1.0 TRADE NAME OF THE MEDICINAL PRODUCT 

Amphocil^TM

2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION  

(a) HCl qs to a target pH of 7.0 ± 0.5. (b) Mean NMT 2.0% residual moisture and no individual vial greater than 2.5%. (c) Used to fill vial headspace.

3.0 PHARMACEUTICAL FORM

Amphotericin B USP, 5% (W/W), lyophilisate for reconstitution.  Each vial contains 50 mg (50,000 IU) or 100mg (100,000 IU) of amphotericin B USP as a complex with sodium cholesteryl sulphate.

4.0 CLINICAL PARTICULARS 

4.1 Therapeutic indications 

Amphocil is indicated for the treatment of severe systemic and/or deep mycoses in cases where toxicity or renal failure precludes the use of conventional amphotericin B in effective doses, and in cases where prior systemic antifungal therapy has failed.  Fungal infections successfully treated with Amphocil include disseminated candidiasis and aspergillosis.  Amphocil has been used successfully in severely neutropenic patients.

Amphocil is not intended for use in common, clinically inapparent fungal diseases diagnosed only by skin tests or serological determinations.

4.2 Posology and method of administration 

Dosage:
     
Therapy may begin at a daily dose of 1.0 mg/kg of body weight, increasing to the recommended dose of 3.0-4.0 mg/kg as required.  Doses as high as 6 mg/kg have been used in patients.  Dosage should be adjusted to the individual requirements of each patient.  The median cumulative dose in clinical studies was 3.5 g and the median treatment duration was 16 days.  Ten percent (10%) of patients received 13 g or more of Amphocil over a period of 27 to 409 days.

Administration:

Amphocil is administered by intravenous infusion at a rate of 1 to 2 mg/kg/hour.  If the patient experiences acute reactions or cannot tolerate the infusion volume, the infusion time may be extended.  Pre-medication (e.g. paracetamol, antihistamines, antiemetics) may be administered to patients who have previously suffered infusion related adverse reactions.

Paediatric Patients:

A limited number of paediatric patients have been treated with Amphocil at daily doses (mg/kg) similar to those in adults.  No unusual adverse events were reported.

Elderly Patients:

A limited number of elderly patients have been treated with Amphocil; available data do not indicate the need for specific dose recommendations or precautions in elderly patients.

4.3   Contraindications

Amphocil should not be administered to patients who have documented hypersensitivity to any of its components, unless, in the opinion of the physician, the advantages of using Amphocil outweigh the risks of hypersensitivity.

4.4 Special warnings and special precautions for use

A test dose, which is advisable when commencing all new courses of treatment should immediately precede the first dose; a small amount of drug (e.g. 20 ml of a solution containing 0.1 g per litre) should be infused over 10 minutes and the patient carefully observed for the next 30 minutes.

In the treatment of diabetic patients: It should be noted that each vial of Amphocil contains lactose monohydrate.

In the treatment of renal dialysis patients: Amphocil should be administered only at the end of each dialysis period.  Serum electrolytes, particularly potassium and magnesium, should be regularly monitored.

4.5  Interaction with other medicinal products and other forms of interaction

There have been no reported interactions between Amphocil and other drugs including cyclosporine.  However, caution should be used in patients receiving concomitant therapy with drugs known to interact with conventional amphotericin B such as nephrotoxic drugs (aminoglycosides, cisplatin and pentamidine), corticosteroids and corticotropin (ACTH) that may potentiate hypokalaemia and digitalis glycosides, muscle relaxants and antiarrhythmic agents whose effects may be potentiated in the presence of hypokalaemia. The use of flucytosine with Amphocil has not been studied.  While the synergy between amphotericin B and flucytosine has been reported, amphotericin B may enhance the toxicity of flucytosine by increasing its cellular uptake and impeding its renal excretion. Acute pulmonary reactions have been noted in patients receiving amphotericin B during or shortly after leukocyte transfusions.

4.6 Pregnancy and lactation

Pregnancy: Animal reproductive toxicology studies with Amphocil have shown no evidence of harm to the foetus.  Although the active ingredient, amphotericin B, has been in wide use for many years without apparent ill consequence, there is inadequate evidence of safety of Amphocil in human pregnancy.  Therefore, it is recommended that administration of Amphocil is avoided in pregnancy unless the anticipated benefit to the patient outweighs the potential risk to the foetus. 
  
Nursing mothers: It is not known whether amphotericin B is excreted in human milk.  Consideration should be given to discontinuation of nursing during treatment with Amphocil.

4.7  Effects on ability to drive and use machines

Not applicable to current indication or expected use.

4.8  Undesirable effects

In general, the physician should monitor the patient for any type of adverse event associated with conventional amphotericin B.  The appearance of adverse reactions does not generally prevent the patient completing the course of treatment.  Caution should be exercised when high doses or prolonged therapy is indicated. Acute reactions including fever, chills and rigours may occur.  Anaphylactoid reactions including hypotension, tachycardia, bronchospasm, dyspnoea, hypoxia and hyperventilation have also been reported.  Most acute reactions are successfully treated by reducing the rate of infusion and prompt administration of anti-histamines and adrenal corticosteroids.  Serious anaphylactoid effects may necessitate discontinuation of Amphocil and treatment with additional supportive therapy (e.g. adrenaline). Clinical studies conducted so far have shown Amphocil to be less nephrotoxic than conventional amphotericin B.  Serum creatinine levels tend to remain consistent throughout the course of therapy even in patients with renal insufficiency.  Patients who developed renal insufficiency during treatment with conventional amphotericin B, were stabilised or improved when Amphocil was substituted.  Decreases in renal function attributable to Amphocil treatment were rare.  However, as with conventional amphotericin B, renal function should be monitored with particular attention to those patients receiving concomitant therapy with nephrotoxic drugs. There have been no reports of unequivocal hepatic toxicity of Amphocil.  Changes in alkaline phosphatase and bilirubin levels were infrequent. Changes in coagulation, thrombocytopenia and hypomagnesemia were sometimes observed on Amphocil.  Anaemia, which is a very common adverse event during treatment with conventional amphotericin B, developed in only 2.5% of the patients treated with Amphocil. Other reported events include nausea, vomiting, hypertension, headache, backache, diarrhoea and abdominal pain.

4.9  Overdose

In case of overdose, stop administration immediately and carefully monitor the patient’s clinical status (renal, liver and cardiac function, haematological stats, serum electrolytes) and institute symptomatic treatment.

5.0   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Amphotericin B is a macrocyclic polyene antibiotic isolated from Streptomyces nodosus.  Amphotericin B has a high affinity for ergosterol, the primary sterol in fungal cell membranes, and a lesser affinity for cholesterol, the predominant sterol of mammalian cell membranes.  Binding of amphotericin B to ergosterol results in damage to the fungal cell membrane, enhanced membrane permeability and eventual cell death.  Mammalian cell membranes also contain sterols, and it has been suggested that the damage caused by amphotericin B to human cells follows a similar mode of action to that of fungal cells.  Amphocil is considered to have the same mode of action as conventional amphotericin B, but with reduced toxicity.         

Amphocil is a novel formulation of amphotericin B based on its unique affinity for sterols.  Amphocil is a stable complex of amphotericin B and sodium cholesteryl sulphate, a naturally occurring cholesterol metabolite.  Amphotericin B and sodium cholesteryl sulphate are complexed in a near equimolar ratio to form uniform disc-shaped microparticles.  Amphocil is not a liposomal formulation but a colloidal dispersion of amphotericin B and sodium cholesteryl sulphate. Pharmacological studies indicated that overall, Amphocil is essentially equivalent, in vitro, to conventional amphotericin B against a variety of fungal pathogens.  Higher doses of Amphocil are tolerated, thus it is generally effective in eradicating fungal infections than conventional amphotericin B in several in vivo models.

5.2  Pharmacokinetic properties

Pharmacokinetic studies in animals demonstrate that the distribution of Amphocil and conventional amphotericin B are notably different.  Lower peak plasma levels of amphotericin B and greater total area under the curve values after Amphocil treatment, compared to comparable doses of conventional amphotericin B have been observed.  Higher concentrations of amphotericin B measured in the liver, spleen and bone marrow after Amphocil administration were not accompanied by evidence of increased toxicity in these organ systems.  Levels in the kidney, a primary site of toxicity of conventional amphotericin B, were 4- to 5-fold lower after treatment with Amphocil and correlated with reduced nephrotoxicity compared to conventional amphotericin.  Maximum plasma concentrations of amphotericin B were lower in Amphocil treated animals.  The terminal half-life was longer in the Amphocil treated animals owing to the accumulation of amphotericin B in the liver and its subsequent slow release. In bone marrow transplant patients administered Amphocil at doses of 0.5 to 8.0 mg/kg/day, there was an increase in both the volume of distribution (Vss) and the total plasma clearance (CIt) as the dose escalated.  The mean values for Vss, CIt and terminal half-life for doses £2.0 mg/kg were 2.25 l/kg, 0.0855 l/h/kg and 22.1 hours, respectively.  The mean values for doses >2.0 mg/kg were 3.61 l/kg, 0.116 l/h/kg and 27.2 hours respectively.  The maximum steady-state concentrations achievable after multiple dosing ranged from 658 to 6212 µg/l for doses of 0.5 to 8.0 mg/kg respectively.  There was no evidence of continued accumulation of Amphocil at doses of 8.0 mg/kg/day.  There was no net change in renal function over the duration of Amphocil treatment (range from 1 to 108 days, median 28 days).

5.3   Preclinical safety data

Amphocil was found to be generally less toxic than conventional amphotericin B in a series of acute and repeat dose studies, with a  4- to 5-fold increased margin of safety.  There were no unique toxicities observed following treatment with Amphocil relative to conventional amphotericin B.  Nephrotoxicity was diminished during Amphocil treatment even at dose levels 4- to 5-fold higher than toxic doses of conventional amphotericin B.  Accumulation of amphotericin B in the liver following Amphocil administration was observed; however, there were no associated signs of increased hepatotoxicity relative to conventional amphotericin B.  In vitro and in vivo tests on induction of gene and chromosome mutations were negative for amphotericin B.  Carcinogenicity studies have not been conducted with amphotericin B or Amphocil.  To date there has been no clinical reports of carcinogenicity associated with the use of amphotericin B.  Embryo-foetal studies in rats and rabbits, at doses of 2.5 mg/kg/day or greater showed maternal toxicity i.e. reduced weight gain and loss of appetite.  There were no adverse effects on embryo-foetal development up to 10 mg/kg/day.  There are no specific data for the effect of Amphocil on human fertility, but in multiple dose toxicity studies of up to 13 weeks (in rats and dogs) there was no effect on ovarian or testicular histology.  Although, amphotericin B has not been associated with peri- or post-natal effects no studies with Amphocil are available.

6.0 PHARMACEUTICAL  PARTICULARS

6.1 List of excipients 

The following excipients are contained in each vial of lyophilised product: Sodium cholesteryl sulphate; Tromethamine, USP; Edetate disodium, Ph Eur; Hydrochloric acid, Ph Eur; Water for injection, Ph Eur; Lactose monohydrate, Ph Eur.

6.2 Incompatibilities 

Do not reconstitute lyophilised powder/cake with saline or dextrose solutions.  Do not add saline or electrolytes to the reconstituted concentrate, or mix with other drugs. If administered through an existing intravenous line, flush with 5% Dextrose for injection prior to infusion of Amphocil, otherwise administer via a separate line. 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 Amphocil. Do not use material that shows evidence of precipitation or any other particulate matter.  Strict aseptic technique should always be followed during reconstitution and dilution since no preservatives are present in the lyophilised drug or in the solutions used for reconstitution and dilution.

6.3 Shelf life  

Unopened vials of lyophilised material have a shelf-life of 36 months and should be stored below 30°C (86°F).  After reconstitution, the drug should be refrigerated at 2-8°C (36-46°F) and used within 24 hours.  Do not freeze.  After further dilution with 5% Dextrose for Injection, the infusion should be stored in a refrigerator (2-8°C) and used within 24 hours.  Partially used vials should be discarded.

6.4 Special precautions for storage 

Store below 30°C (86°F)

6.5 Nature and contents of container 

The container is a Type I moulded glass vial, the stopper is a grey butyl lyophilisation type stopper, and the cap is an aluminium ring with either a green or yellow polypropylene flip-off top.

6.6. Instructions for use/handling 

Direction for reconstitution and dilution: Amphocil must be reconstituted by addition of sterile Water for Injection, Ph Eur, using a sterile syringe and a 20-gauge needle. Rapidly inject into the vial: 50 mg/vial - 10 ml sterile Water for Injection; 100 mg/vial - 20 ml sterile Water for Injection. Shake gently by hand, rotating the vial, until the yellow fluid becomes clear.  Note that the fluid may be opalescent.  The liquid in each reconstituted vial will contain 5 mg of amphotericin B per ml.  For infusion, further dilute to a final concentration of 0.625 mg/ml by diluting 1 volume of the reconstituted Amphocil with 7 volumes of 5% Dextrose for Injection.

7.0 MARKETING AUTHORISATION HOLDER 

Beacon Pharmaceuticals Limited., 85 High Street, Tunbridge Wells, Kent, TN1 1YG, United Kingdom

8.0 MARKETING AUTHORISATION NUMBER 

50 mg/vial PL 18157/0025 and 100 mg/vial PL 18157/0026

9.0 DATE OF FIRST AUTHORISATION

03/07/2006

10.0 DATE OF (PARTIAL) REVISION OF TEXT 

03/07/2006

11.0 LEGAL CLASSIFICATION

POM