Amsa P (Amsacrine)

AMSA P-D™

Parke-Davis

Amsacrine

Antineoplastic

Action And Clinical Pharmacology: Amsacrine is a potent cytotoxic agent. In in vitro studies, the LD50 against cultured L1210 cells is 0.04 µg/mL and 0.2 µg/mL against cultured Novikoff cells at 6 hours. Higher concentrations or longer exposure produce cell destruction. A 3 hour exposure of Novikoff cells to 2 µg 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 0.1 mg/mouse. AMSA P-D binds to DNA both through intercalation and external binding and has base specificity for A-T pairs.

Cycling cells are 2 to 4 times 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 8 hours) accumulation of cells in S phase, followed at later times by arrest in G2 phase. 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 L1210 and P388 leukemias, Lewis lung carcinoma, spontaneous C3H 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 Actinomycin D, cyclophosphamide, cytosine arabinoside, thioguanine and vinblastine, amsacrine produced no such inhibition when administered at the same time as SRBC. However, when given 28 hours following SRBC immunization, the drug caused a 99% suppression of immune activity. After six days, the inhibition was still strongly evident.

Following a 90 mg/minfusion of amsacrine over 60 minutes, the plasma concentration showed a biphasic decrease with an alpha phase half-life of 10 to 15 minutes and a beta phase half-life of 8 to 9 hours. Peak plasma levels were dose dependent, increasing from 0.47 to 12.3 µM as the patient’s dose was escalated from 10 to 90 mg/m In 2 studies, 15 of 54 (27.8%) evaluable patients achieved remission (7 were complete remissions and 8 were partial remissions). Duration of amsacrine remissions is brief and variable if not followed by consolidation or maintenance regimens.

Indications And Clinical Uses: For induction of remission in acute adult leukemia refractory to conventional therapy.

Contra-Indications: 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.

Manufacturers’ Warnings In Clinical States: 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. With recommended dose schedules, leukopenia is usually transient, reaching its nadir at 11 to 13 days after treatment, with recovery usually occurring by the 17th to 25th day (see Dosage). Leukocyte counts as low as 1 000/mmcan 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 the drug 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>2 mg%). The same recommendation applies in cases of significant renal impairment (BUN>20 mg%, creatinine>1.2 mg%), since 35% of the total dose is excreted by the kidney within 72 hours after administration (20% as intact drug).

There is no clear evidence from animal studies and clinical trials that amsacrine is cardiotoxic. There have been eight 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 seven cases have been reported but no documentation is available. Therefore, careful monitoring of cardiac rhythm, during and after drug administration, is strongly recommended.

Pregnancy: 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.

Precautions: 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.

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.

Adverse Reactions: The major toxicities associated with amsacrine have been myelosuppression and mucositis. Other target organ systems of toxicity are the gastrointestinal tract and CNS. Evidence of cumulative toxicity has not been observed.

Myelosuppression: 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, 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, and urticaria.

Hepatotoxicity: Rarely occurred as evidenced by jaundice and increased bilirubin. These effects are usually transient and return to normal after cessation of drug therapy. One death has been attributed to progressive liver failure.

Cardiovascular: See Warnings regarding ventricular arrhythmias. Other effects are phlebitis and inflammation at the injection site, hypotension, and tachycardia. Phlebitis, related to the concentration of amsacrine administered, is reduced by infusing the diluted drug over a period of 60 to 120 minutes (see Dosage).

Systemic: Other effects reported are: asthenia, lethargy, and musculoskeletal pain.

Dosage And Administration: Caution: AMSA P-D must be mixed with the L-lactic acid diluent provided. The resultant solution must be further diluted in 500 mL 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 375 to 625 mg/m 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/md´5 d; 100 mg/md´5 d; and 125 mg/md´5 d (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 4 to 8 weeks depending upon the peripheral blood counts and bone marrow recovery from myelosuppression.

Administration: Because of phlebitis that may occur at doses greater than 70 mg/m AMSA P-D must be diluted in 500 mL 5% Dextrose Injection USP and infused over 60 to 90 minutes. Care must be taken that no extravasation occurs which might produce severe irritation or necrosis.

Method of Preparation: Step 1: Each ampul contains 75 mg (1.5 mL) of AMSA P-D for infusion. Aseptically transfer 1.5 mL from the ampul to the 13.5 mL vial of L-lactic Acid diluent (use only the diluent provided). The resulting orange-red solution contains 5 mg AMSA P-D per mL. It is preferable to use glass syringes for step one, however, plastic syringes can be used, providing the AMSA P-D solution remains in the syringe for no more than 15 minutes. The stock solution is chemically stable for 24 hours at room temperature when protected from exposure to direct sunlight. Since this solution does not contain a preservative, any unused portion should be discarded.

Step Two: Prepare the i.v. infusion solution by aseptically transferring the total daily dose of Stock Solution to 500 mL Dextrose Injection USP. Do not use saline solution. The freshly prepared i.v. infusion is chemically stable for up to 7 days 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 24 hours when stored at room temperature or 72 hours, 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 – Class II).

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 1 000° 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 of 5% sodium hypochlorite and/or 5% sodium thiosulfate.

Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.

Availability And Storage: Each ampul (75 mg/1.5 mL ampul) contains: amsacrine 50 mg/mL. Nonmedicinal ingredients: n,n-dimethylacetamide. Packages of 5 ampuls with 13.5 mL vials of L-lactic acid diluent. Contains no preservatives. Store at controlled room temperature.

AMSA P-D™ Parke-Davis Amsacrine Antineoplastic

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