50 mg/10 ml
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
AMPHOTERICIN B LIPID COMPLEX INJECTION (Amphotericin B) is a polyene, antifungal antibiotic produced from a strain of Streptomyces nodosus. Chemically amphotericin B is (3R,5R,8R,9R,11S,13R, 15S,16R,17S,19R,34S,35R, 36R,37S)-19-(3-amino-3,6-dideoxy b -D-mannopyranosyloxy)-16-carboxy-3, 5, 8, 9, 11, 13, 15, 35- octa-hydroxy-34,36-dimethyl-13, 17-epoxyoctatriaconta-20,22,24,26,28,30,32-heptaen-37-olide. The molecular formula is C47H73NO17 and molecular weight is 924.09.
STRUCTURAL FORMULA :
Its structural formula is :
AMPHOTERICIN B LIPID COMPLEX INJECTION is sterile, yellow coloured suspension, which settles on keeping and gets dispersed uniformly on mild shaking, filled in vial of suitable size.
Each ml contains :
Amphotericin B I.P. 5 mg
Sodium Chloride I.P. 9 mg
Water for Injections I.P. q.s.
Dimyristoylphosphatidylcholine (DPMC) 3.4 mg
(DMPG as sodium salt) 1.5 mg
Combipack with one 5 micron filter needle.
The active component of AMPHOTERICIN B LIPID COMPLEX INJECTION, amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action.
Microbiological activity :
Amphotericin B is active against many fungal pathogens in vitro, including Candida spp., Cryptococcus neoformans, Aspergillus spp., Mucor spp., Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum. Most strains are inhibited by Amphotericin B concentrations of 0.03-1.0 mg/ml. Amphotericin B has little or no activity against bacteria or viruses.
Pharmacokinetic Properties :
The pharmacokinetic properties of AMPHOTERICIN B LIPID COMPLEX INJECTION and conventional formulation of Amphotericin B containing desoxycholate are different. Pharmacokinetic studies in animals showed that, after administration of AMPHOTERICIN B LIPID COMPLEX INJECTION, Amphotericin B levels were higher in the liver and spleen. Amphotericin B in AMPHOTERICIN B LIPID COMPLEX INJECTION was rapidly distributed to tissues. The ratio of drug concentrations in tissues to those in blood increased disproportionately with increasing dose, suggesting that elimination of the drug from the tissues was delayed. Peak blood levels of Amphotericin B were lower after administration of AMPHOTERICIN B LIPID COMPLEX INJECTION than after administration of equivalent amounts of conventional drug. Administration of conventional Amphotericin B resulted in much lower tissue levels than did dosing with AMPHOTERICIN B LIPID COMPLEX INJECTION. The rapid clearance and large volume of distribution of AMPHOTERICIN B LIPID COMPLEX INJECTION result in a relatively low AUC and are consistent with preclinical data showing high tissue concentrations. The kinetics of AMPHOTERICIN B LIPID COMPLEX INJECTION is nonlinear.
Preclinical Safety Data :
Acute toxicity studies in rodents showed that AMPHOTERICIN B LIPID COMPLEX INJECTION was 10-fold to 20-fold less toxic than conventional Amphotericin B. Multiple-dose toxicity studies in dogs lasting 2-4 weeks showed that on a mg/kg basis, AMPHOTERICIN B LIPID COMPLEX INJECTION was 8-fold to 10-fold less nephrotoxic than conventional Amphotericin B. This decreased nephrotoxicity was presumably a result of lower drug concentrations in the kidney.
AMPHOTERICIN B LIPID COMPLEX INJECTION is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy.
SHAKE GENTLY BEFORE USE.
AMPHOTERICIN B LIPID COMPLEX INJECTION should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours. Renal toxicity of AMPHOTERICIN B LIPID COMPLEX INJECTION, as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient. Preparation of Admixture for Infusion : Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of AMPHOTERICIN B LIPID COMPLEX INJECTION from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with AMPHOTERICIN B LIPID COMPLEX INJECTION and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5 % Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/ml. For paediatric patients and patients with cardiovascular disease the drug may be diluted with 5 % Dextrose Injection to a final infusion concentration of 2 mg/ml. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5 % Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of AMPHOTERICIN B LIPID COMPLEX INJECTION, since no bacteriostatic agent or preservative is present.
DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of AMPHOTERICIN B LIPID COMPLEX INJECTION with these materials has not been established. An existing intravenous line should be flushed with 5 % Dextrose Injection before infusion of AMPHOTERICIN B LIPID COMPLEX INJECTION, or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER.
The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion.AMPHOTERICIN B LIPID COMPLEX INJECTION has been administered for as long as 11 months, and cumulative doses have been as high as 56.6 g without significant toxicity.
Paediatric Use :
Systemic fungal infections in children have been treated successfully with AMPHOTERICIN B LIPID COMPLEX INJECTION at doses comparable to the recommended adult dose on a body weight basis.
Use in Elderly Patients :
Systemic fungal infections in elderly patients have been treated successfully with AMPHOTERICIN B LIPID COMPLEX INJECTION doses comparable to the recommended dose on a body weight basis.
Use in Neutropenic Patients :
AMPHOTERICIN B LIPID COMPLEX INJECTION has been successfully used to treat systemic fungal infections in patients who are severely neutropenic as a consequence of haematological malignancy or the use of cytotoxic or immunosuppressive drugs.
AMPHOTERICIN B LIPID COMPLEX INJECTION is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.
Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B containing drugs. Anaphylaxis has been reported with AMPHOTERICIN B LIPID COMPLEX INJECTION with an incidence rate of <0.1 %. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of AMPHOTERICIN B LIPID COMPLEX INJECTION.
As with any amphotericin B-containing product, during the initial dosing of AMPHOTERICIN B LIPID COMPLEX INJECTION, the drug should be administered under close clinical observation by medically trained personnel. Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of AMPHOTERICIN B LIPID COMPLEX INJECTION . These reactions are usually more common with the first few doses of AMPHOTERICIN B LIPID COMPLEX INJECTION and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.
Laboratory Tests :
Serum creatinine should be monitored frequently during AMPHOTERICIN B LIPID COMPLEX INJECTION therapy . It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts.
Systemic Fungal Infections :
AMPHOTERICIN B LIPID COMPLEX INJECTION should not be used for treating common or superficial, clinically inapparent fungal infections that are detectable only by positive skin or serologic tests.
Renal Disease :
Since Amphotericin B is a potentially nephrotoxic drug, monitoring of renal function should be performed before initiating treatment in patients with pre-existing renal disease, and at least once weekly during therapy. AMPHOTERICIN B LIPID COMPLEX INJECTION should be administered to patients undergoing renal dialysis only after the completion of dialysis. Serum potassium and magnesium levels should be monitored regularly.
Liver Disease :
Patients with concurrent hepatic impairment due to infection, graft-versus-host disease, other liver disease or administration of hepatotoxic drugs have been successfully treated with AMPHOTERICIN B LIPID COMPLEX INJECTION. In cases where serum bilirubin, alkaline phosphatase or serum transaminases increased, factors other than AMPHOTERICIN B LIPID COMPLEX INJECTION were present and possibly accounted for the abnormalities. These factors included infection, hyper alimentation, concomitant hepatotoxic drugs and graft-versus-host disease.
Pregnancy : Category B
There are no reports of pregnant women having been treated with AMPHOTERICIN B LIPID COMPLEX INJECTION . Teratogenic Effects : Reproductive studies in rats and rabbits at doses of AMPHOTERICIN B LIPID COMPLEX INJECTION up to 0.64 times the human dose revealed no harm to the foetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women. AMPHOTERICIN B LIPID COMPLEX INJECTION should be used during pregnancy only after taking into account the importance of the drug to the mother.
Nursing mothers :
It is not known whether AMPHOTERICIN B LIPID COMPLEX INJECTION is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast fed infants from AMPHOTERICIN B LIPID COMPLEX INJECTION , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
EFFECT ON ABILITY TO DRIVE AND USE
AMPHOTERICIN B LIPID COMPLEX INJECTION is unlikely to affect the ability of an individual to drive or use machines, since adverse reactions are usually infusion-related. However, the clinical condition of patients who require AMPHOTERICIN B LIPID COMPLEX INJECTION generally precludes driving or operating machinery.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY :
Since conventional Amphotericin B first became available, there have been no reports of drug related carcinogenicity, mutagenicity, teratogenicity or adverse effect on fertility. AMPHOTERICIN B LIPID COMPLEX INJECTION has been shown not to be mutagenic by the in vivo mouse micronucleus assay. It has been shown not to be teratogenic in mice and rabbits. Phospholipids are essential constituents of human cell membranes. The average diet provides several grams of phospholipids each day. There is no evidence that phospholipids, including DMPC and DMPG, are carcinogenic, mutagenic or teratogenic.
INTERACTIONS AND INCOMPATIBILITIES :
No formal clinical studies of drug interactions have been conducted with AMPHOTERICIN B LIPID COMPLEX INJECTION . However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with AMPHOTERICIN B LIPID COMPLEX INJECTION :
Antineoplastic agents :
Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with AMPHOTERICIN B LIPID COMPLEX INJECTION with great caution.
Corticosteroids and corticotropin (ACTH) :
Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalaemia which could predispose the patient to cardiac dysfunction. If used concomitantly with AMPHOTERICIN B LIPID COMPLEX INJECTION, serum electrolytes and cardiac function should be closely monitored.
Cyclosporin A :
Preliminary data suggest that patients receiving AMPHOTERICIN B LIPID COMPLEX INJECTION concomitantly with high dose of cyclosporin experience an increase in serum creatinine. The data also suggest that the increase in serum creatinine is caused by cyclosporin and not by AMPHOTERICIN B LIPID COMPLEX INJECTION.
Digitalis glycosides :
Concurrent use of amphotericin B may induce hypokalaemia and may potentiate digitalis toxicity. When administered concomitantly with AMPHOTERICIN B LIPID COMPLEX INJECTION , serum potassium levels should be closely monitored.
Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with AMPHOTERICIN B LIPID
COMPLEX INJECTION with caution.
Imidazoles (e.g. ketoconazole, miconazole, clotrimazole, fluconazole, etc.) :
Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitro and in vivo animal studies. The clinical significance of these findings has not been determined.
Leukocyte transfusions :
Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and AMPHOTERICIN B LIPID COMPLEX INJECTION should not be given concurrently.
Other nephrotoxic medications :
Concurrent use of amphotericin B and agents such as aminoglcosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with AMPHOTERICIN B LIPID COMPLEX INJECTION only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications.
Skeletal muscle relaxants :
Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine) due to hypokalaemia. When administered concomitantly with AMPHOTERICIN B LIPID COMPLEX INJECTION, serum potassium levels should be closely monitored.
Increased myelotoxicity and nephrotoxicity were observed in dogs when either AMPHOTERICIN B LIPID COMPLEX INJECTION (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with AMPHOTERICIN B LIPID COMPLEX INJECTION, renal and haematologic function should be closely monitored.
SIDE EFFECTS :
Patients in whom significant renal toxicity was observed following conventional Amphotericin B frequently did not experience similar effects when AMPHOTERICIN B LIPID COMPLEX INJECTION was substituted. Adverse reactions related to the administration of AMPHOTERICIN B LIPID COMPLEX INJECTION have generally been mild or moderate, and have been most prevalent during the first 2 days of dosing. Premedication (e.g. paracetamol) may be administered for the prevention of infusion related adverse events. The most common clinical adverse effects have been chills, fever, nausea and vomiting, which may occur during the first 2 days of treatment. Decline in renal function, shown by increased serum creatinine, azotemia and hypokalaemia, have not typically required discontinuation of treatment. AMPHOTERICIN B LIPID COMPLEX INJECTION has not been reported to directly cause changes in hepatic or haematologic function. Adverse reactions that have been reported to occur with conventional Amphotericin B may occur with AMPHOTERICIN B LIPID COMPLEX INJECTION. In general, the physician should monitor the patient for any type of adverse event associated with conventional Amphotericin B.
No serious acute reactions of cardio-respiratory arrest has been reported as found with the over dosage of Amphotericin B desoxycholate.
TREATMENT OF OVERDOSAGE :
If an overdose is suspected, discontinue therapy, monitor the patient’s clinical status, and administer supportive therapy as required. AMPHOTERICIN B LIPID COMPLEX INJECTION is not hemodialyzable.
PHARMACEUTICAL PRECAUTIONS :
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Store in a refrigerator between 2°C to 8°C, protected from light.
Do not freeze.
SHELF LIFE :
24 months from the date of manufacture.
AMPHOTERICIN B LIPID COMPLEX INJECTION is supplied as below table :
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.