Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Gilead Sciences International Ltd, Granta Park, Abington, Cambridge, CB21 6GT
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to AmBisome therapy.
Anaphylaxis and anaphylactoid reactions have been reported in association with AmBisome infusion. Allergic type reactions, including severe infusion-related reactions can occur during administration of amphotericin-containing products, including AmBisome (see section 4.8). Therefore, administration of a test dose is still advisable before a new course of treatment (see section 4.2). If a severe allergic or anaphylactic/anaphylactoid reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusion of AmBisome.
Other severe infusion-related reactions can occur during administration of amphotericin B-containing products, including AmBisome (see section 4.8). Although infusion-related reactions are not usually serious, consideration of precautionary measures for the prevention or treatment of these reactions should be given to patients who receive AmBisome therapy. Slower infusion rates (over 2 hours) or routine doses of diphenhydramine, paracetamol, pethidine and/or hydrocortisone have been reported as successful in their prevention or treatment.
AmBisome has been shown to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity; however, renal adverse reactions may still occur.
In studies comparing AmBisome 3 mg/kg daily with higher doses (5, 6 or 10 mg/kg daily), it was found that the incidence rates of increased serum creatinine, hypokalaemia and hypomagnesaemia were notably higher in the high dose groups.
In particular, caution should be exercised when prolonged therapy is required. Regular laboratory evaluation of serum electrolytes, particularly potassium and magnesium as well as renal, hepatic and haematopoietic function should be performed, at least once weekly. This is particularly important in patients receiving concomitant nephrotoxic medications (see section 4.5). Renal function should be closely monitored in these patients. Due to the risk of hypokalaemia, appropriate potassium supplementation may be required during the course of AmBisome administration. If clinically significant reduction in renal function or worsening of other parameters occurs, consideration should be given to dose reduction, treatment interruption or discontinuation.
Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusions. It is recommended that these infusions are separated by as long a period as possible and pulmonary function should be monitored.
AmBisome contains approximately 900 mg of sucrose in each vial. This should be taken into account when treating diabetic patients.
No specific interaction studies have been performed with AmBisome. However, the following medicinal products are known to interact with amphotericin B and may interact with AmBisome:
Concurrent administration of AmBisome with other nephrotoxic agents (for example ciclosporin, aminoglycosides, polymixins, tacrolimus and pentamidine) may enhance the potential for drug-induced renal toxicity in some patients. However, in patients receiving concomitant ciclosporin and/or aminoglycosides, AmBisome was associated with significantly less nephrotoxicity compared to amphotericin B. Regular monitoring of renal function is recommended in patients receiving AmBisome with any nephrotoxic medications.
Concurrent use of corticosteroids, ACTH and diuretics (loop and thiazide) may potentiate hypokalemia.
AmBisome-induced hypokalemia may potentiate digitalis toxicity.
AmBisome-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine).
No evidence of benefit from the use of flucytosine with AmBisome has been observed. Whilst synergy between amphotericin and flucytosine has been reported, concurrent use may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion.
Concurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic agents should be given concomitantly with caution.
Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusions. It is recommended these infusions are separated by as long a period as possible and pulmonary function should be monitored.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
The safety of AmBisome in pregnant women has not been established.
Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin B without obvious effect on the fetus, but the number of cases reported is insufficient to draw any conclusions on the safety of AmBisome in pregnancy.
AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks to the mother and fetus.
It is unknown whether AmBisome is excreted in human breast milk. A decision on whether to breastfeed while receiving AmBisome should take into account the potential risk to the child as well as the benefit of breast feeding for the child and the benefit of AmBisome therapy for the mother.
No studies on the effects on the ability to drive and use machines have been performed. Some of the undesirable effects of AmBisome presented below may impact the ability to drive and use machines.
The following adverse reactions have been attributed to AmBisome based on clinical trial data and post-marketing experience. The frequency is based on analysis from pooled clinical trials of 688 AmBisome treated patients; the frequency of adverse reactions identified from post-marketing experience is not known. Adverse reactions are listed below by body system organ class using MedDRA and are sorted by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Frequencies are defined as:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Uncommon: thrombocytopenia
Not known: anaemia
Uncommon: anaphylactoid reaction
Not known: anaphylactic reactions, hypersensitivity
Very common: hypokalaemia
Common: hyponatremia, hypocalcaemia, hypomagnesaemia, hyperglycemia,
Common: headache
Uncommon: convulsion
Common: tachycardia
Not known: cardiac arrest, arrhythmia
Common: hypotension, vasodilatation, flushing
Common: dyspnoea
Uncommon: bronchospasm
Very common: nausea, vomiting
Common: diarrhoea, abdominal pain
Common: abnormal liver function tests, hyperbilirubinaemia, increased alkaline phosphatase
Common: rash
Not known: angioneurotic oedema
Common: back pain
Not Known: rhabdomyolysis (associated with hypokalaemia), musculoskeletal pain (described as arthralgia or bone pain)
Common: increased creatinine, increased blood urea
Not known: renal failure, renal insufficiency
Very Common: rigors, pyrexia,
Common: chest pain
Fever and chills/rigors are the most frequent infusion-related reactions expected to occur during AmBisome administration. Less frequent infusion-related reactions may consist of one or more of the following symptoms: chest tightness or pain, dyspnoea, bronchospasm, flushing, tachycardia, hypotension and musculoskeletal pain (described as arthralgia, back pain, or bone pain). These resolve rapidly on stopping the infusion and may not occur with every subsequent dose or when slower infusion rates (over 2 hours) are used. In addition, infusion-related reactions may also be prevented by the use of premedication. However, severe infusion-related reactions may necessitate the permanent discontinuation of AmBisome (see section 4.4).
In two double-blind, comparative studies, AmBisome treated patients experienced a significantly lower incidence of infusion-related reactions, as compared to patients treated with conventional amphotericin B or amphotericin B lipid complex.
In pooled study data from randomised, controlled clinical trials comparing AmBisome with conventional amphotericin B therapy in greater than 1,000 patients, reported adverse reactions were considerably less severe and less frequent in AmBisome treated patients as compared with conventional amphotericin B treated patients.
Nephrotoxicity occurs to some degree with conventional amphotericin B in most patients receiving the product intravenously. In a double-blind study involving 687 patients, the incidence of nephrotoxicity with AmBisome (as measured by serum creatinine increase greater than 2.0 times baseline measurement), was approximately half that for conventional amphotericin B. In another double-blind study involving 244 patients, the incidence of nephrotoxicity with AmBisome (as measured by serum creatinine increase greater than 2.0 times baseline measurement) was approximately half that for Amphotericin B lipid complex.
False elevations of serum phosphate may occur when samples from patients receiving AmBisome are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.
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 national reporting system: United Kingdom, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
AmBisome is incompatible with saline solutions and may not be mixed with other medicinal products or electrolytes.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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