1. NAME OF THE MEDICINAL PRODUCT

Liposomal Amphotericin B for Injection BP 50mg Taj Pharma
Liposomal Amphotericin B for Injection BP 100mg Taj Pharma

  1. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 50mg of amphotericin (50,000 units) encapsulated in liposomes. After reconstitution, the concentrate contains 4 mg/mL amphotericin B.

Each vial contains 100mg of amphotericin (100,000 units) encapsulated in liposomes. After reconstitution, the concentrate contains 4 mg/mL amphotericin B.

Excipient with known effect:

For a full list of excipients, see section 6.1.

  1. PHARMACEUTICAL FORM

Powder for Injection.

  1. CLINICAL PARTICULARS

4.1 Therapeutic indications

(Liposomal Amphotericin B) AmBisome is indicated in adults and children aged 1 month to 18 years old for:

  • 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 (Liposomal Amphotericin B) AmBisome include: disseminated candidiasis, aspergillosis, mucormycosis, chronic mycetoma, cryptococcal meningitis and visceral leishmaniasis.

(Liposomal Amphotericin B) AmBisome should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests.

4.2 Posology and method of administration

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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome over 3 – 4 weeks has been typical. Dosage of amphotericin B as (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome, without reports of unusual adverse events. (Liposomal Amphotericin B) 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.

(Liposomal Amphotericin B) 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

(Liposomal Amphotericin B) 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

(Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome.

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

4.3 Contraindications

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 (Liposomal Amphotericin B) AmBisome therapy.

4.4 Special warnings and precautions for use

Anaphylaxis and anaphylactoid reactions

Anaphylaxis and anaphylactoid reactions have been reported in association with (Liposomal Amphotericin B) AmBisome infusion. Allergic type reactions, including severe infusion-related reactions can occur during administration of amphotericin-containing products, including (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome.

Infusion-related reactions

Other severe infusion-related reactions can occur during administration of amphotericin B-containing products, including (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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.

Renal toxicity

(Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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.

Pulmonary toxicity

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.

Diabetic patients

(Liposomal Amphotericin B) AmBisome contains approximately 900 mg of sucrose in each vial. This should be taken into account when treating diabetic patients.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed with (Liposomal Amphotericin B) AmBisome. However, the following medicinal products are known to interact with amphotericin B and may interact with (Liposomal Amphotericin B) AmBisome:

Nephrotoxic medications

Concurrent administration of (Liposomal Amphotericin B) 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, (Liposomal Amphotericin B) AmBisome was associated with significantly less nephrotoxicity compared to amphotericin B. Regular monitoring of renal function is recommended in patients receiving (Liposomal Amphotericin B) 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

(Liposomal Amphotericin B) AmBisome-induced hypokalemia may potentiate digitalis toxicity.

Skeletal muscle relaxants

(Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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.

4.6 Fertility, pregnancy and lactation

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Pregnancy

The safety of (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome in pregnancy.

(Liposomal Amphotericin B) AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks to the mother and fetus.

Breast-feeding

It is unknown whether (Liposomal Amphotericin B) AmBisome is excreted in human breast milk. A decision on whether to breastfeed while receiving (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome therapy for the mother.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Some of the undesirable effects of (Liposomal Amphotericin B) AmBisome presented below may impact the ability to drive and use machines.

4.8 Undesirable effects

Summary of adverse reactions

The following adverse reactions have been attributed to (Liposomal Amphotericin B) AmBisome based on clinical trial data and post-marketing experience. The frequency is based on analysis from pooled clinical trials of 688 (Liposomal Amphotericin B) 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

Common

Uncommon

Very 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

Uncommon: thrombocytopenia

Not known: anaemia

Immune system disorders

Uncommon: anaphylactoid reaction

Not known: anaphylactic reactions, hypersensitivity

Metabolism and nutrition disorders

Very common: hypokalaemia

Common: hyponatremia, hypocalcaemia, hypomagnesaemia, hyperglycemia,

Nervous system disorders

Common: headache

Uncommon: convulsion

Cardiac disorders

Common: tachycardia

Not known: cardiac arrest, arrhythmia

Vascular disorders

Common: hypotension, vasodilatation, flushing

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea

Uncommon: bronchospasm

Gastrointestinal disorders

Very common: nausea, vomiting

Common: diarrhoea, abdominal pain

Hepatobiliary disorders

Common: abnormal liver function tests, hyperbilirubinaemia, increased alkaline phosphatase

Skin and subcutaneous disorders

Common: rash

Not known: angioneurotic oedema

Musculoskeletal and connective tissue disorders

Common: back pain

Not Known: rhabdomyolysis (associated with hypokalaemia), musculoskeletal pain (described as arthralgia or bone pain)

Renal and urinary disorders

Common: increased creatinine, increased blood urea

Not known: renal failure, renal insufficiency

General disorders and administration site conditions

Very Common: rigors, pyrexia,

Common: chest pain

Description of selected adverse reactions

Infusion-related reactions

Fever and chills/rigors are the most frequent infusion-related reactions expected to occur during (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome (see section 4.4).

In two double-blind, comparative studies, (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome with conventional amphotericin B therapy in greater than 1,000 patients, reported adverse reactions were considerably less severe and less frequent in (Liposomal Amphotericin B) AmBisome treated patients as compared with conventional amphotericin B treated patients.

Renal toxicity

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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome (as measured by serum creatinine increase greater than 2.0 times baseline measurement) was approximately half that for Amphotericin B lipid complex.

Interference with Phosphorus Chemistry Assay

False elevations of serum phosphate may occur when samples from patients receiving (Liposomal Amphotericin B) 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 of suspected adverse reactions

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.

4.9 Overdose

The toxicity of (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome.

Special populations (including paediatric population):

No additional information is available in special populations.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, antibiotics.

Mechanism of action and pharmacodynamic effects

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 molecule 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 molecule 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.

Clinical efficacy and safety

The efficacy of (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome versus conventional amphotericin B in confirmed Aspergillus and Candida 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 (Liposomal Amphotericin B) AmBisome administered at 3 mg/kg/day is as effective as conventional amphotericin B. The efficacy of (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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

(Liposomal Amphotericin B) 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. (Liposomal Amphotericin B) AmBisome and Micafungin were administered for a median duration of 15 days. The favourable overall response was 89.5% (170/190) in the (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome and 85.4% (35/41) for Micafungin (per protocol analysis set).

Invasive mucormycosis (zygomycosis)

There are no large-scale randomised clinical trials in mucormycosis.

The working group in zygomycosis of the European confederation of medical mycology (ECMM) prospectively collected cases of patients with zygomycosis, 130 patients received liposomal amphotericin B (L-AMB) as first-line therapy, either alone (68) or in combination. In patients who received it as the only antifungal medication, the survival rate was 68%. In patients that were cured, the median duration of treatment was 55 days (range 14-169 days) and the median daily dose was 5 mg/kg (range 3-10 mg/kg), (Skiada et al; Clin Microbiol Infect 2011;17 (12):1859-67).

In a prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B for the initial treatment of mucormycosis, 29 patients receiving 10 mg/kg/day had a median treatment duration of 13.5 days (range 0-28 days). The primary endpoint was treatment success at week 4 or at end of treatment (if earlier) and 12 (36%) out of 33 evaluable patients responded, including 18% with complete response; the response rate increased to 45% at week 12. The survival rate was 62% at week 12 and 47% at week 24 (Lanternier et al; J Antimicrob Chemother 2015; 70(11):3116-23).

Paediatric population

The pharmacodynamic profile of (Liposomal Amphotericin B) AmBisome in paediatric patients is consistent with that described in adult patients.

5.2 Pharmacokinetic properties

The pharmacokinetic profile of (Liposomal Amphotericin B) AmBisome (liposomal amphotericin B (L-AmB), 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 L-AmB for 3 to 20 days. L-AmB 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) compared to conventional amphotericin B. After the first dose and last dose, the pharmacokinetic parameters of amphotericin B (mean ± standard deviation) ranged from:

C max7.3 μg/ml (± 3.8) to 83.7 μg/ml (± 43.0)
1/26.3 hr (± 2.0) to 10.7 hr (± 6.4)
AUC 0-2427 μg.hr/ml (±14) to 555 μg.hr/ml (± 311)
Clearance (CI)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 relate to the lowest and highest doses, respectively. Following administration of liposomal amphotericin B (L-AmB) steady state was reached quickly (generally within 4 days of dosing).

Absorption

Amphotericin B pharmacokinetics following the first dose of L-AmB appear non-linear such that amphotericin B concentrations are greater than proportional with increasing dose. This non-proportional dose response is believed to be due to saturation of reticuloendothelial L-AmB clearance. There was no significant drug accumulation in the plasma following repeated administration of 1 to 7.5mg/kg/day.

Distribution

Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of amphotericin B.

Elimination

After repeated administration of L-AmB, the terminal elimination half-life (t½β) of amphotericin B was approximately 7 hours. The excretion of L-AmB has not been studied. The metabolic pathways of amphotericin B and L-AmB are not known. Due to the size of the liposomes, there is no glomerular filtration and renal elimination of L-AmB, 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.

Special populations

Renal Impairment

The effect of renal impairment on the pharmacokinetics of L-AmB has not been formally studied. Data suggest that no dose adjustment is required in patients undergoing haemodialysis or filtration procedures, however, L-AmB administration should be avoided during the procedure.

Pharmacokinetic/pharmacodynamics relationship

Mechanism of resistance

Intrinsic resistance, though rare, may be primarily due to decrease in ergosterol or a change in the target lipid, leading to reduced binding of amphotericin B to the cell membrane.

Breakpoints

EUCAST breakpoints for L-AmB have not yet been established, however, susceptibility to L-AmB may differ to that of amphotericin B deoxycholate.

Amphotericin B, the antifungal component of L-AmB, 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.

L-AmB has been shown to be effective in animal models of visceral leishmaniasis (caused by Leishmania infantum and Leishmania donovani).

5.3 Preclinical safety data

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 L-AmB toxicity were the liver and kidneys with thrombocytopenia also observed. All are known targets for amphotericin B toxicity.

L-AmB was found to be non-mutagenic in bacterial and mammalian systems.

Carcinogenicity studies have not been conducted with L-AmB.

No adverse effects on male or female reproductive function were noted in rats.

  1. Pharmaceutical particulars

6.1 List of excipients

Hydrogenated soy phosphatidylcholine, Cholesterol, Distearoylphosphatidylglycerol, Alpha tocopherol

Sucrose, Disodium succinate hexahydrate as buffer.

For reconstitution use Sterile water for Injection and the resulting pH of the suspension is between 5-6.

6.2 Incompatibilities

(Liposomal Amphotericin B) 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.

6.3 Shelf life

4 years

Shelf –life of (Liposomal Amphotericin B) AmBisome after first opening

As (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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.

DiluentDilutionConcentration of Amphotericin B mg/mLMaximum duration of storage at 2-8°CMaximum duration of storage at 25±2°C
5% Dextrose1 in 22.07 days48 hours
1 in 80.57 days48 hours
1 in 200.24 days24 hours
10% Dextrose1 in 22.048 hours72 hours
20% Dextrose1 in 22.048 hours72 hours

6.4 Special precautions for storage

(Liposomal Amphotericin B) 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.

6.5 Nature and contents of container

(Liposomal Amphotericin B) 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.

6.6 Special precautions for disposal and other handling

READ THIS ENTIRE SECTION AND SECTION 4.4 CAREFULLY BEFORE BEGINNING RECONSTITUTION

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

(Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome.

(Liposomal Amphotericin B) 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, (Liposomal Amphotericin B) AmBisome should be administered through a separate line.

Do NOT mix (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome, or in the materials specified for reconstitution and dilution.

(Liposomal Amphotericin B) AmBisome must be reconstituted by suitably trained staff.

Vials of (Liposomal Amphotericin B) AmBisome containing 50 mg of amphotericin are prepared as follows:

1.Add 12 ml of Sterile Water for Injection to each (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) 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) (Liposomal Amphotericin B) AmBisome to be further diluted (see table below).
4.The infusion solution is obtained by dilution of the reconstituted (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome (see table below).
5.Withdraw the calculated volume of reconstituted (Liposomal Amphotericin B) AmBisome into a sterile syringe. Using the 5 micron filter provided, instill the (Liposomal Amphotericin B) 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 (Liposomal Amphotericin B) AmBisome. However, the mean pore diameter of the filter should not be less than 1.0 micron.

Example of the preparation of (Liposomal Amphotericin B) AmBisome dispersion for infusion at a dose of 3mg/kg/day in dextrose 5% solution for infusion.

Weight (kg)Number of vialsAmount (Liposomal Amphotericin B) AmBisome (mg) to be withdrawn for further dilutionVolume of reconstituted (Liposomal Amphotericin B) 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; (Liposomal Amphotericin B) AmBisome plus 5% dextrose)Volume of 5% dextrose needed (ml)Total volume (ml; (Liposomal Amphotericin B) AmBisome plus 5% dextrose)
101307.5142.51507.515
2527518.75356.2537518.7537.5
403120305706003060
55416541.25783.7582541.2582.5
70521052.5997.5105052.5105
85625563.751211.25127563.75127.5

* Each vial of (Liposomal Amphotericin B) 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.

7. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Liposomal Amphotericin B for Injection BP 50mg Taj Pharma
(Liposomal amphotericin B)
(AmBisome

Package leaflet: Information for the user

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor.
  • If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Liposomal Amphotericin B is and what it is used for
    2. What you need to know before you are given Liposomal Amphotericin B
    3. How to use Liposomal Amphotericin B
    4. Possible side effects
    5. How to store Liposomal Amphotericin B
    6. Content of the pack and other information

 

  1. WHAT LIPOSOMAL AMPHOTERICIN B IS AND WHAT IT IS USED FOR

Liposomal Amphotericin B is an antifungal antibiotic. The active ingredient in Liposomal Amphotericin B is amphotericin B.

Liposomal Amphotericin B is given as an infusion into a vein (a drip) in hospital by a doctor or nurse.

Liposomal Amphotericin B is used to treat serious infections caused by fungi:

  • Fungal infections of one or more deep organs of the body.
  • Suspected fungal infectionsin patients with a raised temperature and neutropenia. Neutropenia is a reduced number of white blood cells called neutrophils. These are important in fighting infections. Neutropenia can be a side effect of cancer treatments.
    Before you are given Liposomal Amphotericin B your doctor will check that your fever is not due to bacteria or viruses. You will probably have had one or more antibiotics already. A fever which continues despite treatment may be due to a fungal infection. It’s difficult to confirm this with current tests, however.
  • Visceral leishmaniasis, a disease caused by a parasite.
  1. WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN LIPOSOMAL AMPHOTERICIN B

Before your first treatment

Before your first treatment your doctor may give you a small amount of Liposomal Amphotericin B. They will then wait for approximately 30 minutes to see whether you have an allergic reaction, before continuing the infusion of the full dose.

Your doctor will not give you Liposomal Amphotericin B

  • If you are allergic(hypersensitive) to Amphotericin B or any of the other ingredients of Liposomal Amphotericin B. However, if your condition is life-threatening you may be given Liposomal Amphotericin B if your doctor believes that only Liposomal Amphotericin B can help you.
  • If you have previously experienced a severe allergic reaction (anaphylactic or anaphylactoid) to Liposomal Amphotericin B. Symptoms of such immediate and life-threatening allergic reactions include: flushing, itching, sickness, swelling of the face, mouth, tongue and airways, often enough to cause difficulty breathing.

Warnings and precautions

Your doctor will take special care with Liposomal Amphotericin B

  • If you have a severe allergic (anaphylactic) reaction.If this happens your doctor will stop the infusion.
  • If you get other reactions related to the infusion. If this happens, your doctor may slow down the infusion, so you receive Liposomal Amphotericin B over a longer period of time (approximately 2 hours). Your doctor may also give you medicines to prevent or treat infusion-related reactions, such as diphenhydramine (an antihistamine), paracetamol, pethidine (for pain relief) and/or hydrocortisone (an anti-inflammatory medicine that works by reducing the response of your immune system).
  • If you are taking other medicines that may cause kidney damagesee Taking other medicines, right. Liposomal Amphotericin B may cause damage to the kidney. Your doctor or nurse will take regular blood samples. This is to test creatinine (a chemical in the blood that reflects kidney function), and electrolyte levels (particularly potassium and magnesium) Both of these can be abnormal if you have kidney problems. This is particularly important if you are taking other medicines that may cause damage to the kidney. The blood samples will also be tested for changes in your liver, and your body’s ability to produce new blood cells and platelets.
  • If blood tests show a change in kidney function,or other important changes. If this happens, your doctor may give you a lower dose of Liposomal Amphotericin B or stop treatment.
  • If blood tests show that your potassium levels are low. If this happens, your doctor may prescribe a potassium supplement for you to take while you are treated with Liposomal Amphotericin B.
  • If you have a white blood cell transfusion. Sudden and severe problems in the lungs can happen if you are given Liposomal Amphotericin B infusion during or shortly after a white blood cell transfusion. Your doctor will recommend that the infusions are separated by as long a period as possible. This will reduce the risk of lung problems, and your lungs will be monitored.
  • If you have had kidney failure and are having dialysis. Your doctor may start Liposomal Amphotericin B treatment after the procedure has ended.
  • If you have diabetes. Liposomal Amphotericin B contains approximately 900 mg of sucrose (sugar) in each vial. Tell your doctor if you have diabetes.

Other medicines and Liposomal Amphotericin B

Tell your doctor if you are taking any other medicines, or have recently taken any. This includes medicines and herbal products you bought without a prescription.

Medicines that may cause kidney damage:

  • Medicines that suppress the immune system(immunosuppressants), such as ciclosporin and tacrolimus.
  • Certain antibioticscalled aminoglycosides (including gentamicin, neomycin and streptomycin) and polymixins.
  • Pentamidinea medicine used to treat pneumonia in people with AIDS and leishmaniasis.
  • Tell your doctor if you are taking any of these medicines. Liposomal Amphotericin B may make any kidney damage caused by the medicine worse. If you are taking any of these medicines, your doctor or nurse will take regular blood samples to check your kidneys.

Medicines that may lower your potassium levels:

  • Corticosteroids,anti-inflammation medicines that work by reducing the response of your immune system.
  • Corticotropin(ACTH), used to control the amount of corticosteroid produced by your body. The body produces corticosteroid in response to stress.
  • Diuretics,medicines that increase the amount of urine your body produces. This includes furosemide.
  • Digitalis glycosides,medicines produced from the foxglove plant and used to treat heart failure. Liposomal Amphotericin B may worsen the side effects of digitalis, such as heart rhythm changes.
  • Muscle relaxantsusually used during surgery, such as tubocurarine. Liposomal Amphotericin B may increase the muscle relaxant effect.

Other medicines:

  • Antifungal medicines,such as flucytosine. Liposomal Amphotericin B may worsen the side effects of flucytosine. This includes changes in the body’s ability to produce new blood cells. This may be seen in blood tests.
  • Certain cancer medicines,such as methotrexate, doxorubicin, carmustine and cyclophosphamide. Taking this type of medicine with Liposomal Amphotericin B may cause kidney damage, wheezing or trouble breathing and low blood pressure.
  • White blood cell (leukocyte) transfusions. Sudden and severe problems in the lungs can happen if you are given Liposomal Amphotericin B infusion during or shortly after a white blood cell transfusion. Your doctor will recommend that the infusions are separated by as long a period as possible. This will reduce the risk of lung problems and your lungs will be monitored.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Your doctor will only prescribe Liposomal Amphotericin B if they think the benefits of treatment outweigh the risks to you and your unborn child or your baby.

Driving and using machines

Do not drive or operate machinery

Some of the possible side effects of Liposomal Amphotericin B could affect your ability to drive or use machines safely, See Section 4, Possible side effects.

Liposomal Amphotericin B contains sugar

Tell your doctor if you have diabetes. Liposomal Amphotericin B contains approximately 900 mg of sugar (sucrose) in each vial.

  1. HOW LIPOSOMAL AMPHOTERICIN B IS GIVEN

Liposomal Amphotericin B is always given to you by a doctor or nurse. It is given into a vein (a drip). Liposomal Amphotericin B must not be given by any other method.

To prepare the infusion Liposomal Amphotericin B must be dissolved in sterile water for injection and then diluted with a solution containing dextrose.

Liposomal Amphotericin B must not be mixed with saline (salt) solutions or with other medicinal products or electrolytes.

Liposomal Amphotericin B is not interchangeable with other amphotericin products.

Before your first treatment

Before your first treatment your doctor may give you a small amount of Liposomal Amphotericin B. They will then wait for approximately 30 minutes to see whether you have an allergic reaction, before continuing the infusion of the full dose.

Use in adults

Your dose of Liposomal Amphotericin B will depend on your body weight.

Fungal infections of one or more deep organs of the body:

Treatment is normally started at 1 mg per kg of body weight, every day over 2 to 4 weeks. Your doctor may decide to increase the amount you receive to as high as 3 mg per kg of body weight.

For mucormycosis the starting dose is normally 5 mg per kg of body weight per day. The duration of therapy will be determined on an individual basis by your Doctor.

Suspected fungal infections in patients with a raised temperature and neutropenia: The recommended daily dose is 3 mg per kg of body weight, per day. Liposomal Amphotericin B will be given to you until your temperature is normal for 3 days in a row. However, Liposomal Amphotericin B must not be given for more than 42 days in a row.

Visceral leishmaniasis:

You may be given a total dose of between 21 and 30 mg per kg of body weight, over a period of 10 to 21 days. Your doctor will decide on the amount of Liposomal Amphotericin B you will receive and over how many days it will be given.

Use in children and adolescents

Liposomal Amphotericin B has been used to treat children. The dose of Liposomal Amphotericin B for a child is calculated per kg of body weight in the same way as for adults.

Liposomal Amphotericin B is not recommended in babies under 1 month old.

Use in elderly patients

No change in dose or frequency of infusion is needed for elderly patients.

Use in patients with kidney problems

Liposomal Amphotericin B has been given to patients with kidney problems at doses ranging from 1 to 5 mg per kg of body weight per day. No change in dose or frequency of infusion is required. Your doctor or nurse will take regular blood samples to test for changes in kidney function during Liposomal Amphotericin B treatment.

How long will the infusion take?

Normally the infusion will take 30 to 60 minutes. For doses greater than 5 mg per kg of body weight per day, the infusion could take up to 2 hours.

If you receive a higher dose of Liposomal Amphotericin B than you should

You should tell your doctor immediately if you think you received too much Liposomal Amphotericin B.

If you have any further questions on the use of this product, ask your doctor.

  1. POSSIBLE SIDE EFFECTS

Like all medicines, Liposomal Amphotericin B can cause side effects, although not everybody gets them.

Side effects during the infusion

You may get side effects during the infusion:

  • Very common(These can affect more than 1 in every 10 people): fever, chills, and shivering.
  • Less frequent infusion-related side effects include:chest tightness, chest pain, breathlessness, difficulty breathing (possibly with wheezing), flushing, a faster heart rate than normal, low blood pressure and musculoskeletal pain (described as joint pain, back pain, or bone pain).

These side effects clear up quickly when the infusion is stopped. These reactions may not happen with future infusions of Liposomal Amphotericin B or with a slower infusion (over 2 hours). Your doctor may give you other medicines to prevent infusion-related reactions, or to treat the symptoms if you do get them. If you have a severe infusion-related reaction, your doctor will stop the Liposomal Amphotericin B infusion and you should not receive this treatment in the future.

Very common side effects

These can affect more than 1 in every 10 people:

  • Low blood potassium levels, leading to feeling tired, confused, having muscle weakness or cramps
  • Feeling sick or being sick
  • Fever, chills or shivering.

Common side effects

These can affect up to 1 in every 10 people:

  • Low magnesium, calcium or sodium blood levels, leading to feeling tired, confused, muscle weakness or cramps
  • High blood sugar levels
  • Headache
  • A faster heart rate than normal
  • Widening of the blood vessels, causing low blood pressure and flushing
  • Breathlessness
  • Diarrhoea
  • Stomach (abdominal) pain
  • Rash
  • Chest pain
  • Back pain
  • Abnormal results for liver or kidney function showing up in blood tests or urine tests.

Uncommon side effects

These can affect up to 1 in every 100 people:

  • Bleeding into the skin, unusual bruising and bleeding for a long time after injury
  • Severe allergic (anaphylactoid) reaction
  • Fits or seizures (convulsions)
  • Difficulty breathing, possibly with wheezing.

Other side effects

It is not known how frequently these side effects occur:

  • Anaemia (low red blood cell levels), with symptoms of excessive tiredness, being out of breath after light activity, and a pale complexion
  • Severe allergic (anaphylactic) or sensitivity reactions
  • Heart attacks and heart rhythm changes
  • Kidney failure and kidney problems. Signs include tiredness and passing less urine
  • Severe swelling of the skin around the lips, eyes or tongue.
  • Breakdown of muscle
  • Bone pain and joint pain

Interference with Phosphorus blood test results. False readings showing an increase in the levels of phosphate in your blood may occur when samples from patients receiving Liposomal Amphotericin B are analyzed using a specific system called a PHOSm assay.

If your test results show high levels of phosphate, then further analysis using a different system may be necessary to confirm the results.

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.

  1. HOW TO STORE LIPOSOMAL AMPHOTERICIN B

Liposomal Amphotericin B is stored in the hospital pharmacy.

Keep this medicine out of the sight and reach of children.

Do not use Liposomal Amphotericin B after the date which is stated on the label after {EXP}. The expiry date refers to the last day of the month.

Do not store above 25°C.

Do not store partially used vials for future patient use.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

  1. Contents of the pack and other information

What Liposomal Amphotericin B contains

The active ingredient is amphotericin B.

Each vial contains 50mg of amphotericin (50,000 units) encapsulated in liposomes. After reconstitution, the concentrate contains 4 mg/mL amphotericin B.

Each vial contains 100mg of amphotericin (100,000 units) encapsulated in liposomes. After reconstitution, the concentrate contains 4 mg/mL amphotericin B.

The other ingredients are: hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, alpha tocopherol, sucrose (sugar), disodium succinate hexahydrate, sodium hydroxide and hydrochloric acid.

What Liposomal Amphotericin B looks like and contents of the pack

Liposomal Amphotericin B is a sterile, bright yellow lyophilisate (freeze-dried powder) for dispersion for infusion.

It is presented in a 15-ml, 20-ml or 30-ml glass vial.

Each vial contains 50 mg of the active ingredient amphotericin B.

The closure consists of a rubber stopper and an aluminium ring seal fitted with a removable plastic cap.

Each carton contains 10 vials and 10 filters.

Not all pack sizes may be marketed.

7. Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com