AMBISOME Powder for solution for infusion Ref.[6180] Active ingredients: Amphotericin B

Non-equivalence of amphotericin products

Different amphotericin products (sodium deoxycholate, liposomal, lipid complex) are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing and so the products should not be used interchangeably without accounting for these differences. Both the trade name, common name and dose should be verified pre-administration.

There is a risk of under-dose if AmBisome is administered at a dose recommended for amphotericin B deoxycholate.

Posology

Administration of a test dose is advisable before a new course of treatment. A small amount of an AmBisome infusion (e.g. 1 mg) can be administered for about 10 minutes and then stopped and the patient observed carefully for the next 30 minutes. If there have been no severe allergic or anaphylactic/anaphylactoid reactions the infusion of AmBisome dose can be continued.

Treatment of mycoses

Therapy is usually instituted at a daily dose of 1.0 mg/kg of body weight, and increased stepwise to 3.0 mg/kg, as required. Data are presently insufficient to define total dosage requirements and duration of treatment necessary for resolution of mycoses. However, a cumulative dose of 1.0-3.0 g of amphotericin B as AmBisome over 3-4 weeks has been typical. Dosage of amphotericin B as AmBisome must be adjusted to the specific requirements of each patient.

Mucormycosis

The recommended starting dose is 5 mg/kg/day. The duration of therapy should be determined on an individual basis. Courses of up to 6–8 weeks are commonly used in clinical practice; longer durations of therapy may be required for deep seated infections or in cases of prolonged courses of chemotherapy or neutropenia.

Although doses greater than 5 mg/kg and up to a maximum of 10 mg/kg have been used in clinical trials and clinical practice, data on the safety and efficacy of AmBisome for the treatment of mucormycosis at these higher doses are limited. Therefore, a benefit:risk assessment should be made on an individual patient level to determine whether the potential benefits of treatment are considered to outweigh the known increased risk of toxicity at higher AmBisome doses (see section 4.4).

Treatment of visceral leishmaniasis

A total dose of 21.0-30.0 mg/kg of body weight given over 10-21 days may be used in the treatment of visceral leishmaniasis. Particulars as to the optimal dosage and the eventual development of resistance are as yet incomplete. The product should be administered under strict medical supervision.

Empirical treatment of febrile neutropenia

The recommended daily dose is 3 mg/kg body weight per day. Treatment should be continued until the recorded temperature is normalised for 3 consecutive days. In any event, treatment should be discontinued after a maximum of 42 days.

Paediatric population

Both systemic fungal infections in children and presumed fungal infections in children with febrile neutropenia have been successfully treated with AmBisome, without reports of unusual adverse events. AmBisome has been studied in paediatric patients aged one month to 18 years old. Doses used in these clinical studies were the same as those used in adults on a mg/kg body weight basis.

AmBisome is not recommended for use in children below 1 month old due to lack of data on safety and efficacy.

Elderly patients

No alteration in dose or frequency of dosing is required.

Renal impairment

AmBisome has been administered to a large number of patients with pre-existing renal impairment at starting doses ranging from 1-3 mg/kg/day in clinical trials and no adjustment in dose or frequency of administration was required (See section 4.4).

Hepatic impairment

No data are available on which to make a dose recommendation for patients with hepatic impairment (See section 4.4).

Method of administration

AmBisome should be administered by intravenous infusion over a 30-60 minute period. For doses greater than 5mg/kg/day, intravenous infusion over a 2 hour period is recommended (see section 4.4). The recommended concentration for intravenous infusion is 0.20 mg/ml to 2.00 mg/ml amphotericin B as AmBisome.

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

The toxicity of AmBisome due to acute overdose has not been defined. If overdose should occur, cease administration immediately. Carefully monitor clinical status including renal and hepatic function, serum electrolytes and haematological status. Haemodialysis or peritoneal dialysis does not appear to affect the elimination of AmBisome.

Special populations (including paediatric population): No additional information is available in special populations.

Shelf life: 4 years.

Shelf –life of AmBisome after first opening:

As AmBisome does not contain any bacteriostatic agent, from a microbiological point of view, the reconstituted or diluted product should be used immediately.

In-use storage times and conditions prior to administration are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

However, the following chemical and physical in-use stability data for AmBisome has been demonstrated:

Shelf-life after reconstitution:

Glass vials for 24 hours at 25±2°C exposed to ambient light.

Glass vials and polypropylene syringes up to 7 days at 2-8°C.

Do not freeze.

DO NOT STORE partially used vials for future patient use.

Shelf-life after dilution with Dextrose:

PVC or Polyolefin infusion bags: 25±2°C exposed to ambient light or at 2-8°C. Do not freeze. See table below for recommendations.

AmBisome unopened vials.

Do not store above 25°C. Keep the container in the outer carton.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

AmBisome is presented in 15 ml, 20 ml or 30 ml sterile, Type I glass vials. The closure consists of a grey butyl rubber stopper and aluminium ring seal fitted with a removable plastic cap. Single-dose vials are packed ten per carton with 10 filters. Not all pack sizes may be marketed.

READ THIS ENTIRE SECTION AND SECTION 4.4 CAREFULLY BEFORE BEGINNING RECONSTITUTION

AmBisome is not equivalent to other amphotericin products (see section 4.2).

AmBisome must be reconstituted using Sterile Water for Injection (without a bacteriostatic agent) and diluted in Dextrose solution (5%, 10% or 20%) for infusion only.

The use of any solution other than those recommended, or the presence of a bacteriostatic agent (e.g. benzyl alcohol) in the solution, may cause precipitation of AmBisome.

AmBisome is NOT compatible with saline and must not be reconstituted or diluted with saline or administered through an intravenous line that has previously been used for saline unless first flushed with dextrose solution (5%, 10% or 20%) for infusion. If this is not feasible, AmBisome should be administered through a separate line.

Do NOT mix AmBisome with other medicinal products or electrolytes.

Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in AmBisome, or in the materials specified for reconstitution and dilution.

AmBisome must be reconstituted by suitably trained staff.

Vials of AmBisome containing 50 mg of amphotericin are prepared as follows:

1. Add 12 ml of Sterile Water for Injection to each AmBisome vial, to yield a preparation containing 4 mg/ml amphotericin.
2. IMMEDIATELY after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. After reconstitution the concentrate is a translucent, yellow dispersion. Visually inspect the vial for particulate matter and continue shaking until complete dispersion is obtained. Do not use if there is any evidence of precipitation of foreign matter.
3. Calculate the amount of reconstituted (4 mg/ml) AmBisome to be further diluted (see table below).
4. The infusion solution is obtained by dilution of the reconstituted AmBisome with between one (1) and nineteen (19) parts dextrose solution (5%, 10% or 20%) for infusion by volume, to give a final concentration in the recommended range of 2.00 mg/ml to 0.20 mg/ml amphotericin as AmBisome (see table below).
5. Withdraw the calculated volume of reconstituted AmBisome into a sterile syringe. Using the 5 micron filter provided, instill the AmBisome preparation into a sterile container with the correct amount of dextrose solution (5%, 10% or 20%) for infusion.

An in-line membrane filter may be used for intravenous infusion of AmBisome. However, the mean pore diameter of the filter should not be less than 1.0 micron.

Example of the preparation of AmBisome solution for infusion at a dose of 3mg/kg/day in dextrose 5% solution for infusion.

* Each vial of AmBisome (50mg) is reconstituted with 12ml Water for Injection to provide a concentration of 4mg/ml amphotericin B.

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