AmBisome Inj. (amphotericin B liposome for injection)

Transcription

1 Prescription drug Drug Classification no.: 616 AmBisome Inj. (amphotericin B liposome for injection) Composition Per 1 vial Active ingredient : Amphotericin B mg (titer) Additives (Stabilizer) : alpha tocopherol 0.64 mg, sucrose 900 mg Other additives : hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, cholesterol, disodium succinate hexahydrate, hydrochloric acid, sodium hydroxide Form Vial filled with yellow, liposomal and lyophilized cake or powder Indications Valid species In in vitro trials, this drug showed antifungal activity against the following fungus: Histoplasma capsulatum, Coccidioides immitis, Candida, Blastomyces, dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, Aspergillus fumigatus. In the in vitro trials, it suppresses most species at the concentration of 0.03~1.0 g/ml. Indications - Following systemic fungal infections sensitive to this drug: cryptococcosis, North American Blastomycosis, sporadic candidiasis, coccidioidomycosis, aspergillosis, mucormycosis and American mucocutaneous leishmaniasis - Fever of unknown origin show in patients with neutropenia (Persistent fever of unknown origin which is not improved even after 96-hour treatment with antibiotics) - Primary treatment of visceral leishmaniasis in immunocompetent adults and children - Primary treatment of visceral leishmaniasis in immunocompromised patients (HIV-positive patients etc.) Page 1

2 Dosage & Administration Trial dosage (1mg) should be slowly injected for 10 mins. and patient s condition should be carefully monitored for 30 mins. Adults and children This drug should be administered via intravenous infusion for 30~60 mins. The most desirable concentration in the intravenous infusion is 0.2~2.0 mg/ml of amphotericin B. Dosing should be individualized to the needs of the specific patient. 1. Systemic fungal infections: Although 1.0 mg(titer)/kg/day is usually administered, the dosage can be gradually increased to 5.0 mg(titer)/kg/day, if required. No toxicity was shown even when this drug was given for 3 months, resulting in the accumulated dose of amphotericin B to 16.8 g(titer). This drug successfully treated systemic fungal infections in pediatric patients with no particular adverse reactions. 2. Fever of unknown origin show in patients with neutropenia 1.0 mg(titer)/kg/day is administered as initial dose, which can be increased to 3.0 mg(titer)/kg/day according to symptoms. 3. Visceral leishmaniasis: 1.0~1.5 mg(titer)/kg/dayis administered for 21 days or 3.0 mg(titer)/kg/day for 10 days. For immunocompromised patients (HIVpositive patients etc.), 1.0~1.5 mg(titer)/kg/day is administered for 21 days. Maintenance therapy or responsive therapy is performed if required due to the risk of recurrence. Administration to elderly patients No separate administration & dosage or precautions are decided. <How to reconstitute this drug> Please note the following directions before reconstitution. This drug should be reconstituted with Sterile Water for Injection, not with saline. The vial containing 50 mg of amphotericin B should be reconstituted according to the following procedures: 1) Aseptically add 12 ml of Sterile Water for Injection to each AmBisome vial to yield a preparation containing 4 mg/ml of amphotericin B. Page 2

3 2) Immediately after the addition of water, shake the vial vigorously for 30 seconds to completely disperse this drug. Visually inspect the vial for particulate matter and continue shaking until completely dispersed. 3) Calculate the amount of reconstituted (4 mg/ml) AmBisome to be further diluted. 4) AmBisome must be diluted with 5% Dextrose Injection in 1:1~1:19 ratio to a final concentration of 2.0 ~ 0.2 mg(titer)/ml of amphotericin B. 5) Withdraw the calculated amount (amount intended to be given) of reconstituted AmBisome into a sterile syringe. Inject the reconstituted solution into the sterile syringe containing 5% Dextrose Injection using 5-micron filter provided. <Precautions in reconstitution> 1) Only Sterile Water for Injection should be used in the reconstitution. As the use of saline is not physically appropriate for the reconstitution of this drug, it should not be mixed with other drugs or electrolytes. Do not reconstitute with saline or add saline to the reconstituted concentration, or mix with other drugs. 2) The use of any solution other than those recommended, or the presence of preservative (e.g., benzyl alcohol) in the solution, may cause precipitation of this drug. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in this drug or in the materials specified for reconstitution and dilution. 3) 5% Dextrose Injection should be used for dilution. 4) An in-line membrane filter may be used for the intravenous infusion of this drug; provided the mean pore diameter of the filter should be not less than 1.0 micron. 5) An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of this drug. If this is not feasible, this drug must be administered through a separate line. 6) Part of the vial of this drug should not be used for next administration. Page 3

4 Precautions in Use 1. Warnings This drug is not used for usual and indefinite fungal infections due to its strong activity. It is not administered only with the condition that a patient has positive skin or serum test for fungus. In addition, it is not used for bacterial infections or viral diseases due to no efficacy. In the treatment of fever of unknown origin, it is not used for fever caused by infections due to usual viruses, parasites or mycobacterium. 2. Contraindications 1) Patients with the hypersensitivity to this drug or any component of the drug (unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk) 2) Patients with nitrogen retention 3. Adverse reactions 1) A randomized, controlled clinical trial which compared this drug with existing amphotericin B injections in more than 1000 patients showed this drug caused much less frequent and serious adverse reactions compared to other amphotericin B injections. In patients given AmBisome in two double-blind, controlled studies, the incidence of treatment-related adverse reactions was significantly low compared to other patients given existing amphotericin B drugs or amphotericin B lipid complex. Among low back pain, tightness in chest/chest pain, dyspnea, bronchospasm, flushing, rapid pulse rate (tachycardia), low blood pressure (hypotension) and vasomotor abnormalities, more than one symptom may occur at low frequency as IV infusion-related adverse reactions. These resolve rapidly on stopping the infusion. They may not occur with every subsequent dose or when slower infusion rates (over 2 hours) are used. The following adverse reactions may be caused by this drug. Their incidences were based on a clinical trial conducted in 688 patients given AmBisome. (1) 10% : Fever, coldness/chills, hypokalemia, nausea, vomiting (2) 1~<10%: Elevations in creatinine and BUN, hypomagnesemia, hypocalcemia, hyperglycemia, hyponatremia, increased ALP, bilirubinemia, abnormal liver function test results, diarrhea, abdominal pain, dyspnea, flushing/vasodilation, headache, low back pain, chest pain, rapid pulse rate (tachycardia) and rash (3) 0.1~<1%: Convulsion, bronchospasm, thrombocytopnea, anaphylactoid reaction, anemia and phlebitis Page 4

5 In two double-blind trials, the incidence of nephrotoxicity shown in patients administered this drug was about half of that shown in patients administered amphotericin B drugs or amphotericin B lipid complex (nephrotoxicity is measured by increases of serum creatinine from baseline by more than twice). In post-marketing surveillance, anaphylactic reaction was uncommonly reported and angioedema was very rarely reported. Occasionally, there were cases of not severe hypersensitivity. 2) Types of adverse reactions observed in the use of this drug may be similar to those observed in the use of existing amphotericin B drugs. However, the medication compliance of AmBisome is better than that of existing amphotericin B drugs. In addition, comparative clinical trials showed the frequencies of nephrotoxicity and intravenous-related adverse reactions were lower in the use of this drug. Hematological changes, temporary hearing impairments, tinnitus, visual impairments, double vision, increase and decrease in blood pressure, arrhythmia, cardiac arrest, reversible increase of liver enzyme levels (transaminase), leukocytopenia, agranulocytosis, increase in leukocytes and eosinophil, and rarely reversible renal dysfunction may occur. 3) Rhabdomyolysis accompanied by hypokalemia may be caused by amphotericin B. Therefore, if myalgia, feelings of burnout, increases in creatine kinase (CK, CPK) and increase of myoglobin in the blood and urine occur, administration should be discontinued and appropriate actions be taken. 4. General precautions 1) It is recommended to check susceptibility for the prevention of the occurrence of resistant bacteria and to administer this drug for the minimum period required for the treatment. 2) Anaphylaxis has been rarely reported in the use of this drug. It should be tested whether idiopathic anaphylactoid reactions are shown or not and trial dosage should be administered first to minimize the real dosage. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome. Patients who will receive this drug should be informed of the precautions for the prevention or treatment of such reactions though they are not usually serious. This drug has caused substantially less toxicity than existing amphotericin B drugs. However, adverse events still occur. Careful attention should be paid especially if it is required to prolong the treatment period. 3) Patient management should include routine laboratory evaluation of hepatic, renal and hematopoietic function. And serum electrolyte, Page 5

6 particularly potassium and magnesium, should be evaluated. If a patient s renal function is clinically much decreased or other parameters show bad signs, dose should be decreased or infusion should be discontinued based on laboratory values. 4) Amphotericin B has nephrotoxicity. If the renal function is substantially worsened during the period of treatment with AmBisome, dose should be decreased or infusion be discontinued until a patient recovers the renal function. However, such decisions should be made after considering whether other nephrotoxic medications were concomitantly used. 5) Patients with diabetes should bear in mind that each vial contains 900 mg of white sugar. 6) Although patients on hemodialysis or peritoneal dialysis do not require dosage adjustment, this drug should not be given during the dialysis. 5. Drug interactions 1) No formal clinical studies of drug interactions have been conducted with this drug. Drug interactions of this drug and other drugs have not been reported, but patients requiring concomitant administration with other drugs should be closely monitored. 2) It has been reported existing amphotericin B drugs had interactions with antitumor agents or nephrotoxic drugs. As with other amphotericin B drugs causing hypokalemia, this drug increases the effects of digitalis glycosides or muscle relaxant. And the concomitant administration of this drug and corticoid/adnrenalcorticotropic hormone (ACTH) may increase potassium loss. 3) Concomitant administration with nephrotoxic drugs (e.g.: aminoglycosides, cyclosporine and tacrolimus etc.) may increase renal toxicity. However, the renal toxicity related with AmBisome shown in patients concomitantly given cyclosporine or aminoglycosides was significantly lower than that of existing amphotericin B drugs. 4) All the cases of hypokalemia should be treated and clinical monitoring of electrolytes and ECG should be done before the concomitant administration with drugs used for ventricular beats, especially, Torsades de point. 5) Concurrent use with zidovudine may increase hemotoxicity. 6) All the cases of hypokalemia should be treated and clinical monitoring of electrolytes and ECG should be done before the concomitant administration of imidazole and amphotericin B drug. 7) Concurrent use with digitalis glycosides may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored. Page 6

7 8) As acute pulmonary toxicity has been reported in patients simultaneously receiving AmBisome and leukocyte transfusions, dosing interval should be prolonged and pulmonary function be monitored. 6. Use in pregnant women and nursing mothers 1) Studies in both rats and rabbits have concluded that this drug had no teratogenic potential in these species. Studies on the effect of this drug on the fertility and toxicity have not been conducted. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small. The safety of this drug has not been established in pregnant women. 2) It is not known whether this drug is excreted in human milk. This drug should only be used during pregnancy and breast-feeding if the possible benefits to be derived outweigh the potential risks involved. 7. Pediatric use 1) Pediatric patients, age 1 month to 16 years, with presumed fungal infection by empirical therapy, confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with this drug. 2) Safety and effectiveness in pediatric patients below the age of one month have not been established. 8. Overdosage The toxicity of this drug due to overdose has not been defined. Repeated daily doses up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients have been administered in clinical trials with no reported doserelated toxicity. If overdosage should occur, cease administration immediately. Particular attention should be given to monitoring of renal and hepatic function, serum electrolytes and hematological status. 9. Precautions in storage and handling 1) Unopened vials should be stored at 1~25. 2) If not immediately used, the stability of reconstituted and undiluted drugs is guaranteed at 2~8 for 24 hours under the verified sterile conditions. 3) 5% Dextrose Injection used for the dilution of AmBisome should not be frozen. As it does not contain bacteriostatic agent, it should be used as soon as possible after the dilution with 5% Dextrose Injection. 4) The stability of reconstituted and diluted drugs is guaranteed as follows under the controlled and verified sterile condition: - Glass vial: can be stored at 25±2 for 24 hours not away from light Page 7

8 - Glass via: can be stored at 2~8 for the maximum 7 days not away from light - Polypropylene syringe: can be stored at 2~8 for the maximum 7 days not away from light 5) Concentration after the dilution with dextrose solution: When PVC or polyoletin injection bag is used as a container for dilution, stability was verified only under the following conditions: Diluted solution Dilution ratio Concentration of amphotericin B (mg/ml) Storage duration at 2~8 Storage duration at 25±2 1: days 48 hours 5% Dextrose Injection 1: days 48 hours 1: days 24 hours 10% Dextrose 1: hours 72 hours 20% Dextrose 1: hours 72 hours Storage Condition Stored in hermetic container at room temperature (1~25 ) Date of preparation: Apr 1, 2013 You can find the latest labelling and more information on the internet site of Ministry of Food and Drug Safety- ezdrug( Drug Info. Page 8