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Amsa P-D (Amsacrine)
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Pharmacology
Amsacrine is a potent cytotoxic agent. In in vitro studies, the LD 50 against cultured L1210 cells is 0.04µg/mL and 0.2µg/mL against cultured Novikoff cells at 6hours. Higher concentrations or longer exposure produce cell destruction. A 3-hour exposure of Novikoff cells to 2µg of AMSA P-D indicated 62% inhibition of DNA synthesis (incorporation of radioactive thymidine) while RNA synthesis was not affected (incorporation of radioactive uridine). Essentially the same results were obtained in vivo when L1210-inoculated mice were treated with a dose of 0.1mg/mouse. AMSAP-D binds to DNAboth through intercalation and external binding and has base specificity for A-T pairs.
Cycling cells are 2to 4times more sensitive to AMSA P-D than are resting cells. Cycling cells initially in S and G2 phases were grossly delayed in their capacity for normal progression, leading to a transitory (approximately 8hours) accumulation of cells in S phase, followed at later times by arrest in G2phase. A limited degree of mitotic nondisjunction and a high degree of polyploidization was seen. Examination of chromosome damage indicated incomplete condensation and chromosome stickiness, which are characterisitics of DNA intercalators.
Amsacrine is active against a wide spectrum of murine tumors. These include the ascitic form of L1210and P388 leukemias, Lewis lung carcinoma, spontaneous C 3H mammary adenocarcinoma, mammary tumor in CD8F mice, and the commonly resistant B16 melanoma. No antitumor activity was detected in intra-cerebrally inoculated L1210 leukemia, which suggests that the drug penetration across the blood-brain barrier in mice did not achieve significant levels.
The effect of amsacrine on the immune system was also investigated. The production of hemolytic plaque-forming cells (PFC) in mice in response to immunization with sheep red blood cells (SRBC) was used as the indicator of activity. In contrast to the 95%inhibition of PFC formation caused by ActinomycinD, cyclophosphamide, cytosine arabinoside, thioguanine and vinblastine, amsacrine produced no such inhibition when administered at the same time asSRBC. However, when given 28hours followingSRBC immunization, the drug caused a 99%suppression of immune activity. After 6 days, the inhibition was still strongly evident.
Following a 90mg/m 2 infusion of amsacrine over 60minutes, the plasma concentration showed a biphasic decrease with an alpha phase half-life of10to 15minutes and a beta phase half-life of8to 9hours. Peak plasma levels were dose dependent, increasing from 0.47to 12.3µM as the patient's dose was escalated from 10to 90mg/m 2. In 2 studies, 15of 54(27.8%) evaluable patients achieved remission (7were complete remissions and 8were partial remissions). Duration of amsacrine remissions is brief and variable if not followed by consolidation or maintenance regimens.
Amsacrine is a potent cytotoxic agent. In in vitro studies, the LD 50 against cultured L1210 cells is 0.04µg/mL and 0.2µg/mL against cultured Novikoff cells at 6hours. Higher concentrations or longer exposure produce cell destruction. A 3-hour exposure of Novikoff cells to 2µg of AMSA P-D indicated 62% inhibition of DNA synthesis (incorporation of radioactive thymidine) while RNA synthesis was not affected (incorporation of radioactive uridine). Essentially the same results were obtained in vivo when L1210-inoculated mice were treated with a dose of 0.1mg/mouse. AMSAP-D binds to DNAboth through intercalation and external binding and has base specificity for A-T pairs.
Cycling cells are 2to 4times more sensitive to AMSA P-D than are resting cells. Cycling cells initially in S and G2 phases were grossly delayed in their capacity for normal progression, leading to a transitory (approximately 8hours) accumulation of cells in S phase, followed at later times by arrest in G2phase. A limited degree of mitotic nondisjunction and a high degree of polyploidization was seen. Examination of chromosome damage indicated incomplete condensation and chromosome stickiness, which are characterisitics of DNA intercalators.
Amsacrine is active against a wide spectrum of murine tumors. These include the ascitic form of L1210and P388 leukemias, Lewis lung carcinoma, spontaneous C 3H mammary adenocarcinoma, mammary tumor in CD8F mice, and the commonly resistant B16 melanoma. No antitumor activity was detected in intra-cerebrally inoculated L1210 leukemia, which suggests that the drug penetration across the blood-brain barrier in mice did not achieve significant levels.
The effect of amsacrine on the immune system was also investigated. The production of hemolytic plaque-forming cells (PFC) in mice in response to immunization with sheep red blood cells (SRBC) was used as the indicator of activity. In contrast to the 95%inhibition of PFC formation caused by ActinomycinD, cyclophosphamide, cytosine arabinoside, thioguanine and vinblastine, amsacrine produced no such inhibition when administered at the same time asSRBC. However, when given 28hours followingSRBC immunization, the drug caused a 99%suppression of immune activity. After 6 days, the inhibition was still strongly evident.
Following a 90mg/m 2 infusion of amsacrine over 60minutes, the plasma concentration showed a biphasic decrease with an alpha phase half-life of10to 15minutes and a beta phase half-life of8to 9hours. Peak plasma levels were dose dependent, increasing from 0.47to 12.3µM as the patient's dose was escalated from 10to 90mg/m 2. In 2 studies, 15of 54(27.8%) evaluable patients achieved remission (7were complete remissions and 8were partial remissions). Duration of amsacrine remissions is brief and variable if not followed by consolidation or maintenance regimens.
Indications
Amsacrine Is A Potent Cytotoxic Agent. In In Vitro Studies, The LD 50 Against Cultured L1210 Cells Is 0.04µg/mL And 0.2µg/mL Against Cultured Novikoff Cells At 6hours. Higher Concentrations Or Longer Exposure Produce Cell Destruction. A 3-hour Exposure Of Novikoff Cells To 2µg Of AMSA P-D Indicated 62% Inhibition Of DNA Synthesis (incorporation Of Radioactive Thymidine) While RNA Synthesis Was Not Affected (incorporation Of Radioactive Uridine). Essentially The Same Results Were Obtained In Vivo When L1210-inoculated Mice Were Treated With A Dose Of 0.1mg/mouse. AMSAP-D Binds To DNAboth Through Intercalation And External Binding And Has Base Specificity For A-T Pairs.
Cycling Cells Are 2to 4times More Sensitive To AMSA P-D Than Are Resting Cells. Cycling Cells Initially In S And G2 Phases Were Grossly Delayed In Their Capacity For Normal Progression, Leading To A Transitory (approximately 8hours) Accumulation Of Cells In S Phase, Followed At Later Times By Arrest In G2phase. A Limited Degree Of Mitotic Nondisjunction And A High Degree Of Polyploidization Was Seen. Examination Of Chromosome Damage Indicated Incomplete Condensation And Chromosome Stickiness, Which Are Characterisitics Of DNA Intercalators.
Amsacrine Is Active Against A Wide Spectrum Of Murine Tumors. These Include The Ascitic Form Of L1210and P388 Leukemias, Lewis Lung Carcinoma, Spontaneous C 3H Mammary Adenocarcinoma, Mammary Tumor In CD8F Mice, And The Commonly Resistant B16 Melanoma. No Antitumor Activity Was Detected In Intra-cerebrally Inoculated L1210 Leukemia, Which Suggests That The Drug Penetration Across The Blood-brain Barrier In Mice Did Not Achieve Significant Levels.
The Effect Of Amsacrine On The Immune System Was Also Investigated. The Production Of Hemolytic Plaque-forming Cells (PFC) In Mice In Response To Immunization With Sheep Red Blood Cells (SRBC) Was Used As The Indicator Of Activity. In Contrast To The 95%inhibition Of PFC Formation Caused By ActinomycinD, Cyclophosphamide, Cytosine Arabinoside, Thioguanine And Vinblastine, Amsacrine Produced No Such Inhibition When Administered At The Same Time AsSRBC. However, When Given 28hours FollowingSRBC Immunization, The Drug Caused A 99%suppression Of Immune Activity. After 6 Days, The Inhibition Was Still Strongly Evident.
Following A 90mg/m 2 Infusion Of Amsacrine Over 60minutes, The Plasma Concentration Showed A Biphasic Decrease With An Alpha Phase Half-life Of10to 15minutes And A Beta Phase Half-life Of8to 9hours. Peak Plasma Levels Were Dose Dependent, Increasing From 0.47to 12.3µM As The Patient's Dose Was Escalated From 10to 90mg/m 2. In 2 Studies, 15of 54(27.8%) Evaluable Patients Achieved Remission (7were Complete Remissions And 8were Partial Remissions). Duration Of Amsacrine Remissions Is Brief And Variable If Not Followed By Consolidation Or Maintenance Regimens.
Amsacrine Is A Potent Cytotoxic Agent. In In Vitro Studies, The LD 50 Against Cultured L1210 Cells Is 0.04µg/mL And 0.2µg/mL Against Cultured Novikoff Cells At 6hours. Higher Concentrations Or Longer Exposure Produce Cell Destruction. A 3-hour Exposure Of Novikoff Cells To 2µg Of AMSA P-D Indicated 62% Inhibition Of DNA Synthesis (incorporation Of Radioactive Thymidine) While RNA Synthesis Was Not Affected (incorporation Of Radioactive Uridine). Essentially The Same Results Were Obtained In Vivo When L1210-inoculated Mice Were Treated With A Dose Of 0.1mg/mouse. AMSAP-D Binds To DNAboth Through Intercalation And External Binding And Has Base Specificity For A-T Pairs.
Cycling Cells Are 2to 4times More Sensitive To AMSA P-D Than Are Resting Cells. Cycling Cells Initially In S And G2 Phases Were Grossly Delayed In Their Capacity For Normal Progression, Leading To A Transitory (approximately 8hours) Accumulation Of Cells In S Phase, Followed At Later Times By Arrest In G2phase. A Limited Degree Of Mitotic Nondisjunction And A High Degree Of Polyploidization Was Seen. Examination Of Chromosome Damage Indicated Incomplete Condensation And Chromosome Stickiness, Which Are Characterisitics Of DNA Intercalators.
Amsacrine Is Active Against A Wide Spectrum Of Murine Tumors. These Include The Ascitic Form Of L1210and P388 Leukemias, Lewis Lung Carcinoma, Spontaneous C 3H Mammary Adenocarcinoma, Mammary Tumor In CD8F Mice, And The Commonly Resistant B16 Melanoma. No Antitumor Activity Was Detected In Intra-cerebrally Inoculated L1210 Leukemia, Which Suggests That The Drug Penetration Across The Blood-brain Barrier In Mice Did Not Achieve Significant Levels.
The Effect Of Amsacrine On The Immune System Was Also Investigated. The Production Of Hemolytic Plaque-forming Cells (PFC) In Mice In Response To Immunization With Sheep Red Blood Cells (SRBC) Was Used As The Indicator Of Activity. In Contrast To The 95%inhibition Of PFC Formation Caused By ActinomycinD, Cyclophosphamide, Cytosine Arabinoside, Thioguanine And Vinblastine, Amsacrine Produced No Such Inhibition When Administered At The Same Time AsSRBC. However, When Given 28hours FollowingSRBC Immunization, The Drug Caused A 99%suppression Of Immune Activity. After 6 Days, The Inhibition Was Still Strongly Evident.
Following A 90mg/m 2 Infusion Of Amsacrine Over 60minutes, The Plasma Concentration Showed A Biphasic Decrease With An Alpha Phase Half-life Of10to 15minutes And A Beta Phase Half-life Of8to 9hours. Peak Plasma Levels Were Dose Dependent, Increasing From 0.47to 12.3µM As The Patient's Dose Was Escalated From 10to 90mg/m 2. In 2 Studies, 15of 54(27.8%) Evaluable Patients Achieved Remission (7were Complete Remissions And 8were Partial Remissions). Duration Of Amsacrine Remissions Is Brief And Variable If Not Followed By Consolidation Or Maintenance Regimens.
Contraindications
In patients who are hypersensitive to amsacrine or to acridine derivatives (e.g., acriflavine) and in patients who have pre-existing drug-induced or radiotherapy-induced bone marrow suppression.
Amsacrine treatment is not contraindicated in patients who have received previous treatment with doxorubicin or daunorubicin.
In patients who are hypersensitive to amsacrine or to acridine derivatives (e.g., acriflavine) and in patients who have pre-existing drug-induced or radiotherapy-induced bone marrow suppression.
Amsacrine treatment is not contraindicated in patients who have received previous treatment with doxorubicin or daunorubicin.
Safety Information / Warning
Amsacrine is a potent bone marrow suppressant. In some patients prolonged bone marrow aplasia may occur, necessitating intensive supportive therapy. Patients receiving the drug must be under close medical supervision by physicians skilled in cancer chemotherapy. During induction therapy, leukocyte and platelet count determinations are mandatory and should be performed frequently especially during the 2- to 3-week period following administration of the drug. With recommended dose schedules, leukopenia is usually transient, reaching its nadir at 11to 13days after treatment, with recovery usually occurring by the 17thto 25th day (see Dosage). Leukocyte counts as low as 1000/mm 3 can be expected during drug therapy. Red cell and platelet concentrations should be monitored because they also may be depressed. Doses higher than those recommended may produce more severe or more prolonged marrow suppression.
Facilities should be available for management of complications of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses, and hemorrhage secondary to thrombocytopenia). Periodic monitoring of bone marrow should be performed. Hematologic toxicity may require dose reduction, suspension, or delay of amsacrine therapy.
Toxicity at recommended doses of amsacrine is enhanced by hepatic or renal impairment. Laboratory evaluation of hepatic and renal function is necessary prior to and during administration. Liver metabolism and biliary excretion appear to be the major routes of amsacrine elimination in man. Therefore, dose reduction is recommended in patients with significant hepatic dysfunction (bilirubin >2mg/dL). The same recommendation applies in cases of significant renal impairment (BUN >20mg/dL), (creatinine >1.2mg/dL), since 35% of the total dose is excreted by the kidney within 72hours after administration (20% as intact drug).
There is no clear evidence from animal studies and clinical trials that amsacrine is cardiotoxic. There have been 8 documented cases in which an acute arrhythmia developed during or immediately after amsacrine infusion. Several of these patients had received prior anthracycline treatment or were hypokalemic. An additional 7 cases have been reported but no documentation is available. Therefore, careful monitoring of cardiac rhythm, during and after drug administration, is strongly recommended.
Patients with hypokalemia are at increased risk of ventricular fibrillation. The risk of developing arrhythmias can be minimized by ensuring a normal serum potassium level immediately prior to and during amsacrine administration. Careful monitoring of cardiac rhythm is recommended for detection of cardiotoxicity. Fluid or electrolyte imbalance should be corrected prior to amsacrine administration.
Use caution in handling and preparing the amsacrine solution. The use of gloves, gown and eye protection are recommended (see Dosage, General Information for the Safe Handling of Cytotoxic Agents).
Pregnancy and Lactation: Safe use of amsacrine in pregnancy has not been established. Reproduction studies have not been performed in animals. Thus, there is no evidence as to whether this drug may adversely affect fertility in either men or women or have teratogenic or other adverse effects on the fetus and embryo. Therefore, benefit/risk considerations should be carefully weighed in using the drug in pregnant women or in patients of either sex in the reproductive age group.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving amsacrine. It is not known if amsacrine is excreted in breast milk. Therefore, breast-feeding should be discontinued before receiving amsacrine.
Geriatrics: Safety and effectiveness in the elderly have not been established.
Amsacrine is a potent bone marrow suppressant. In some patients prolonged bone marrow aplasia may occur, necessitating intensive supportive therapy. Patients receiving the drug must be under close medical supervision by physicians skilled in cancer chemotherapy. During induction therapy, leukocyte and platelet count determinations are mandatory and should be performed frequently especially during the 2- to 3-week period following administration of the drug. With recommended dose schedules, leukopenia is usually transient, reaching its nadir at 11to 13days after treatment, with recovery usually occurring by the 17thto 25th day (see Dosage). Leukocyte counts as low as 1000/mm 3 can be expected during drug therapy. Red cell and platelet concentrations should be monitored because they also may be depressed. Doses higher than those recommended may produce more severe or more prolonged marrow suppression.
Facilities should be available for management of complications of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses, and hemorrhage secondary to thrombocytopenia). Periodic monitoring of bone marrow should be performed. Hematologic toxicity may require dose reduction, suspension, or delay of amsacrine therapy.
Toxicity at recommended doses of amsacrine is enhanced by hepatic or renal impairment. Laboratory evaluation of hepatic and renal function is necessary prior to and during administration. Liver metabolism and biliary excretion appear to be the major routes of amsacrine elimination in man. Therefore, dose reduction is recommended in patients with significant hepatic dysfunction (bilirubin >2mg/dL). The same recommendation applies in cases of significant renal impairment (BUN >20mg/dL), (creatinine >1.2mg/dL), since 35% of the total dose is excreted by the kidney within 72hours after administration (20% as intact drug).
There is no clear evidence from animal studies and clinical trials that amsacrine is cardiotoxic. There have been 8 documented cases in which an acute arrhythmia developed during or immediately after amsacrine infusion. Several of these patients had received prior anthracycline treatment or were hypokalemic. An additional 7 cases have been reported but no documentation is available. Therefore, careful monitoring of cardiac rhythm, during and after drug administration, is strongly recommended.
Patients with hypokalemia are at increased risk of ventricular fibrillation. The risk of developing arrhythmias can be minimized by ensuring a normal serum potassium level immediately prior to and during amsacrine administration. Careful monitoring of cardiac rhythm is recommended for detection of cardiotoxicity. Fluid or electrolyte imbalance should be corrected prior to amsacrine administration.
Use caution in handling and preparing the amsacrine solution. The use of gloves, gown and eye protection are recommended (see Dosage, General Information for the Safe Handling of Cytotoxic Agents).
Pregnancy and Lactation: Safe use of amsacrine in pregnancy has not been established. Reproduction studies have not been performed in animals. Thus, there is no evidence as to whether this drug may adversely affect fertility in either men or women or have teratogenic or other adverse effects on the fetus and embryo. Therefore, benefit/risk considerations should be carefully weighed in using the drug in pregnant women or in patients of either sex in the reproductive age group.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving amsacrine. It is not known if amsacrine is excreted in breast milk. Therefore, breast-feeding should be discontinued before receiving amsacrine.
Geriatrics: Safety and effectiveness in the elderly have not been established.
Precautions
Laboratory Tests: Complete blood counts, liver and renal function tests, and electrolytes should be performed regularly. Electrolytes should be re-evaluated before each day's treatment.
Information to Be Provided to the Patients: The patient should be instructed to report any signs of side effects. In addition, the patient should be instructed not to receive any vaccine while receiving amsacrine therapy.
Like other cytotoxic drugs, amsacrine may induce hyperuricemia secondary to rapid lysis of neoplastic cells. Careful monitoring of the patient's blood uric acid level should be performed. Consideration may be given to reducing uric acid levels prophylactically, prior to or concurrent with amsacrine treatment.
Pregnancy: See Warnings.
Drug Interactions : Data available suggest that AMSA P-D does not potentiate the increased risk of doxorubicin-induced cardiac toxicity.
Although animal studies suggested cross-resistance between the anthracyclines and AMSA P-D, clinical studies indicate that this is not true.
Sufficient data are not available to prove or disprove AMSA P-D potentiation of the toxicities of other anticancer drugs.
Concomitant influenza or pneumococcal vaccination and immunosuppressive therapy have been associated with impaired immune response to the vaccine.
Antineoplastic agents may increase the likelihood of infections following live virus vaccines. Therefore, live virus vaccines should be avoided. Amsacrine may be displaced from serum albumin, with consequential increase in free drug and toxicity if used with other protein bound drugs.
Laboratory Tests: Complete blood counts, liver and renal function tests, and electrolytes should be performed regularly. Electrolytes should be re-evaluated before each day's treatment.
Information to Be Provided to the Patients: The patient should be instructed to report any signs of side effects. In addition, the patient should be instructed not to receive any vaccine while receiving amsacrine therapy.
Side Effects / Adverse Effects
The major toxicities associated with amsacrine have been myelosuppression and mucositis. Amsacrine is a potent myelosuppressive drug and pancytopenia usually persists for about 3 weeks after administration. Hemorrhage may occur during this period and severe or life-threatening infections may be experienced. Pyrexia, unrelated to sepsis, has been reported. Other target organ systems of toxicity are the gastrointestinal tract and CNS. Evidence of cumulative toxicity has not been observed.
Myelosuppression: Myelosuppression is rapid in onset, and is consistent with the requirement to produce significant bone marrow hypoplasia to achieve a response. Using recommended doses and schedules, leukopenia occurs in most patients. Mild to severe anemia and mild to moderate thrombocytopenia also develop in the majority of patients.
Patients with leukemia have pancytopenia due to the disease state as well as to prior therapy. While the goal of amsacrine therapy is myelosuppression, this can become an untoward effect if therapy is prolonged.
Gastrointestinal: Effects reported in over 10% of patients in decreasing order of frequency are: nausea, vomiting, stomatitis, diarrhea, perirectal abscess, and abdominal pain. Other effects are: anorexia, dysphagia, hematemesis, jaundice, gum hemorrhage, and gingivitis.
Mucositis has been reported as a serious side effect at higher dose levels.
CNS: headache, confusion, paresthesias, hypoesthesia, and dizziness. Seizures occurred in several patients, all of whom had metabolic conditions that may have caused the seizures or made these patients more susceptible to them.
Integumentary: rashes (purpuric or maculopapular), alopecia, urticaria, cutaneous inflammatory reaction, and dermatologic allergic reaction.
Hepatotoxicity: Jaundice, hepatitis, hepatic insufficiency and increased bilirubin. Jaundice and increased bilirubin effects are usually transient and return to normal after cessation of drug therapy. One death has been attributed to progressive liver failure.
Cardiovascular: Cardiac arrhythmias, such as sinus tachycardia or atrial fibrillation, may occur. Fatal or life-threatening ventricular fibrillation, usually in patients with hypokalemia, has been reported. Cardiomyopathy has been reported in patients who had generally been pretreated with anthracylcine antibiotics (see Warnings). Other effects are phlebitis and inflammation at the injection site, hypotension, tachycardia, bradycardia, ECG changes, congestive heart failure, ejection fraction decrease, ventricular arrhythmias, and death. Phlebitis, related to the concentration of amsacrine administered, is reduced by infusing the diluted drug over a period of60to 120minutes (see Dosage).
Body as a Whole: Weight decrease, weight increase, fever, infection, asthenia, lethargy and musculoskeletal pain or phlebitis on infusion has been reported.
Hematologic System: hemorrhage, leukopenia, granulocytopenia.
Respiratory: dyspnea.
Urogenital System: hematuria, proteinuria.
Psychobiologic Function: emotional lability.
Renal: Renal failure has occasionally been reported.
Laboratory Values: elevated bilirubin, BUN, alkaline phosphatase, creatinine, AST.
The major toxicities associated with amsacrine have been myelosuppression and mucositis. Amsacrine is a potent myelosuppressive drug and pancytopenia usually persists for about 3 weeks after administration. Hemorrhage may occur during this period and severe or life-threatening infections may be experienced. Pyrexia, unrelated to sepsis, has been reported. Other target organ systems of toxicity are the gastrointestinal tract and CNS. Evidence of cumulative toxicity has not been observed.
Myelosuppression: Myelosuppression is rapid in onset, and is consistent with the requirement to produce significant bone marrow hypoplasia to achieve a response. Using recommended doses and schedules, leukopenia occurs in most patients. Mild to severe anemia and mild to moderate thrombocytopenia also develop in the majority of patients.
Patients with leukemia have pancytopenia due to the disease state as well as to prior therapy. While the goal of amsacrine therapy is myelosuppression, this can become an untoward effect if therapy is prolonged.
Gastrointestinal: Effects reported in over 10% of patients in decreasing order of frequency are: nausea, vomiting, stomatitis, diarrhea, perirectal abscess, and abdominal pain. Other effects are: anorexia, dysphagia, hematemesis, jaundice, gum hemorrhage, and gingivitis.
Mucositis has been reported as a serious side effect at higher dose levels.
CNS: headache, confusion, paresthesias, hypoesthesia, and dizziness. Seizures occurred in several patients, all of whom had metabolic conditions that may have caused the seizures or made these patients more susceptible to them.
Integumentary: rashes (purpuric or maculopapular), alopecia, urticaria, cutaneous inflammatory reaction, and dermatologic allergic reaction.
Hepatotoxicity: Jaundice, hepatitis, hepatic insufficiency and increased bilirubin. Jaundice and increased bilirubin effects are usually transient and return to normal after cessation of drug therapy. One death has been attributed to progressive liver failure.
Cardiovascular: Cardiac arrhythmias, such as sinus tachycardia or atrial fibrillation, may occur. Fatal or life-threatening ventricular fibrillation, usually in patients with hypokalemia, has been reported. Cardiomyopathy has been reported in patients who had generally been pretreated with anthracylcine antibiotics (see Warnings). Other effects are phlebitis and inflammation at the injection site, hypotension, tachycardia, bradycardia, ECG changes, congestive heart failure, ejection fraction decrease, ventricular arrhythmias, and death. Phlebitis, related to the concentration of amsacrine administered, is reduced by infusing the diluted drug over a period of60to 120minutes (see Dosage).
Body as a Whole: Weight decrease, weight increase, fever, infection, asthenia, lethargy and musculoskeletal pain or phlebitis on infusion has been reported.
Hematologic System: hemorrhage, leukopenia, granulocytopenia.
Respiratory: dyspnea.
Urogenital System: hematuria, proteinuria.
Psychobiologic Function: emotional lability.
Renal: Renal failure has occasionally been reported.
Laboratory Values: elevated bilirubin, BUN, alkaline phosphatase, creatinine, AST.
Overdose
Symptoms and Treatment: Hemorrhage and infection, resulting from bone marrow hypoplasia or aplasia, may require intensive supportive treatment with red cell, granulocyte, or platelet transfusions and appropriate antibiotics. Vigorous symptomatic treatment may be necessary for severe mucositis, vomiting or diarrhea.
Symptoms and Treatment: Hemorrhage and infection, resulting from bone marrow hypoplasia or aplasia, may require intensive supportive treatment with red cell, granulocyte, or platelet transfusions and appropriate antibiotics. Vigorous symptomatic treatment may be necessary for severe mucositis, vomiting or diarrhea.
Recommended Dosage
Caution: AMSA P-D must be mixed with the L-lactic acid diluent provided. The resultant solution must be further diluted in 500mL dextrose injection, USP. Do not use saline solutions. AMSA P-D is incompatible with solutions containing chloride ions.
For i.v. infusion only.
The following schedules are recommended for acute adult leukemia:
Induction: The total recommended dose for each 5-day course of therapy is 375to 625mg/m 2. Each course is repeated at 3-to 4-week intervals. Two courses may be necessary to achieve induction. This may be given according to the following schedules: 75mg/m 2/d´5d; 100mg/m 2/d´5d; and 125mg/m 2/d´5d (the preferred regimen).
The dose of amsacrine should be increased by 20% in the second and each subsequent course if the patient has had no significant toxicity in the preceding course, and if marrow hypoplasia has not been achieved. If patients have had life-threatening infection or hemorrhage during the preceding course, consideration should be given to decreasing the dose by 20%. Second and subsequent courses should not be initiated until recovery from drug-induced myelosuppression or evidence of residual leukemic infiltrate is evident.
Maintenance: Once remission has been achieved the maintenance dose should be about one half that described above, repeated every 4to 8weeks depending upon the peripheral blood counts and bone marrow recovery from myelosuppression.
Administration: Because of phlebitis that may occur at doses greater than 70mg/m 2, AMSA P-D must be diluted in 500mL 5% Dextrose Injection USP and infused over 60to 90minutes. Care must be taken that no extravasation occurs which might produce severe irritation or necrosis.
Method of Preparation: Step1: Each ampul contains 75mg (1.5mL) of AMSA P-D for infusion. Aseptically transfer 1.5mL from the ampul to the vial which contains 13.5mL of L-lactic acid diluent (use only the diluent provided). The resulting orange-red solution is the stock solution which contains 5mg AMSA P-D/mL. It is preferable to use glass syringes for step1; however, plastic syringes can be used, providing that AMSA P-D remains in the syringes for no longer than 15minutes. The stock solution is chemically stable for 24hours at room temperature when protected from exposure to direct sunlight. Since this solution does not contain a preservative, any unused portion should be discarded.
Step2: Prepare the i.v. infusion solution by aseptically transferring the total daily dose of Stock Solution to 500mL Dextrose Injection USP. Do not use saline solution. The freshly prepared i.v. infusion is chemically stable for up to 7days when using an Abbott plastic container or glass bottle.
As with all i.v. admixtures containing no preservatives (microbiological) the solution should be used within 24hours when stored at room temperature, or 72hours when refrigerated.
Caution in the handling and preparation of the solution should be exercised, and the use of gloves is recommended. If AMSA P-D solution contacts the skin or mucosa, immediately wash thoroughly with soap and water.
General Information for the Safe Handling of Cytotoxic Agents:
Preparation of all antineoplastic agents should be done in a vertical laminar flow hood (Biological Safety Cabinet--ClassII).
Personnel preparing parenteral antineoplastic agents should wear PVC gloves, safety glasses, disposable gowns and masks.
All needles, syringes, vials, ampuls, and other materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1000°C or more. Sealed containers may explode sealed.
Intact vials or ampuls, unopened bottles, or oral medication should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. If incineration is not available, neutralization should be done (the manufacturer can supply this information), usually with the use of5% sodium hypochlorite and/or 5% sodium thiosulfate.
Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.
Caution: AMSA P-D must be mixed with the L-lactic acid diluent provided. The resultant solution must be further diluted in 500mL dextrose injection, USP. Do not use saline solutions. AMSA P-D is incompatible with solutions containing chloride ions.
For i.v. infusion only.
The following schedules are recommended for acute adult leukemia:
Induction: The total recommended dose for each 5-day course of therapy is 375to 625mg/m 2. Each course is repeated at 3-to 4-week intervals. Two courses may be necessary to achieve induction. This may be given according to the following schedules: 75mg/m 2/d´5d; 100mg/m 2/d´5d; and 125mg/m 2/d´5d (the preferred regimen).
The dose of amsacrine should be increased by 20% in the second and each subsequent course if the patient has had no significant toxicity in the preceding course, and if marrow hypoplasia has not been achieved. If patients have had life-threatening infection or hemorrhage during the preceding course, consideration should be given to decreasing the dose by 20%. Second and subsequent courses should not be initiated until recovery from drug-induced myelosuppression or evidence of residual leukemic infiltrate is evident.
Maintenance: Once remission has been achieved the maintenance dose should be about one half that described above, repeated every 4to 8weeks depending upon the peripheral blood counts and bone marrow recovery from myelosuppression.
Administration: Because of phlebitis that may occur at doses greater than 70mg/m 2, AMSA P-D must be diluted in 500mL 5% Dextrose Injection USP and infused over 60to 90minutes. Care must be taken that no extravasation occurs which might produce severe irritation or necrosis.
Method of Preparation: Step1: Each ampul contains 75mg (1.5mL) of AMSA P-D for infusion. Aseptically transfer 1.5mL from the ampul to the vial which contains 13.5mL of L-lactic acid diluent (use only the diluent provided). The resulting orange-red solution is the stock solution which contains 5mg AMSA P-D/mL. It is preferable to use glass syringes for step1; however, plastic syringes can be used, providing that AMSA P-D remains in the syringes for no longer than 15minutes. The stock solution is chemically stable for 24hours at room temperature when protected from exposure to direct sunlight. Since this solution does not contain a preservative, any unused portion should be discarded.
Step2: Prepare the i.v. infusion solution by aseptically transferring the total daily dose of Stock Solution to 500mL Dextrose Injection USP. Do not use saline solution. The freshly prepared i.v. infusion is chemically stable for up to 7days when using an Abbott plastic container or glass bottle.
As with all i.v. admixtures containing no preservatives (microbiological) the solution should be used within 24hours when stored at room temperature, or 72hours when refrigerated.
Caution in the handling and preparation of the solution should be exercised, and the use of gloves is recommended. If AMSA P-D solution contacts the skin or mucosa, immediately wash thoroughly with soap and water.
General Information for the Safe Handling of Cytotoxic Agents:
Preparation of all antineoplastic agents should be done in a vertical laminar flow hood (Biological Safety Cabinet--ClassII).
Personnel preparing parenteral antineoplastic agents should wear PVC gloves, safety glasses, disposable gowns and masks.
All needles, syringes, vials, ampuls, and other materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1000°C or more. Sealed containers may explode sealed.
Intact vials or ampuls, unopened bottles, or oral medication should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. If incineration is not available, neutralization should be done (the manufacturer can supply this information), usually with the use of5% sodium hypochlorite and/or 5% sodium thiosulfate.
Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.
Supplied / Packaging
Each package contains: one 75 mg ampul of AMSA P-D (50 mg/mL) in 1.5 mL n,n-dimethylacetamide, and one 13.5 mL vial of L-lactic acid diluent (0.0353 M). Trays of 5 individual packages. Preservative-free. Store at controlled room temperature (15 to 25°C).
Each package contains: one 75 mg ampul of AMSA P-D (50 mg/mL) in 1.5 mL n,n-dimethylacetamide, and one 13.5 mL vial of L-lactic acid diluent (0.0353 M). Trays of 5 individual packages. Preservative-free. Store at controlled room temperature (15 to 25°C).
