Mitoxantrone injection, NOVANTRONE(r) (USA)
intercalating agent-antitumour antibiotic, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Mitoxantrone is a synthetic anthracenedione that is structurally similar to doxorubicin and daunorubicin.2,4 It was synthesized with the goal to reduce anthracycline side effects, particularly cardiotoxicity.5 Mitoxantrone inhibits DNA repair by inhibiting topoisomerase II4,6 which results in fragmentation of DNA.7 Mitoxantrone is an immunosuppressive agent4,6 that may also generate free radicals, inhibit protein kinase C, cause electrostatic DNA cross-links, and induce apoptosis.2 Although maximally cytotoxic in the S-phase, mitoxantrone is not cell cycle phase-specific.2,8 Cross-resistance with anthracyclines has been demonstrated.2
| Oral Absorption | poor 6 | |
| Distribution | extensive tissue distribution; 3X greater AUC in patients with severe hepatic dysfunction | |
| cross blood brain barrier? | not to an appreciable extent | |
| volume of distribution 6 | 14 L/kg; distributes into pleural fluid, kidney, thyroid, liver, heart, and red blood cells | |
| plasma protein binding 6 | >95%; 76% to albumin | |
| Metabolism | hepatic, pathways undetermined | |
| active metabolite(s) | no information found | |
| inactive metabolite(s) 9 | yes | |
| Excretion | urine 2,6 | 6-11%; 65% unchanged |
| feces 6 | 25%; 65% unchanged | |
| terminal half life | 23-215 h; prolonged by hepatic impairment | |
| clearance 10 | 10.9-37.4 L/hr/m 2 | |
| Elderly | decreased clearance | |
Adapted from standard reference4 unless specified otherwise.
| Primary uses: | Other uses: |
| *Leukemia, including acute non-lymphocytic | *Breast cancer |
| Prostate cancer 11 | *Hepatoma |
| * Lymphoma | |
| Pediatric sarcoma 6 | |
*Health Canada approved indication
history of hypersensitivity reaction to anthracyclines or mitoxantrone4 severe hepatic impairment4; safety in patients with hepatic impairment has not been established4; reduced dosage has been used4 Caution: when used in combination regimens, the initial dose should be reduced by 2-4 mg/m2 below the recommended dose for single-agent usage4 Cardiac toxicity is a risk of mitoxantrone therapy that may be manifested by acute or delayed events4; see paragraph following the Side Effects table for more information. Risk factors for developing mitoxantrone-induced cardiotoxicity include4: high cumulative dose (>100 mg/m2); if exceeded, monitor for evidence of cardiac toxicity prior to each subsequent dose previous therapy with other anthracyclines or anthracenediones prior or concomitant radiotherapy to the mediastinal/pericardial area pre-existing heart disease [left ventricular ejection fraction (LVEF) <50% or a clinically-significant reduction in LVEF] concomitant use of other cardiotoxic drugs Carcinogenicity: Studies not preformed to date.4 Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) have been reported when used alone but more so when used with other antineoplastic agents and/or radiation.4 Mutagenicity: Mutagenic in microbial mutagenicity tests.4 Mitoxantrone is clastogenic in mammalian in vivo chromosome tests; at doses approximating clinical use levels, the clastogenic effect is reversible.4 Fertility: Amenorrhea and a typically reversible reduction in spermatogenesis have been reported.4,9,12 At the highest tolerated doses allowing evaluation of reproduction in rats, mitoxantrone had no effect on fertility.4 Pregnancy: FDA Pregnancy Category D.6 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
is not recommended due to 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.13
| ORGAN SITE | SIDE EFFECT Mitoxantrone is typically well tolerated at standard doses. 4 |
| Clinically important side effects are in bold, italics | |
| allergy/immunology | allergic reactions; including anaphylaxis (<1%) 6 |
| blood/bone marrow/ febrile neutropenia | anemia (5-75%) 6 |
| leukopenia (9-100%) 6 ; nadir typically occurs on day 10 with recovery by day 21 | |
| myelosuppression ; dose-limiting; severe myelosuppression is rare | |
| thrombocytopenia (33-39%) 6 | |
| cardiovascular (arrhythmia) | arrhythmia (3-18%) 6 ; including sinus bradycardia |
| ECG changes 6 (11%) 6 | |
| ORGAN SITE | SIDE EFFECT Mitoxantrone is typically well tolerated at standard doses. 4 |
| Clinically important side effects are in bold, italics | |
| cardiovascular (general) | cardiomyopathy |
| CHF (2-5%) 4,6 ; may occur during and months to years after treatment; deaths have occurred | |
| decreased left ventricular ejection fraction ( < 13%) 4,6 ; may occur during and months to years after treatment | |
| hypertension 6 (4%) 6 | |
| hypotension | |
| ischemia 6 (5%) 6 | |
| myocardial infarction | |
| constitutional symptoms | diaphoresis 6 (9%) 6 |
| fatigue ( < 39%) 6 | |
| fever (6-78%) 6 | |
| weight changes (13-17%) 6 | |
| dermatology/skin | extravasation hazard: irritant 14 ; rare cases of tissue necrosis have been reported; reversible blue discolouration of the skin has occurred with extravasation |
| alopecia * (15-61%, severe 1%) 4,6 ; typically mild; case reports of selective alopecia of white but not dark hair 9 | |
| bruising 6 (6-11%) 6 | |
| nail pigmentation | |
| onycholysis (11%) 6 | |
| gastrointestinal | emetogenic potential: low to low- moderate 15 |
| anorexia (22-25%) 6 | |
| constipation (10-16%) 6 | |
| diarrhea * (4-47%) 6,9 | |
| dyspepsia 6 (5-14%) 6 | |
| nausea and vomiting * (10-35%, severe 4%) 4,9 typically mild and transient | |
| stomatitis/mucositis * (4-54%, severe <1%) 4,6,9 ; typically occurs within 1 week of treatment 9 | |
| ulcers 6 (10%) 6 | |
| hemorrhage | gastrointestinal bleed (2-16%) 6 |
| hemorrhage * (6%) 6 | |
| hepatobiliary/pancreas | hepatic toxicity * (<1%) 9 ; severe impairment reported in leukemic patients |
| infection | infection *; including urinary tract (7-32%), 6 upper respiratory tract (7-53%), 6 pneumonia (9%) 6 |
| lymphatics | edema (10-31%) 6 |
| metabolic/laboratory | hyperglycemia 6 (10-31%) 6 ; likely related to concurrent steroid administration 13 |
| hyperuricemia | |
| hypocalcemia (10%) 6 | |
| ORGAN SITE | SIDE EFFECT Mitoxantrone is typically well tolerated at standard doses. 4 |
| Clinically important side effects are in bold, italics | |
| hypokalemia (7-10%) 6 | |
| hyponatremia 6 (9%) 6 | |
| increased blood urea nitrogen (22%) | |
| increased liver enzymes ( < 37%) 6,9 | |
| increased serum creatinine (13%) 6 | |
| proteinuria 6 (6%) 6 | |
| musculoskeletal | weakness (24%) 6 |
| neurology | anxiety (5%) 6 |
| confusion | |
| depression 6 (5%) 6 | |
| drowsiness | |
| paraesthesia | |
| seizures 6 (2-4%) 6 | |
| ocular/visual | blue discolouration of the sclera (<1%); reversible |
| blurred vision 6 (3%) 6 | |
| conjunctivitis 6 (5%) 6 | |
| pain | headache (6-13%) 6 |
| pain 6 (8-41%) 6 ; including abdominal pain (9-15%), 6 back pain 6 (8%), 6 myalgia 6 (5%), 6 arthralgia 6 (5%) 6 | |
| pulmonary | cough 6 (5-13%) 6 |
| dyspnea (6-18%) 6 | |
| rhinitis/sinusitis 6 (5-6%) 6 | |
| renal/genitourinary | blue-green colouration of urine (6-11%) 6 ; typically occurs for 24h after treatment |
| hematuria 6 (11%) 6 | |
| renal toxicity (8%) 6 | |
| secondary malignancy | AML and MDS (~1-2%) 4,6 |
| sexual/reproductive function | amenorrhea (28-53%), 6 menstrual disorder 6 (26-61%) 6 |
| impotence 6 (7%) 6 | |
| reduction in spermatogenesis; typically reversible 4,9,12 | |
| syndromes | tumour lysis syndrome (<1%) |
Adapted from standard reference4 unless specified otherwise. *In leukemic patients, due to higher doses used, the side effects profile may differ; the following toxicities have been reported6,8: diarrhea, 9-13% increased incidence of bleeding and infection; sepsis, 31-34% moderate nausea or vomiting, 8% moderate or severe alopecia, 11 % moderate or severe stomatitis/mucositis, 9-29% moderate or severe jaundice or hepatitis, 8% Cardiotoxicity may manifest as EKG changes, an asymptomatic decrease in LVEF, cardiomyopathy, and symptomatic congestive heart failure (CHF).4,6 Evaluation of LVEF is recommended4: prior to initiating therapy if signs and symptoms of CHF develop in patients with risk factors; see paragraph in the Special Precautions section for more information prior to all doses received after a cumulative dose of 100 mg/m2 is reached Cardiotoxicity is cumulative across all anthracyclines and anthracenediones and is thought to be due to in part to free radical damage.2,16 Irreversible CHF may occur during therapy or months to years afterwards; deaths have occurred. At the cumulative dose of 140 mg/m2, the incidence of symptomatic CHF and moderate or severe decline in LVEF are 2.6 and 13 percent respectively.4 Like the anthracyclines, mitoxantrone-induced heart failure responds to standard medical therapy.4 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/hr 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.19It 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 |
| quinolones (e.g., ciprofloxacin) 20 | delayed, moderate, possible; the antimicrobial effect of quinolones may be decreased | quinolone absorption decreased due to alteration of the intestinal mucosa | monitor for response to quinolone therapy, adjust quinolone dose as necessary |
: Hospira Healthcare Corporation supplies mitoxantrone as a 2 mg/mL dark blue solution in 10 and 12.5 mL single-use vials. Store at room temperature; do not freeze. Protect from light.
Novopharm Limited supplies mitoxantrone as a 2 mg/mL dark blue solution in 10 mL single-use vial. Store at room temperature; do not freeze. Protect from light.8 Pharmaceutical Partners of Canada supplies mitoxantrone as a 2 mg/mL dark blue solution in 10 mL single-use vial. Store at room temperature; do not freeze.7 Product is not light- sensitive.21
should be diluted to at least 50 mL prior to use
consult detailed reference
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous 4 | not recommended |
| Intramuscular 4 | not recommended |
| Direct intravenous | not recommended; has been used 6,22-24 |
| Intermittent infusion 2,4 | slowly (over 3-5 minutes ; typically given over 15-30 minutes ) into tubing of running IV |
| Continuous infusion 1,6 | has been used |
| Intraperitoneal 4,9 | has been used |
| Intrapleural 25 | investigational |
| Intrathecal 4 | not recommended; neuropathy and neurotoxicity including paralysis, seizures, and bowel and bladder dysfunction have occurred |
| Intra-arterial 4 | not recommended; local/regional neuropathy which may be irreversible has been reported |
| Intravesical 26,27 | investigational |
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:
| BCCA usual dose noted in bold, italics | ||
| Cycle Length: | ||
| Intravenous: | 3 -4 weeks 2,4,6,11 : | 12 -14 mg/m 2 IV for one dose on day 1 (total dose per cycle 12-14 mg/m 2 ) |
| induction 4 : | 12 mg/m 2 IV once daily for 5 consecutive days starting on day 1 (total dose 60 mg/m 2 ) | |
Cycle Length: induction and re- induction2,4: BCCA usual dose noted in bold, italics 10-12 mg/m2 IV once daily for 2-3 consecutive days starting on day 1 (total dose per cycle 20-36 mg/m2) consodildation:2,4: 12 mg/m2 IV once daily for 2 consecutive days starting on day 1 (total dose per cycle 24 mg/m2)
Suggested maximum cumulative dose4: 100 mg/m2; see cardiotoxicity paragraph following the Side Effects table
Concurrent radiation:
has been used
28-31
Dosage in myelosuppression:
modify according to protocol by which patient is being treated or the product
monograph; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression" Dosage in renal failure: safety and effectiveness have not been established4; limited renal excretion, adjustment likely not required2 Dosage in hepatic failure: consider dosage adjustment6; no dosing details found, contraindicated in severe hepatic impairment4
Dosage in dialysis:
extensive tissue binding; unlikely cleared by dialysis; supplemental dose not
required
6,32
Children:
Cycle Length: Intravenous: safety and effectiveness have not been established4; has been used1,4,33 n/a1,33: 8-12 mg/m2 IV once daily for 3-5 consecutive days starting on day 1 (total dose 24-60 mg/m2) n/a1: 0.4 mg/kg/day IV once daily for 3-5 consecutive days starting on day 1 (total dose 1.2-2.0 mg/kg) n/a1: 12 mg/m2 IV once daily for 2-3 consecutive days starting on day 1 (total dose 24-36 mg/m2) 3-4 weeks1: 18-20 mg/m2 IV for one dose on day 1 (total dose per cycle 18-20 mg/m2)
Rose BD editor. Mitoxantrone: Pediatric drug information. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate(r); 2008.
McEvoy GK, editor. AHFS 2007 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 1143-1145.
National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; September 2004. p. 31-40.
Hospira Healthcare Corporation. Mitoxantrone Injection, USP Product Monograph. Saint-Laurent, Quebec; 13 June 2007.
Floyd J, Morgan JP, Perry MC. Cardiotoxicity of anthracycline-like chemotherapy agents. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate(r); 2007.
Rose BD editor. Mitoxantrone. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate(r); 2008.
Pharmaceutical Partners of Canada. Mitoxantrone Injection Package Insert. Richmond Hill, Ontario; February 2007.
Novopharm Limited. Mitoxantrone Injection Product Monograph. Toronto, Ontario; 19 May 2005.
DRUGDEX(r) Evaluations (database on the Internet). Mitoxantrone. Thomson MICROMEDEX(r), 2008. Available at: www.micromedex.com. Accessed 25 January 2008.
Ehninger G, Schuler U, Proksch B, et al. Pharmacokinetics and metabolism of mitoxantrone. Clin Pharmacokinet. 1990; 18(5):365-380.
BC Cancer Agency Genitourinary Tumour Group. (GUPMX) BCCA Protocol Summary for Palliative Therapy for Hormone Refractory Prostate Cancer Using Mitoxantrone and Prednisone. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
Lemez P, Urbanek V. Chemotherapy for acute myeloid leukemias with cytosine arabinoside, daunorubicin, etoposide, and mitoxantrone may cause permanent oligoasthenozoospermia or amenorrhea in middle-aged patients. Neoplasma 2005; 52(5):398- 401.
Lyly Le MD. Personal communication. BC Cancer Agency Genitourinary Tumour Group; 12 March 2008.
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 September 2006.
BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
Mott MG. Anthracycline cardiotoxicity and its prevention.824:221-8. Annals of the New York Academy of Sciences. 1997; 824:221-228.
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.
Abraxis Pharmaceutical Products. Dacarbazine product information package. Schaumburh, IL; December 2006.
Drug Interaction Facts (database on the Internet). Procarbazine. Facts and Comparisons 4.0, 2008. Available at: http://online.factsandcomparisons.com. Accessed 7 March 2008.
Josephine Holmes. Personal communication. Manager Regulatory Affairs, Pharmaceutical Partners of Canada Inc.; 28 Jan 2008.
Hainsworth JD, Jones SE, Mennel RG, et al. Paclitaxel with mitoxantrone, fluorouracil, and high-dose leucovorin in the treatment of metastatic breast cancer: A phase II trial. Journal of Clinical Oncology 1996; 14(5):1611-1616.
Carmo-Pereira J, Costa FO, Henriques E. Mitoxantrone, folinic acid, 5-fluorouracil and prednisone as first-line chemotherapy for advanced breast carcinoma. A phase II study. European Journal of Cancer Part A: General Topics 1993; 29(13):1814-1816.
Kakolyris S, Samonis G, Koukourakis M, et al. First-line treatment with mitoxantrone, methotrexate, vincristine, and carboplatine (MIMOC) plus cyclical hormonotherapy with tamoxifen and megestrol acetate in advanced breast cancer. American Journal of Clinical Oncology: Cancer Clinical Trials 1999; 22(3):273-277.
Windsor PG, Como JA, Windsor KS. Sclerotherapy for malignant pleural effusions: Alternatives to tetracycline. South.Med.J. 1994; 87(7):709-714.
Flamm J, Donner G, Oberleitner S, et al. Adjuvant intravesical mitoxantrone after transurethral resection of primary superficial transitional cell carcinoma of the bladder. A prospective randomised study. European Journal of Cancer Part A: General Topics 1995; 31(2):143-146.
Porter P, Cornaby AJ, Al-Hilali M, et al. Primary lymphoma of the bladder treated successfully with mitozantrone gel. Postgrad.Med.J. 1999; 75(888):609-610.
Toledano A, Azria D, Garaud P, et al. Phase III trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: Final results of the ARCOSEIN trial. Journal of Clinical Oncology 2007; 25(4):405-410.
Rouesse J, De La Lande B, Bertheault-Cvitkovic F, et al. A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: Final results. International Journal of Radiation Oncology Biology Physics 2006; 64(4):1072-1080.
Macquart-Moulin G, Viens P, Genre D, et al. Concomitant chemoradiotherapy for patients with nonmetastatic breast carcinoma: Side effects, quality of life, and daily organization. Cancer 1999; 85(10):2190-2199.
Gedlicka C, Schull B, Formanek M, et al. Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies. Anticancer Drugs 2002; 13(5):491-495.
Aronoff GR, Bennett WM, Berns JS, Brier ME, et al. Drug Prescribing in Renal Failure: Dosing guidelines for adults and children. 5th ed. Philadelphia, Pennsylvania: American College of Physicians; 2007. p. 101.
Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006. p. 303.