AmBisome 50 mg Powder for solution for infusion
Each vial contains 50 mg of amphotericin (50,000 units) encapsulated in liposomes. After reconstitution, the concentrate contains 4 mg/mL amphotericin B.
For a full list of excipients, see section 6.1.
AmBisome is a sterile, Powder for solution for infusion. AmBisome is a yellow lyophilised cake or powder. After reconstitution, the product is an injectable intended to be administered by intravenous infusion.
AmBisome is indicated in:
• the treatment of severe systemic and/or deep mycoses
• the treatment of visceral leishmaniasis in immunocompetent patients including both adults and children.
• the empirical treatment of presumed fungal infections in febrile neutropenic patients, where the fever has failed to respond to broad spectrum antibiotics and appropriate investigations have failed to define a bacterial or viral cause.
Infections successfully treated with AmBisome include: disseminated candidiasis, aspergillosis, mucormycosis, chronic mycetoma, cryptococcal meningitis and visceral leishmaniasis.
This drug should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests.
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.
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.
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 Patients: 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).
For instructions on reconstitution and dilution of the product before administration, see section 6.6.
AmBisome is contraindicated in those patients who have shown hypersensitivity to the active substance or to any of the excipients 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. For this purpose a small amount of an AmBisome infusion (e.g. 1 mg) can be administered for about 10 minutes, the infusion 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. 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, adverse reactions including 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.
In the Treatment of Diabetic Patients: It should be noted that AmBisome contains approximately 900 mg of sucrose in each vial.
No specific interaction studies have been performed with AmBisome. However, the following drugs are known to interact with amphotericin B and may interact with AmBisome:
Nephrotoxic medications: 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.
Corticosteroids, corticotropin (ACTH) and diuretics: Concurrent use of corticosteroids, ACTH and diuretics (loop and thiazide) may potentiate hypokalemia.
Digitalis glycosides: AmBisome-induced hypokalemia may potentiate digitalis toxicity.
Skeletal muscle relaxants: AmBisome-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine).
Antifungals: 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.
Antineoplastic agents: Concurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic agents should be given concomitantly with caution.
Leukocyte transfusions: 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.
Teratogenicity studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species (See also section 5.3).
The safety of AmBisome in pregnant women has not been established. AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks to the mother and foetus.
Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin B without obvious effect on the foetus, but the number of cases reported is insufficient to draw any conclusions on the safety of AmBisome in pregnancy.
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.
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 drug 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) is approximately half that for Amphotericin B lipid complex.
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 commonCommonUncommonVery rare
||(≥ 1/10)(≥ 1/100 to < 1/10)(≥ 1/1,000 to < 1/100)(<1/10,000), not known (cannot be estimated from the available data)|
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Not known: anemia
IMMUNE SYSTEM DISORDERS
Uncommon: anaphylactoid reaction
Not known: anaphylactic reactions, hypersensitivity
METABOLISM AND NUTRITION DISORDERS
Very common: hypokalemia
Common: hyponatremia, hypocalcemia, hypomagnesaemia hyperglycemia,
NERVOUS SYSTEM DISORDERS
Not known: cardiac arrest, arrhythmia
Common: hypotension, vasodilatation, flushing,
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Very common: nausea, vomiting
Common: diarrhoea, abdominal pain
Common: liver function tests abnormal, hyperbilirubinaemia, alkaline phosphatase increased
SKIN AND SUBCUTANEOUS DISORDERS
Not known: angioneurotic oedema
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Common: back pain
Not Known: rhabdomyolysis (associated with hypokalemia), musculoskeletal pain (described as arthralgia or bone pain)
RENAL AND URINARY DISORDERS
Common: increased creatinine, blood urea increased
Not known: renal failure, renal insufficiency
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Very Common: rigors, pyrexia,
Common: chest pain
Interference with Phosphorus Chemistry Assay:
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.
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.
Pharmacotherapeutic group: Antimycotics for systemic use, antibiotics; ATC code: J02AA01.
Mode of action
Amphotericin B is a macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus. Amphotericin B is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. The drug is thought to act by binding to sterols in the fungal cell membrane, with a resulting change in membrane permeability, allowing leakage of a variety of small molecules.
Mammalian cell membranes also contain sterols, and it has been suggested that the damage to human cells and fungal cells caused by amphotericin B may share common mechanisms. The lipophilic moiety of amphotericin allows the drug to be integrated into the lipid bilayer of the liposomes. Liposomes are closed, spherical vesicles formed from a variety of amphiphilic substances such as phospholipids.
Phospholipids arrange themselves into membrane bilayers when exposed to aqueous solutions.
Mechanism of resistance
Intrinsic resistance, though rare, maybe primarily due to decrease in ergosterol or a change in the target lipid; Leading to reduced binding of amphotericin B to the cell membrane.
EUCAST breakpoints for AmBisome have not yet been established, however, susceptibility to AmBisome may differ to that of amphotericin B deoxycholate.
Amphotericin B, the antifungal component of AmBisome is active in vitro against many species of fungi., most strains of Histoplasma capsulatum, Coccidioides immitis, Candida spp, Blastomyces dermatidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenkii and Aspergillus fumigatus, Penicillium marneffi, and members of the mucormycetes group of moulds including Mucor mucedo, Rhizomucor and Rhizopus oryzae.
The majority of clinically important fungal species seem to be susceptible to Amphotericin B, although intrinsic resistance has rarely been reported for example, for some strains of S. schenckii, C. glabrata, C.krusei, C. tropicalis, C. lusitaniae, C parapsilosis and Aspergillus terreus.
AmBisome has been shown to be effective in animal models of visceral leishmaniasis (caused by Leishmania infantum and Leishmania donovani).
The efficacy of AmBisome has been established in a number of clinical trials for the treatment of systemic mycotic infections, as empirical therapy for fever of unknown origin in neutropenic patients and for the treatment of visceral leishmaniasis. These studies include comparative randomized studies of AmBisome versus conventional amphotericin B in confirmed Aspergillus
infections where the efficacy of both medicinal products was equivalent. In both adult and paediatric febrile neutropenic patients presumed to have fungal infection, the results of a randomized, double-blind clinical trial demonstrated that AmBisome administered at 3 mg/kg/day is as effective as conventional amphotericin B. The efficacy of AmBisome in the treatment of visceral leishmaniasis has been clearly demonstrated in a large population of immunocompetent and immunocompromised patients.
Invasive Filamentous Fungal Infections (IFFI) including Aspergillus
spp.: The efficacy of AmBisome has been demonstrated in a prospective, randomised, multicentre study as first line treatment in immunocompromised, mainly neutropenic adults and children (> 30 days old) with proven or probable IFFIs (AmBiLoad Study).
Patients were monitored for 12 weeks. A standard-dose regimen of 3 mg/kg/day (N=107) was compared to a loading dose regimen of 10 mg/kg/day (N=94) for the first 14 days of treatment. The favourable overall response rates were 50% of subjects in the standard-dose group and 46% of the subjects in the loading-dose group in the modified intent-to-treat analysis set. Differences were not statistically significant. The median time to resolution of fever was similar in the standard-dose and loading-dose groups (6 and 5 days, respectively). Twelve weeks after the first dose of AmBisome, survival was 72% in the standard-dose group and 59% in the loading-dose group, a difference that was not statistically significant.
Invasive candidiasis: AmBisome (3 mg/kg/day) was as effective as Micafungin (100 mg/day [Body weight > 40 kg] or 2 mg/kg/day [Body weight ≤ 40 kg]) as first line treatment of candidaemia and invasive candidiasis in a randomised, double-blind, multinational non-inferiority study in adults and children. AmBisome and Micafungin were administered for a median duration of 15 days. The favourable overall response was 89.5% (170/190) in the AmBisome group and 89.6% (181/202) in the Micafungin group (per protocol analysis set). The paediatric sub-study, which enrolled 98 patients of whom 57 were <2 years old, (including 19 premature infants), showed favourable overall response rates of: 88.1% (37/42) for AmBisome and 85.4% (35/41) for Micafungin (per protocol analysis set).
Invasive zygomycosis: A retrospective analysis covering a 15-year period included 59 patients with haematological malignancies with proven or probable mucormycosis.
Therapy was successful in 16 patients (37%): 9 of 39 patients who received conventional amphotericin B (23%) and 7 of the 12 patients who received AmBisome (58%) responded to therapy.
The pharmacokinetic profile of AmBisome, based upon total plasma concentrations of amphotericin B, was determined in cancer patients with febrile neutropenia and bone marrow transplant patients who received 1 hour infusions of 1.0 to 7.5mg/kg/day AmBisome for 3 to 20 days. AmBisome has a significantly different pharmacokinetic profile from that reported in the literature for conventional presentations of amphotericin B, with higher amphotericin B plasma concentrations (Cmax) and increased exposure (AUC0-24
) following administration of AmBisome as compared to conventional amphotericin B. After the first dose and last dose, the pharmacokinetic parameters of AmBisome (mean ± standard deviation) ranged from:
||7.3 μg/ml (± 3.8) to 83.7 μg/ml (± 43.0)
|T 1/2||6.3 hr (± 2.0) to 10.7 hr (± 6.4)
|AUC 0-24||27 μg.hr/ml (±14) to 555 μg.hr/ml (± 311)
||11 ml/hr/kg (± 6) to 51 ml/hr/kg (± 44)
|Volume of distribution (Vss)
||0.10 L/kg (± 0.07) to 0.44 L/kg (±0.27)
Minimum and maximum pharmacokinetic values do not necessarily come from the lowest and highest doses, respectively. Following administration of AmBisome steady state was reached quickly (generally within 4 days of dosing). AmBisome pharmacokinetics following the first dose appear non-linear such that serum AmBisome concentrations are greater than proportional with increasing dose. This non-proportional dose response is believed to be due to saturation of reticuloendothelial AmBisome clearance. There was no significant drug accumulation in the plasma following repeated administration of 1 to 7.5mg/kg/day. Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of AmBisome. After repeated administration of AmBisome, the terminal elimination half-life (t½β
) for AmBisome was approximately 7 hours. The excretion of AmBisome has not been studied. The metabolic pathways of amphotericin B and AmBisome are not known. Due to the size of the liposomes, there is no glomerular filtration and renal elimination of AmBisome, thus avoiding interaction of amphotericin B with the cells of the distal tubuli and reducing the potential for nephrotoxicity seen with conventional amphotericin B presentations.
The effect of renal impairment on the pharmacokinetics of AmBisome has not been formally studied. Data suggest that no dose adjustment is required in patients undergoing haemodialysis or filtration procedures, however, AmBisome administration should be avoided during the procedure.
In subchronic toxicity studies in dogs (1 month), rabbits (1 month) and rats (3 months) at doses equal to or, in some species, less than the clinical therapeutic doses of 1 to 3 mg/kg/day, the target organs for AmBisome toxicity were the liver and kidneys with thrombocytopenia also observed. All are known targets for amphotericin B toxicity.
AmBisome was found to be non-mutagenic in bacterial and mammalian systems.
Carcinogenicity studies have not been conducted with AmBisome.
No adverse effects on male or female reproductive function were noted in rats.
Hydrogenated soy phosphatidylcholine
Disodium succinate hexahydrate
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
AmBisome is incompatible with saline solutions and may not be mixed with other drugs or electrolytes.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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.
||Concentration of Amphotericin B mg/mL
||Maximum duration of storage at 2-8°C
||Maximum duration of storage at 25±2°C
||1 in 2
|1 in 8
|1 in 20
||1 in 2
||1 in 2
AmBisome: Unopened vials; Do not store above 25°C. Keep container in the outer carton.
For storage conditions of the reconstituted and diluted 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 RECONSTITUTIONAmBisome is not interchangeable with other amphotericin products
.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 drugs 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:
||Add 12 ml of Sterile Water for Injection to each AmBisome vial, to yield a preparation containing 4 mg/ml amphotericin.
||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.
||Calculate the amount of reconstituted (4 mg/ml) AmBisome to be further diluted (see table below).
||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).
||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.
||Number of vials
||Amount AmBisome (mg) to be withdrawn for further dilution
||Volume of reconstituted AmBisome (ml)*
||To make up a 0.2mg/ml concentration
(1 in 20 dilution)
||To make up a 2.0mg/ml concentration
(1 in 2 dilution)
| || || || ||Volume of 5% dextrose needed (ml)
||Total volume (ml; AmBisome plus 5% dextrose)
||Volume of 5% dextrose needed (ml)
||Total volume (ml; AmBisome plus 5% dextrose)
Each vial of AmBisome (50mg) is reconstituted with 12ml Water for Injection to provide a concentration of 4mg/ml Amphotercin B.
Any unused product or waste material should be disposed of in accordance with local requirements.
Gilead Sciences International Limited,
11 September 1998/24 September 2004.