Mitoxantrone hydrochloride

517.4

516.154236

274-619-1

U6USW86RD0

DTXSID0045173

C665

Blue-black solid from water ethanol

2914610000

163

2.39260

5-203 °C

805.7ºC at 760 mmHg

441.1ºC

soluble to 5 mM in water and to 75 mM in DMSO;Methanol < 1 (mg/mL)

Intact vials of the dark blue concentrate should be stored at room temp & protected from freezing. Refrigeration of the concentrate may cause a precipitate, which redissolves upon warming to room temp.

195.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroscopic

III

6.1(b)

3249

3

46-61-26/27/28

53-36/37/39-45-22

CB5748500

T,T+

Bulk: After 30 days at 60 ° C, no decomposition was observed (UV or TLC). Solution: The solution undergoes 6% decomposition in H over 5 days (UV).

P201-P280-P308 + P313

H340-H360

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

|Danger|H340 (92.86%): May cause genetic defects [Danger Germ cell mutagenicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 42 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P262, P264, P270, P280, P281, P301+P312, P302+P350, P307+P311, P308+P313, P310, P314, P321, P322, P330, P361, P363, P405, and P501

Chemotherapy with mitoxantrone alone is associated with serum enzyme elevations in up to 40% of patients, but these elevations are generally mild-to-moderate in severity, transient and not accompanied by symptoms or jaundice. Higher rates of liver enzyme elevations have been reported with combination chemotherapeutic regimens that include mitoxantrone. In high doses, mitoxantrone has been associated with a high rate of jaundice, but the degree of hyperbilirubinemia has been mild, transient and not associated with significant serum enzyme elevations or evidence of hepatitis. Rare instances of acute liver injury have been reported in patients taking mitoxantrone, including a single case of drug-rash with eosinophilia and systemic symptoms (DRESS). The latency to onset was 8 weeks and the pattern of serum enzyme elevations was cholestatic and later mixed. Immunoallergic features were prominent and appeared to respond to corticosteroid therapy. Other drugs were being taken and the association with mitoxantrone was not definite (Case 1). Thus, idiosyncratic and clinically apparent liver injury from mitoxantrone may occur but is quite rare.

Supportive care in tumour chemotherapy is a subject of intensive research. The complications of cytostatic therapy are a cause of extensive research of their pharmacological interactions and side effects. The immunologic and biochemical changes accompanying tumours are the factor that is most responsible for the worsening of the physiology of the host. Regimens containing carnitine and it's acetyl-derivative are used in many cases, among others even for preventing hepatotoxicity. Our hypothesis was to verify the supporting metabolic effects of acetyl-L-carnitine hydrochloride (ALC) in combined therapy with mitoxantrone (MX) and hepatotoxic cytostatic drugs including alkylating agents. This present report describes the effect of ALC in combination with MX on DBA/2 male mice bearing a transplantable L1210 leukemia resistant to MX. The criterion for evaluation of effect was the length of survival time of experimental animals. The proportional-hazards model quadratic in the drug dose (7) was used for survival time evaluation and optimal dose calculation. The hazard functions and the index of relative hazard were determined using Weibull distribution after logarithmic transformation of the entered data in each particular group. The dose-response curve was represented by a second-degree polynomial without absolute term. The combination therapy revealed that the optimal dose of ALC was 186 mg/kg s.c. A significant effect of ALC (s.c.) in combined therapy with MX (6 mg/kg i.v.) given to animals bearing an experimental form of leukemia L1210/MX resistant to MX was proven at a level of probability p < or = 0.001. The effect of ALC in monotherapy was not demonstrable.|... The ability of dipyridamole to /enhance/ the cytotoxic effects of mitoxantrone hydrochloride was studied in hamster ovary cells in vitro. Clonogenic assays indicated that one, 2.5, and 5 uM decreased the survival of cells treated with 5-25 nM mitoxantrone in a dose dependent manner. Doses of one and 5 uM dipyridamole decreased the mitoxantrone concentration required for 50% inhibition of cell growth from 3.2 to 1.8 and from 3 to 0.5 nM, respectively, over 3 days. Dipyridamole increased the accumulation of mitoxantrone by 1.8 fold in exponentially growing cells exposed to mitoxantrone. It was concluded that dipyridamole augments the cytotoxic effects of mitoxantrone in vitro.|Uptake of weak acid and weak base chemotherapeutic drugs by tumors is greatly influenced by the tumor extracellular/interstitial pH (pH(e)), the intracellular pH (pH(i)) maintained by the tumor cells, and by the ionization properties of the drug itself. The acid-outside plasmalemmal pH gradient in tumors acts to exclude weak base drugs like the anthracyclines, anthraquinones, and vinca alkaloids from the cells, leading to a substantial degree of "physiological drug resistance" in tumors. We have induced acute metabolic alkalosis in C3H tumor-bearing C3H/hen mice, by gavage and by intraperitoneal (i.p.) administration of NaHCO(3). (31)P magnetic resonance spectroscopic measurements of 3-aminopropylphosphonate show increases of up to 0.6 pH units in tumor pH(e), and 0.2 to 0.3 pH units in hind leg tissue pH(e), within 2 hours of i.p. administration of NaHCO(3). Theoretical calculations of mitoxantrone uptake into tumor and normal (hind leg) tissue at the measured pH(e) and pH(i) values indicate that a gain in therapeutic index of up to 3.3-fold is possible with NaHCO(3) pretreatment. Treatment of C3H tumor-bearing mice with 12 mg/kg mitoxantrone resulted in a tumor growth delay of 9 days, whereas combined NaHCO(3)--mitoxantrone therapy resulted in an enhancement of the TGD to 16 days.

LD50 Rat oral 682 mg/kg|LD50 Rat skin 1640 mg/kg|LD50 Rat ip 8 mg/kg|LD50 Rat sc 5500 ug/kg|For more Non-Human Toxicity Values (Complete) data for NOVANTRONE (9 total), please visit the HSDB record page.

Drug: Mitoxantronehydrochloride

Mitoxantrone is an antineoplastic antibiotic that is used in the treatment of acute leukemia, lymphoma, and prostate and breast cancer, but also for late stage, severe multiple sclerosis. Mitoxantrone therapy is often accompanied by mild to moderate elevations in serum aminotransferase levels, but in typical doses it rarely causes clinically apparent, acute liver injury.

Antineoplastic Agents; Multiple Sclerosis Agents

Mitoxantrone (NOVANTRONE) is supplied for iv infusion. To induce remission in acute nonlymphocytic leukemia in adults, the drug is given in a daily dose ... for 3 days as a component of a regimen that also includes cytosine arabinoside. Mitoxantrone also is used in advanced hormone-resistant prostate cancer ... . In 2000, mitoxantrone was approved by the FDA for the treatment of late-stage secondary progressive multiple sclerosis.

NOVANTRONE (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. NOVANTRONE should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration.|NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result from intrathecal administration.|Except for the treatment of acute nonlymphocytic leukemia, NOVANTRONE therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/cu m. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving NOVANTRONE.|Use of NOVANTRONE has been associated with cardiotoxicity. Cardiotoxicity can occur at any time during NOVANTRONE therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of NOVANTRONE therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed. Multiple sclerosis patients with a baseline LVEF <50% should not be treated with NOVANTRONE. LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis. Additional doses of NOVANTRONE should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during NOVANTRONE therapy. Patients with multiple sclerosis should not receive a cumulative dose greater than 140 mg/sq m. In cancer patients, the risk of symptomatic congestive heart failure (CHF) was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/sq m. Presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with NOVANTRONE may occur whether or not cardiac risk factors are present.|For more Drug Warnings (Complete) data for NOVANTRONE (11 total), please visit the HSDB record page.

Compounds capable of relieving pain without the loss of CONSCIOUSNESS. (See all compounds classified as Analgesics.)|Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II. (See all compounds classified as Topoisomerase II Inhibitors.)|Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

An optimum procedure was established for preparing mitoxantrone albumin microspheres (DHAQ-BSA-MS) with emulsion-heating solidification. The morphology, diameters, drug loading, release characteristics, stability and its distribution in vivo of the drug-loaded albumin microspheres were studied. The results showed that the surface was regular, the average diameter was 0.99 micron, mean surface diameter was 1.24 microns and mean volume diameter was 1.44 microns, apparent drug loading was 2.558 +/- 0.101 micrograms.mg-1 (n = 5), effective drug loading was 1.503% +/- 0.127% (n = 5), embedding ratio was 92.82% +/- 6.48% (n = 5), and the release characteristics were in accord with "biphase kinetics equation": 1 - Q = 0.6428e-0.2132t + 0.3988e-0.00150t (gamma 1 = -0.9951, gamma 2 = -0.9982); T1/2 alpha = 3.250 h, T1/2 beta = 461.7 h. The stability of the drug-loaded albumin microspheres was good after three months storage at room temperature. The results determined by HPLC showed that the drug accumulated about 77.6% +/- 1.38% of the dose in the liver 20 minutes after intravenous injection to mice. This indicates that DHAQ-BSA-MS showed remarkable targeting for liver, and it seems to have important value for increasing the antihepatoma effect and decreasing the toxicity of mitoxantrone.|... /Pharmacokinetics/ 1,4 dihydroxy 5,8 bis((2 ((2 hydroxyethyl)amino)ethyl)amino) 9,10 an6 thracenedione hydrochloride (I; NSC 301739; mitoxantrone hydrochloride) were determined in 6 metastatic cancer patients who each received 100 200 mCi, one to 3 mg/sq m of I in 12 ml of normal saline solution as an IV bolus over 15 min. Plasma clearance of I followed a biphasic pattern with a harmonic mean initial half life of 13.7 min and a terminal half life of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. The apparent volume of distribution of I was about 13.8 + 2.9 liters/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.|... Pharmacokinetic studies in humans and animals with mitoxantrone hydrochloride (Novantrone) are /discussed/ Intravenously administered novantrone disappears from the plasma of humans and animals with multiexponential kinetics and with a terminal half life ranging from 38 hr to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues; however, redistribution back into the plasma and elimination from the body are slow processes, In both animals and humans, novantroneis metabolized to the mono and dicarboxylic acid derivatives, as well as the glucuronide conjugates of these acids. Following IV administration, it is unchanged novantrone that binds to most tissues. Elimination is slow and predominantly via the kidney. Interaction studies with doxorubicin (II) indicate that prior administration of doxorubicin may prolong the half life of novantrone but that concurrent administration may not involve problems after the first dose.|Uptake of weak acid and weak base chemotherapeutic drugs by tumors is greatly influenced by the tumor extracellular/interstitial pH (pH(e)), the intracellular pH (pH(i)) maintained by the tumor cells, and by the ionization properties of the drug itself. The acid-outside plasmalemmal pH gradient in tumors acts to exclude weak base drugs like the anthracyclines, anthraquinones, and vinca alkaloids from the cells, leading to a substantial degree of "physiological drug resistance" in tumors. We have induced acute metabolic alkalosis in C3H tumor-bearing C3H/hen mice, by gavage and by intraperitoneal (i.p.) administration of NaHCO(3). (31)P magnetic resonance spectroscopic measurements of 3-aminopropylphosphonate show increases of up to 0.6 pH units in tumor pH(e), and 0.2 to 0.3 pH units in hind leg tissue pH(e), within 2 hours of i.p. administration of NaHCO(3). Theoretical calculations of mitoxantrone uptake into tumor and normal (hind leg) tissue at the measured pH(e) and pH(i) values indicate that a gain in therapeutic index of up to 3.3-fold is possible with NaHCO(3) pretreatment. Treatment of C3H tumor-bearing mice with 12 mg/kg mitoxantrone resulted in a tumor growth delay of 9 days, whereas combined NaHCO(3)--mitoxantrone therapy resulted in an enhancement of the TGD to 16 days.

... Pharmacokinetic studies in humans and animals with mitoxantrone hydrochloride (Novantrone) are /discussed/ Intravenously administered novantrone disappears from the plasma of humans and animals with multiexponential kinetics and with a terminal half life ranging from 38 hr to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues; however, redistribution back into the plasma and elimination from the body are slow processes, In both animals and humans, novantroneis metabolized to the mono and dicarboxylic acid derivatives, as well as the glucuronide conjugates of these acids. Following IV administration, it is unchanged novantrone that binds to most tissues. Elimination is slow and predominantly via the kidney. Interaction studies with doxorubicin (II) indicate that prior administration of doxorubicin may prolong the half life of novantrone but that concurrent administration may not involve problems after the first dose.

Mitoxantrone has limited ability to produce quinone-type free radicals & causes less cardiac toxicity than does doxorubicin. Mitoxantrone exerts its antitumor action by stimulating the formation of strand breaks in DNA; this is mediated by topoisomerase II; it also intercalates with DNA.|Intercalation allows binding to nucleic acids inhibiting DNA & RNA synthesis & causing DNA strand breaks; inhibits topoisomerase II. /From table/|The mechanisms of the inotropic effect of mitoxantrone (MTO), a synthetic dihydroxyanthracenedione derivative with antineoplastic activity, was investigated in guinea pig ventricular myocytes using whole-cell patch-clamp methods combined with fura-2 fluorescence and cell-edge tracking techniques. In right ventricular papillary muscles, 30 microM MTO increased isometric force of contraction as well as action potential duration (APD) in a time-dependent manner. The force of contraction was increased approximately 3-fold within 4 h. This positive inotropic effect was accompanied by a prolongation of time to peak force and relaxation time. In current-clamped single myocytes treated with 30 microM MTO for 30 min, an increase of cell shortening by 77% and a prolongation of APD by 19% was observed. Peak amplitude of the intracellular Ca(2+) transients was also increased by 10%. The contribution of APD prolongation to the enhancement of cell shortening induced by MTO was assessed by clamping control myocytes with action potentials of various duration. Prolongation of APD(90) (ADP measured at 90% of repolarization) by 24% led to an increase of cell shortening by 13%. When the cells were clamped by an action potential with constant APD, MTO still caused an increase of cell shortening by 59% within 30 min. No increase of the peak intracellular Ca(2+) transients, however, was observed under this condition. We conclude that both the APD prolongation and a direct interaction with the contractile proteins contributed to the positive inotropic effect of MTO.|We show here that mitoxantrone and ametantrone induce interstrand DNA cross-links in HeLa S3 cells. These cross-links were observed only in cellular system suggesting that metabolism of the drugs is a necessary step leading to DNA cross-linking. Biologically inactive analogue of mitoxantrone, compound NSC 321458, did not induce cross-links in DNA of tumour cells which suggests that DNA cross-linking is associated with the cytotoxic and anti-tumour activity of these compounds.|For more Mechanism of Action (Complete) data for NOVANTRONE (7 total), please visit the HSDB record page.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Mitoxantrone is an anthraquinone related chemically to the anthracyclines. Overdoses of 140-180 mg/sq m have led to death with severe leukopenia, thrombocytopenia, & infection.

Acetate, Mitoxantrone

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients