miscellaneous, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Although its mechanism of action is incompletely defined, amsacrine inhibits DNA synthesis by binding to and intercalating with DNA. Amsacrine also inhibits topoisomerase II activity4,5 and may exert an effect on cell membranes.2,6 This agent also possesses immunosuppressive and antiviral properties.4 While amsacrine is not cell cycle phase-specific,4,7 cytotoxicity is maximal during the G2 and S phases.4,6
| Oral Absorption | poor 6 | |
| Distribution | high levels achieved in gallbladder and kidneys; lower levels in lung, testes, muscle, fat, spleen, bladder, pancreas, colon, prostate, brain, and CSF 2 | |
| cross blood brain barrier? 5 | minimal | |
| volume of distribution 1 | 1.67 L/kg | |
| plasma protein binding 5 | 96-98% | |
| Metabolism | hepatic 5 | |
| active metabolite(s) | no information found | |
| inactive metabolite(s) 5 | yes; including 5'-glutathione conjugate | |
| Excretion | primarily biliary 2,6 | |
| urine 2,4,5 | 35%; 2-20% unchanged | |
| feces 2 | ~80% | |
| terminal half life 5 | 5-8 h; severe hepatic dysfunction 2 : 17 h | |
| clearance 8 | 150 mL/min/m 2 | |
| Children | longer half life, 9 ~18 h | |
Adapted from standard reference4 unless specified otherwise.
Primary uses: Other uses:
*
Leukemia, acute
*Health Canada approved indication
history of hypersensitivity reaction to amsacrine or acridine derivatives (e.g., acriflavine)4 pre-existing drug-induced or radiotherapy-induced bone marrow suppression4
dose reduce with significant hepatic dysfunction (bilirubin >34 umol/L) or renal impairment (BUN >7 mmol/L or serum creatinine >106 umol/L)4; see Dosage Guidelines monitor cardiac rhythm during and after drug administration4 correct fluid or electrolyte imbalances, including serum potassium, prior to administration4 in patients who have received high cumulative doses of anthracyclines5; amsacrine is not contraindicated in patients who have received previous treatment with anthracyclines4 safety and efficacy in the elderly have not been established4
carcinogenic in rats
Mutagenicity: Mutagenic in mammalian in vitro mutation test.10 Amsacrine is clastogenic in mammalian in vitro chromosome tests.10 Fertility: reversible decreased sperm production5 and motility reported1; reproductive studies in animals not performed to date4 Pregnancy: The risks of amsacrine in pregnancy are undetermined. The drug is cytotoxic, therefore, the risks may be substantial.4,11 No human studies of pregnancy outcomes after exposure have been published to date and there have been no reports of outcomes following inadvertent exposure during pregnancy. Amsacrine given intraperitoneally to rats resulted in decreased fetal weight and eye and jaw malformations.1
is not recommended due to the potential secretion into breast milk.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.12
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| allergy/immunology | allergic reaction (0.4%) 5 ; some patients have been able continue therapy with antihistamine or corticosteroid pretreatment 2 |
| blood/bone marrow/ febrile neutropenia | myelosuppression ; dose-limiting; prolonged bone marrow aplasia has occurred |
| anemia (1-10%) 5 ; mild to severe | |
| leukopenia; nadir days 11-13, recovery by days 17-25; granulocytopenia | |
| thrombocytopenia; mild to moderate; nadir days 12-14, recovery 1,5 by days 21-25 | |
| cardiovascular (arrhythmia) | arrhythmia (<1%); including acute and ventricular arrhythmia, atrial fibrillation, tachycardia, sinus tachycardia, and bradycardia; typically occurs during or immediately following infusion; several patients had received prior anthracycline therapy or were hypokalemic |
| ECG changes | |
| cardiovascular (general) | cardiomyopathy; typically occurs days to weeks following therapy 13 |
| congestive heart failure; typically occurs in patients who had been pre-treated with anthracyclines | |
| decreased ejection fraction | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| hypotension | |
| constitutional symptoms | fatigue |
| fever; unrelated to sepsis | |
| weigh gain/loss | |
| dermatology/skin | extravasation hazard: vesicant 14 |
| alopecia ( < 100%) 12 ; dose-related 7,15 | |
| injection site reactions including: irritation, necrosis, inflammation, and cutaneous inflammatory reaction | |
| rash; including purpuric and maculopapular | |
| urticaria | |
| gastrointestinal | emetogenic potential: low 16 |
| anorexia | |
| diarrhea ( < 30%) 4,5 | |
| dysphagia | |
| gingivitis | |
| nausea and vomiting 4,5 ( < 30%) 4,5 ; typically mild to moderate 6 ; not dose-related 7 | |
| mucositis/stomatitis ( < 32%) 4,5 ; dose-limiting 4,5 | |
| perirectal abscess (>10%) | |
| hemorrhage | gum hemmorhage |
| hematemesis | |
| hematuria | |
| hemorrhage, not otherwise specified | |
| purpura | |
| hepatobiliary/pancreas | hepatic insufficiency, hepatitis, hepatic failure; deaths have occurred |
| infection | infections, not otherwise specified |
| metabolic/laboratory | elevated alkaline phosphatase and AST (10%) 5 |
| elevated bilirubin (30%) 5 ; typically transient | |
| elevated BUN | |
| elevated creatinine | |
| hyperuricemia | |
| hypomagnesemia 1 | |
| proteinuria | |
| neurology | confusion (1-10%) 5 |
| dizziness (1-10%) 5 | |
| emotional lability | |
| paresthesia (1-10%) 5 ; hypoesthesia | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| seizure (1-10%) 5 ; typically occur in patients who have metabolic conditions | |
| ocular/visual | blurred vision 5 (1-10%) 5 |
| pain | abdominal pain (>10%) |
| headache (1-10%) 5 | |
| musculoskeletal pain | |
| pulmonary | dyspnea |
| renal/genitourinary | orange-red discolouration of urine 5 (>10%) 5 |
| renal failure | |
| sexual/reproductive function | decreased sperm production 5 and motility 1 (<1%) 5 ; reversible 1 |
| vascular | phlebitis (>10%) 5 ; concentration-related; incidence is reduced by infusing over at least 60 minutes |
Adapted from standard reference4 unless specified otherwise. Cardiotoxicity: Similar to the anthracyclines, both acute (arrhythmia) and chronic (cardiomyopathy) cardiac toxicities have been reported.13 These toxicities are rare, occurring in 1-2% of patients who have not received prior chemotherapy.2,13 Though amsacrine should be used with caution in patients who have received high cumulative doses of anthracyclines,5 it does not potentiate the increased risk of doxorubicin-induced cardiac toxicity4 and is not contraindicated in patients who have received previous treatment with anthracyclines.4 The exact mechanism by which amsacrine causes arrhythmias is unknown,15 though QT interval prolongation does occur.7 Hypokalemia, which also causes QT prolongation, may contribute to the risk of developing arrhythmias.4,7 This risk may be minimized by ensuring a normal serum potassium level immediately prior to and during amsacrine administration.4 As arrhythmias typically occur during or immediately following infusion, monitor cardiac rhythm during and after drug administration.4 Fluid imbalance should also be corrected prior to amsacrine administration.4 Patients with arrhythmias may receive amsacrine with careful monitoring and correction of electrolyte abnormalities.2 Unlike the anthracyclines, the risk of acute congestive heart failure is not related to cumulative dose.13 Hyperuricemia may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or acute renal failure.17 It is most likely with highly proliferative tumours of massive burden, such as leukemias, high- grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting renal dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients18: aggressive hydration: 3 L/m2/24 hr with target urine output > 100 mL/h if possible, discontinuation of drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates) monitoring of electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hours electrolyte replacement as required allopurinol 600 mg po initially, then 300 mg po q6h x 6 doses, then 300 mg po daily x 5-7 days Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to maintain urine pH > 7. Rasburicase (FASTURTEC(r)) is a novel uricolytic agent that catalyzes the oxidation of uric acid to a water-soluble metabolite, removing the need for alkalinization of the urine.19 It may be used for treatment or prophylaxis of hyperuricemia, 0.2 mg/kg IV daily for up to 7 days; however, its place in therapy has not yet been established.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| doxorubicin 4 | no increased risk of doxorubicin-induced cardiotoxicity |
Highly protein bound drugs may displace amsacrine from albumin resulting in increased free amsacrine levels and toxicity.4
Erfa Canada Inc. supplies 75 mg preservative-free ampoules of amsacrine in N,N-dimethylacetamide solvent. 13.5 mL of preservative-free L-lactic acid diluent also supplied. Store at room temperature.
Dilute only with supplied L-lactic acid diluent.4 Amsacrine forms an immediate precipitate in the presence of chloride ions; do not dilute with saline solutions or solutions containing chloride ions or mix with drugs that are chloride or hydrochloride salts.4,5 Catheters flushed with heparin/saline solutions should be rinsed with D5W before administering amsacrine.1 Use of glass syringes and avoidance of plastic filters to draw up undiluted amsacrine solutions is recommended as the N,N-dimethylacetamide solvent has been reported to dissolve plastic syringes and filters. Plastic syringes can be used, providing that amsacrine remains in the syringes for no longer than 15 minutes.4 The solution can be placed in plastic bags when diluted for IV infusion.4,5
consult detailed reference
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous 4 | not used due to corrosive nature |
| Intramuscular 4 | not used due to corrosive nature |
| Direct intravenous 4 | not used due to corrosive nature |
| Intermittent infusion 4 | over 60-90 minutes |
| Continuous infusion | has been used but not recommended 1,5 (more toxic than intermittent infusion) 1 |
| Intraperitoneal 4 | not used due to corrosive nature |
| Intrapleural 4 | not used due to corrosive nature |
| Intrathecal 4 | not used due to corrosive nature |
| Intra-arterial 4 | not used due to corrosive nature |
| Intravesical | no information found |
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults: Cycle Length: BCCA usual dose noted in bold, italics
3-4 weeks,
75-125 mg/m2 IV once daily for 5 consecutive days starting on day 1 (total dose per cycle 375-625 mg/m2) dose should be increased by 20% in the second and each subsequent cycle if marrow hypoplasia has not been achieved and the patient has had no significant toxicity in the preceding cycle 4-8 weeks, maintenance4: approximately half of the induction dose
dependant on blood counts
Concurrent radiation: 12
limited experience, avoid combination
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression" Dosage in renal failure: dose reduction recommended4; the following guidelines have been used: BUN >7 mmol/L or serum creatinine >106 umol/L: give 70-75% of normal dose
1,2
Dosage in hepatic failure: dose reduction recommended4; the following guidelines have been used: bilirubin >34 umol/L: give 70-75% of normal dose
1,2,5
Dosage in dialysis:
no information found
Children:
has been used
1,5
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Weiss RB, Grillo-Lopez AJ, Marsoni S. Amsacrine-associated cardiotoxicity: An analysis of 82 cases. Journal of Clinical Oncology 1986; 4(6):918-928.
BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 December 2007.
Hornedo J, Van Echo DA. Amsacrine (m-AMSA): A new antineoplastic agent. Pharmacology, clinical activity and toxicity. Pharmacotherapy 1985; 5(2):78-90.
BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 March 2008.
DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2001. p. 2640.
Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27.
Sanofi-Synthelabo. Rasburicase product information. Markham, Ontario; 2004.