solution for infusion should be inspected visually for particulate matter prior to administration, and discarded if particulate matter is visible.

Detailed information on the time by which reconstitution, dilution and infusion must complete is provided in section 6.3.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.