Amsacrine

PHARMACOLOGIC CATEGORY
Antineoplastic Agent

DOSING: ADULTS — Details concerning dosing in combination regimens should also be consulted.

Acute leukemia: I.V.:
Induction: 75-125 mg/m2/day for 5 days every 3-4 weeks (125 mg/m2/day is preferred; two courses may be necessary to achieve induction; increase dose by 20% in second and subsequent cycles if marrow hypoplasia not achieved and in absence of significant toxicity in previous course.)
Maintenance: Once remission has been achieved, maintenance dose should be ~50% of induction dose, administered every 4-8 weeks, depending on blood counts and marrow recovery

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:

Hall, 1983:
Serum creatinine 1.2-1.8 mg/dL: No adjustment recommended
Serum creatinine 2-3 mg/dL, oliguric patients: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.

Hornedo, 1985: BUN >20 mg/dL or serum creatinine >1.5 mg/dL: Administer 75% of dose

DOSING: HEPATIC IMPAIRMENT — Bilirubin >2 mg/dL: Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:

Hall, 1983: Bilirubin >2 mg/dL: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.

Hornedo, 1985: Bilirubin >2 mg/dL: Administer 75% of dose

Koren, 1992: Severe hepatic dysfunction: Administer ≤ 50% of dose

DOSING: ADJUSTMENT FOR TOXICITY — Consider decreasing dose by 20% if life-threatening infection or hemorrhage occurred in previous cycle; delay second and subsequent cycles until recovery from myelosuppression or evidence of leukemic infiltrate is evident.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name

Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [supplied with L-lactic acid 0.0353 M 13.5 mL] [not available in the U.S.]

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [not available in the U.S.]

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — I.V.: Infuse over 60-90 minutes; avoid extravasation.

COMPATIBILITY — Stable in D5W; incompatible with BNS, D5NS, D51/4NS, D51/2NS, D5LR, D10NS, NSS, LR, chloride ion. Amsacrine forms an immediate precipitate in the presence of chloride ion; do not mix with drugs that are chloride or hydrochloride salts.

Y-site administration: Compatible: Amikacin, chlorpromazine, clindamycin, cytarabine, dexamethasone, diphenhydramine, famotidine, fludarabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium succinate, hydromorphone, lorazepam, morphine, prochlorperazine, promethazine, ranitidine, sodium bicarbonate, tobramycin, vancomycin. Incompatible: Acyclovir, amphotericin, aztreonam, calcium chloride, ceftazidime, ceftriaxone, cephalothin, cimetidine, cisplatin, filgrastim, furosemide, ganciclovir, heparin, methylprednisolone, metoclopramide, ondansetron, potassium chloride, sargramostim.

Compatibility when admixed: Compatible: Sodium bicarbonate, bleomycin

USE — Canada: Refractory acute leukemia

USE - UNLABELED / INVESTIGATIONAL — Acute myeloid leukemia (AML)

ADVERSE REACTIONS SIGNIFICANT
>10%:
Gastrointestinal: Nausea (>10%), vomiting (>10%), stomatitis (>10%), diarrhea (>10%), perirectal abscess (>10%), abdominal pain (>10%)
Hematologic: Myelosuppression, leukopenia (nadir: 11-13 days; recovery: days 17-25)

Frequency not defined:

Cardiovascular: Atrial tachyarrhythmia, atrial tachycardia, atrial fibrillation, bradycardia, cardiomyopathy (rare), cardiopulmonary arrest, CHF (rare); ECG changes (QT prolongation, nonspecific ST segment or T wave changes); ejection fraction decreased, hypotension, sinus tachycardia, tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular tachyarrhythmia

Central nervous system: Confusion, dizziness, emotional lability, fever, headache, hypoesthesia, lethargy, seizure

Dermatologic: Alopecia, cutaneous inflammatory reaction, dermatologic reaction, purpura, rash (purpuric or maculopapular), urticaria

Gastrointestinal: Anorexia, dysphagia, gingivitis, gum hemorrhage, hematemesis, weight changes

Genitourinary: Orange-red discoloration of the urine

Hematologic: Anemia, granulocytopenia, hemorrhage, pancytopenia, thrombocytopenia

Hepatic: Alkaline phosphatase increased, AST increased, bilirubin increased, hepatic insufficiency, hepatitis, hepatotoxicity, jaundice, progressive liver failure

Local: Injection site inflammation, phlebitis

Neuromuscular & skeletal: Musculoskeletal pain, paresthesia, weakness

Renal: BUN increased, creatinine increased, hematuria, proteinuria, renal failure

Respiratory: Dyspnea

Miscellaneous: Allergic reaction, infection

CONTRAINDICATIONS — Hypersensitivity to amsacrine, acridine derivatives, or any component of the formulation; pre-existing bone marrow suppression due to chemotherapy or radiation therapy

WARNINGS / PRECAUTIONS
Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects: Bone marrow suppression: Myelosuppression, including transient leukopenia, is a common toxicity; prolonged marrow aplasia may occur. May require dose reduction, therapy interruption or treatment delay. Cardiovascular effects: Acute cardiotoxicity, including arrhythmia, ECG changes, and rarely, cardiomyopathy and CHF, have been reported with use, although generally not considered to be a cumulative dose effect. Risk factors for cardiotoxicity may include hypokalemia and a history of anthracycline therapy. Correct fluid and electrolyte imbalance prior to treatment initiation. Use with caution in patients with underlying cardiovascular disease. Tumor lysis syndrome: Tumor lysis syndrome may occur; adequate hydration and prophylactic uric acid reduction should be considered prior to or during treatment; monitor closely.

Disease-related concerns: Hepatic impairment: Use with caution in patients with significant hepatic impairment (bilirubin >2 mg/dL); toxicity may be increased. Hepatic metabolism and biliary excretion are major routes of elimination. Dosage reductions may be recommended. Evaluate hepatic function prior to and during treatment. Hypokalemia: Serum potassium should be >4 mEq/L prior to administration (Arlin, 1988). The risk for arrhythmia is decreased by ensuring normal potassium levels. Renal impairment: Use with caution in patients with significant renal impairment (BUN >20 mg/dL; serum creatinine >1.2 mg/dL); toxicity may be increased. Dosage reductions may be recommended. Evaluate renal function prior to and during treatment.

Concurrent drug therapy issues: Anthracyclines: Use with caution in patients who have received high cumulative doses of anthracyclines (may increase the risk for cardiotoxicity). Vaccinations: Avoid vaccination with live virus vaccines during treatment.

RESTRICTIONS — Not available in U.S.

DRUG INTERACTIONS
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted. Women of childbearing potential should avoid becoming pregnant while receiving treatment.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Breast-feeding should be discontinued prior to treatment.

MONITORING PARAMETERS
CBC with differential, bone marrow studies, serum potassium, hepatic function, renal function; ECG (during and after infusion)

CANADIAN BRAND NAMES — AMSA PD

INTERNATIONAL BRAND NAMES — Amekrin (DK, SE); Amsidine (BE, NL); Amsidyl (AU)

MECHANISM OF ACTION — Amsacrine has been shown to inhibit DNA synthesis by binding to, and intercalating with, DNA; inhibits topoisomerase II activity.

PHARMACODYNAMICS / KINETICS
Distribution: Vd: 1.67 L/kg; minimal CNS penetration

Protein binding: 96% to 98%

Metabolism: Hepatic, to inactive metabolites (major metabolite is 5' glutathione conjugate)

Half-life elimination: 1.4-5 hours; Terminal: 8-9 hours

Excretion: Bile; urine (35%; 20% as unchanged drug)

PATIENT INFORMATION — This drug may cause darkening or discoloration of the urine for 24-48 hours. Watch for fever, malaise, bleeding, bruising, sore throat or mouth, difficulty swallowing, or for pain, redness, or swelling at the injection site.