Amphotericin B (lipid complex).
Pharmacology: Ampholip contains the antifungal agent, amphotericin B, complexed with phospholipids. Amphotericin B is a macrocyclic, polyene, broad-spectrum antifungal antibiotic produced by Streptomyces nodosus. The lipophilic moiety of amphotericin B allows molecules of the drug to be complexed in a ribbon-like structure with the phospholipids.
Mechanism of Action: Amphotericin B, the active antifungal agent in Ampholip, may be fungistatic or fungicidal, depending on its concentration and on fungal susceptibility. Amphotericin B acts by binding to ergosterol in the fungal cell membrane causing subsequent membrane damage. As a result, cell contents leak from the fungal cell and ultimately, cell death occurs.
Microbiology: Amphotericin B is active against many fungal pathogens in vitro, including Candida sp, Cryptococcus neoformans, Aspergillus sp, Mucor sp, Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum: Most strains are inhibited by amphotericin B at concentrations of 0-1 mg/mL. Amphotericin B has little or no activity against bacteria or viruses.
Pharmacokinetics: The pharmacokinetic properties of Ampholip and conventional formulation of amphotericin B containing desoxycholate are different. Pharmacokinetic studies in animals showed that, after administration of Ampholip, amphotericin B levels were higher in the liver and spleen. Amphotericin B in Ampholip was rapidly distributed to tissue. The ratio of drug concentrations in tissues to those in blood increased disproportionately with increasing dose, suggesting that elimination of the drug from the tissue was delayed. Peak blood levels of amphotericin B were lower after administration of Ampholip than after administration of equivalent amounts of conventional drug. Administration of conventional amphotericin B resulted in much lower tissue levels than did dosing with Ampholip.
The rapid clearance and large volume of distribution of Ampholip result in a relatively low AUC and are consistent with preclinical data showing high tissue concentrations. The kinetics of Ampholip are nonlinear.
Toxicology: Preclinical Safety Data: Acute toxicity studies in rodents showed that Ampholip was 10- 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, Ampholip was 8- to 10-fold less nephrotoxic than conventional amphotericin B. This decreased nephrotoxicity was presumably a result of lower drug concentrations in the kidney.
Treatment of severe systemic fungal infections including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcsis, histoplasmosis, mucormycosis, paracoccidioidomycosis and sporotrichosis and is the usual treatment of choice in fungal endocarditis, meningitis, peritonitis or severe respiratory tract infection.
Severe Systemic Infections: Recommended Dose: 5 mg/kg for at least 14 days. It should be administered by IV infusion at a rate of 2.5 mg/kg/hr. An initial test dose of 1 mg should be infused IV >15 min.
Ampholip has been administered for as long as 11 months and cumulative doses have been as high as 56.6 g without significant toxicity.
Children and Elderly with Systemic Fungal Infections: Systemic fungal infections in children and elderly have been treated successfully with Ampholip at doses comparable to the recommended adult dose on a body weight basis.
Neutropenic Patients with Systemic Fungal Infections: Ampholip has been successfully used to treat systemic fungal infections in patients who are severely neutropenic as a consequence of hematological malignancy or the use of cytotoxic or immunosuppressive drugs.
Administration: Ampholip suspension is to be diluted for IV infusion only.
As for use with all amphotericin B products, facilities for cardiopulmonary resuscitation should be readily at hand when administering Ampholip, due to the possible occurrence of anaphylactoid reactions.
During administration of Ampholip, serum creatinine levels should be measured to monitor the renal toxicity. Dose adjustments should be made only after taking into account the overall clinical condition of the patient.
No serious acute reactions of cardiorespiratory arrest had been reported as found with overdosage of amphotericin B desoxycholate. If an overdosage is suspected, discontinue the therapy, monitor the patient closely, and administer supportive therapy are required. Ampholip is not hemodialyzable.
Patients with known hypersensitivity to amphotericin B or any of the components of Ampholip, unless the advantages of using Ampholip outweigh the risks of hypersensitivity.
Systemic Fungal Infections: Ampholip should not be used for treating common or superficial, inapparent fungal infections that are detectable only by positive skin or serologic tests.
Renal Disease: Since amphotericin B is potentially nephrotoxic drug, monitoring of renal function should be performed before initiating treatment in patients with preexisting renal disease and at least once weekly during therapy. Ampholip 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 Ampholip. In cases where serum bilirubin alkaline phosphatase or serum transaminase is increased, factors other than Ampholip were present and possibly accounted for the abnormalities. These factors included infection, hyperalimentation, concomitant hepatotoxic drugs and graft-versus-host disease.
Effects on the Ability to Drive or Operate Machinery: Ampholip 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 Ampholip generally precludes driving or operating machinery.
Carcinogenicity, Mutagenicity & 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. Ampholip has not been shown to be mutagenic by in vivo mouse micronucleus assay. It has not been shown 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.
Use in pregnancy & lactation: Conventional amphotericin B has been used successfully to treat systemic fungal infections in pregnant women with no obvious effects on the fetus, but only a small number of cases have been reported. Reproductive toxicity studies of amphotericin B in rats and rabbits showed no evidence of embryotoxicity, fetotoxicity or teratogenicity. However, safety for use in pregnant or lactating women has been established to pregnant or lactating women only for life-threatening disease when the likely benefit exceeds the risk to the mother and fetus.
Patients in whom significant renal toxicity was observed following conventional amphotericin B frequently did not experience similar effects when Ampholip was substituted. Adverse reactions related to the administration of Ampholip have generally been mild to moderate and have been most prevalent during the first 2 days of dosing.
Premedication (eg, 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 hypokalemia, have not typically required discontinuation of treatment. Ampholip has not been reported to directly cause changes in hepatic or hematologic function.
Adverse reactions that have been reported to occur with conventional amphotericin B may occur in Ampholip. In general, the physician should monitor the patient for any type of adverse event associated with conventional amphotericin B.
Nephrotoxic Drugs: Amphotericin B is potentially nephrotoxic and particularly close monitoring of renal function is required in patients receiving nephrotic drugs concomitantly.
Zidovudine: In dogs, exacerbated myelotoxicity and nephrotoxicity were observed when Ampholip was administered concomitantly with zidovudine. If concomitant treatment with zidovudine is required, renal and hematologic function should be closely monitored.
Cyclosporin: Preliminary data suggest that patients receiving Ampholip 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 Ampholip.
Conventional amphotericin B has been reported to interact with antineoplastic agents, corticosteroids and corticotrophin (ACTH), digitalis glycosides and skeletal muscle relaxants.
Direction for Reconstitution: Ampholip should be mixed with 5% dextrose injection and administered as a 1 mg/mL infusion mixture. However, pediatric patients and patients with cardiovascular disease could administer Ampholip as a 2 mg/mL infusion mixture after diluting with 5% dextrose injection.
Preparation of Infusion Mixture:
1. Shake the vial gently and withdraw the required dose of amphotericin B from the vials into ≥1 syringes of suitable capacity (≤20 mL) using 18 gauge needle.
2. Remove the needle from each syringe filled with Ampholip and replace with 5u filter needle supplied with each vial pack.
3. Insert the filter needle of the syringe into an IV bag containing 5% dextrose injection and empty the content of the syringe into the bag.
4. Shake the bag until the contents are thoroughly mixed.
Do not use infusion mixture if there is any evidence of foreign matter.
The infusion is best administered by means of an infusion pump.
Aseptic technique must be strictly observed throughout handling of Ampholip, since no preservative or bacteriostatic agent is present in Ampholip.
Ampholip vials are for single use and hence, any unused material should be discarded.
Do not dilute with sodium chloride injection (saline) or mix with over drugs or electrolytes.
Do not use an on-line microbial filter during administration of Ampholip mixture (1 mg/mL), the contents of the bag should be mixed by shaking the infusion bag every 2 hrs.
It is not advisable to store the diluted Ampholip infusion mixture.
Store at temperatures between 2-8°C. Do not freeze. Protect from direct exposure to light.
Shelf-Life: 24 months.
J02AA01 - amphotericin B ; Belongs to the class of antibiotics. Used in the systemic treatment of mycotic infections.
Lyophilized susp for inj (sterile, isotonic, pyrogen-free susp, yellow and opaque) 5 mg/mL x 10 mL x 1's.