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mitoxantrone Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
antineoplastics; anthraquinone derivatives	1821	65271-80-9

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: mitoxantrone mitoxantrone hydrochloride dihydroxyanthraquinone mitoxanthrone mitozantrone nimitoxantron mitoxantrone dihydrochloride mitoxantrone HCl	An anthracenedione-derived antineoplastic agent. Molecular weight: 444.49 Formula: C22H28N4O6 CLOGP: 2.30 LIPINSKI: 1 HAC: 10 HDO: 8 TPSA: 163.18 ALOGS: -2.78 ROTB: 12 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

mitoxantrone
mitoxantrone hydrochloride
dihydroxyanthraquinone
mitoxanthrone
mitozantrone
nimitoxantron
mitoxantrone dihydrochloride
mitoxantrone HCl

An anthracenedione-derived antineoplastic agent.

Molecular weight: 444.49
Formula: C22H28N4O6
CLOGP: 2.30
LIPINSKI: 1
HAC: 10
HDO: 8
TPSA: 163.18
ALOGS: -2.78
ROTB: 12

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

None

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	3	Benet LZ, Broccatelli F, Oprea TI
S (Water solubility)	7.50 mg/mL	Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine)	7 %	Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose)	0.78 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability)	0 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
Vd (Volume of distribution)	12 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	7.90 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.25 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	53 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
Dec. 23, 1987	FDA

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Febrile neutropenia	259.79	26.57	149	4988	94478	46586447
Acute myeloid leukaemia	248.15	26.57	85	5052	15693	46665232
Myelodysplastic syndrome	158.45	26.57	61	5076	15650	46665275
Second primary malignancy	117.32	26.57	39	5098	6545	46674380
Acute promyelocytic leukaemia	112.87	26.57	25	5112	896	46680029
Pancytopenia	105.85	26.57	82	5055	84976	46595949
Sepsis	101.80	26.57	98	5039	135916	46545009
Neutropenia	97.53	26.57	98	5039	143106	46537819
Leukaemia recurrent	83.81	26.57	21	5116	1288	46679637
Thrombocytopenia	77.75	26.57	82	5055	126499	46554426
Acute myeloid leukaemia recurrent	77.57	26.57	20	5117	1376	46679549
Haemophagocytic lymphohistiocytosis	72.13	26.57	29	5108	8313	46672612
Progressive multifocal leukoencephalopathy	66.71	26.57	30	5107	11316	46669609
Bone marrow failure	66.15	26.57	41	5096	29628	46651297
Acute lymphocytic leukaemia recurrent	65.09	26.57	19	5118	2076	46678849
Bronchopulmonary aspergillosis	64.61	26.57	26	5111	7470	46673455
Chronic hepatitis	56.66	26.57	14	5123	810	46680115
Febrile bone marrow aplasia	56.38	26.57	23	5114	6839	46674086
Product use in unapproved indication	52.74	26.57	57	5080	90216	46590709
Lower respiratory tract infection fungal	49.32	26.57	10	5127	232	46680693
Mucormycosis	46.56	26.57	15	5122	2277	46678648
Chloroma	45.29	26.57	9	5128	188	46680737
Haematotoxicity	42.88	26.57	19	5118	6914	46674011
Abdominal wall wound	41.55	26.57	7	5130	55	46680870
Streptococcal bacteraemia	41.14	26.57	12	5125	1307	46679618
Cardiac failure	40.70	26.57	47	5090	79901	46601024
B precursor type acute leukaemia	39.28	26.57	8	5129	190	46680735
Bone marrow infiltration	38.33	26.57	9	5128	419	46680506
Graft versus host disease	37.39	26.57	17	5120	6571	46674354
Hypogammaglobulinaemia	37.20	26.57	16	5121	5422	46675503
Myeloblast percentage decreased	36.35	26.57	6	5131	41	46680884
Refractory cytopenia with multilineage dysplasia	35.75	26.57	7	5130	135	46680790
Hepatitis E	33.10	26.57	10	5127	1229	46679696
Stenotrophomonas infection	30.46	26.57	10	5127	1610	46679315
Stem cell transplant	29.61	26.57	10	5127	1756	46679169
Diffuse large B-cell lymphoma	29.58	26.57	14	5123	5924	46675001
Bacterial sepsis	29.45	26.57	12	5125	3555	46677370
Colitis	27.99	26.57	27	5110	37320	46643605
Clostridium bacteraemia	27.77	26.57	6	5131	191	46680734
Aspergillus infection	27.60	26.57	14	5123	6876	46674049
Venoocclusive liver disease	27.42	26.57	12	5125	4239	46676686
Differentiation syndrome	27.14	26.57	8	5129	903	46680022

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Febrile neutropenia	331.34	21.69	231	6134	106462	29839651
Acute myeloid leukaemia	182.91	21.69	85	6280	17921	29928192
Myelodysplastic syndrome	161.29	21.69	79	6286	18699	29927414
Neutropenia	100.96	21.69	130	6235	128410	29817703
Septic shock	83.37	21.69	84	6281	63523	29882590
Bone marrow failure	81.51	21.69	60	6305	29725	29916388
Mucormycosis	73.15	21.69	31	6334	5237	29940876
Acute lymphocytic leukaemia recurrent	70.28	21.69	25	6340	2642	29943471
Fungal infection	68.10	21.69	40	6325	13560	29932553
Bronchopulmonary aspergillosis	66.48	21.69	38	6327	12246	29933867
Second primary malignancy	64.43	21.69	30	6335	6326	29939787
Minimal residual disease	53.59	21.69	12	6353	228	29945885
Ameloblastoma	52.19	21.69	10	6355	84	29946029
Leukaemia recurrent	46.37	21.69	16	6349	1545	29944568
Aspiration bone marrow abnormal	44.53	21.69	9	6356	102	29946011
Hypertensive hydrocephalus	42.10	21.69	8	6357	64	29946049
High-grade B-cell lymphoma	40.92	21.69	9	6356	157	29945956
Neoplasm progression	37.71	21.69	31	6334	17992	29928121
Haematopoietic neoplasm	37.53	21.69	7	6358	50	29946063
Thrombocytopenia	36.50	21.69	86	6279	136958	29809155
Neoplasm recurrence	36.30	21.69	14	6351	1853	29944260
Aspergillus infection	35.88	21.69	24	6341	10190	29935923
Abscess fungal	35.53	21.69	8	6357	156	29945957
Cytogenetic abnormality	35.13	21.69	11	6354	783	29945330
Clostridium bacteraemia	33.54	21.69	7	6358	94	29946019
Cardiotoxicity	33.21	21.69	17	6348	4397	29941716
Multiple organ dysfunction syndrome	33.13	21.69	53	6312	63434	29882679
Pneumonia fungal	32.31	21.69	18	6347	5515	29940598
Product use in unapproved indication	31.15	21.69	56	6309	73637	29872476
Gallbladder adenocarcinoma	30.36	21.69	5	6360	15	29946098
Acute lymphocytic leukaemia	29.58	21.69	14	6351	3058	29943055
Venoocclusive liver disease	29.33	21.69	18	6347	6595	29939518
Bacteraemia	28.92	21.69	25	6340	15535	29930578
Mucosal inflammation	28.90	21.69	34	6331	30460	29915653
Klebsiella infection	28.66	21.69	18	6347	6869	29939244
Respiratory tract infection fungal	28.56	21.69	9	6356	654	29945459
Refractory anaemia with an excess of blasts	28.53	21.69	8	6357	388	29945725
Pancytopenia	27.83	21.69	58	6307	84994	29861119
Colitis	26.97	21.69	33	6332	30787	29915326
Enamel anomaly	26.84	21.69	6	6359	113	29946000
Klebsiella sepsis	26.84	21.69	11	6354	1706	29944407
Genotoxicity	26.77	21.69	5	6360	36	29946077
Cystitis haemorrhagic	26.40	21.69	15	6350	4772	29941341
Hyperammonaemic encephalopathy	26.08	21.69	11	6354	1833	29944280
Large granular lymphocytosis	25.75	21.69	6	6359	137	29945976
Disease progression	25.58	21.69	54	6311	79820	29866293
Sepsis	24.98	21.69	78	6287	146317	29799796
Progressive multifocal leukoencephalopathy	24.27	21.69	18	6347	8995	29937118
Fungaemia	24.07	21.69	11	6354	2220	29943893
Gene mutation	22.78	21.69	8	6357	813	29945300
Osteonecrosis	22.35	21.69	22	6343	16113	29930000
Cholangitis infective	21.98	21.69	6	6359	263	29945850
Drug resistance	21.70	21.69	24	6341	20109	29926004

Pharmacologic Action:

Source	Code	Description
ATC	L01DB07	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS CYTOTOXIC ANTIBIOTICS AND RELATED SUBSTANCES Anthracyclines and related substances
FDA MoA	N0000000176	Topoisomerase Inhibitors
FDA EPC	N0000175609	Topoisomerase Inhibitor
MeSH PA	D000700	Analgesics
MeSH PA	D000970	Antineoplastic Agents
MeSH PA	D002491	Central Nervous System Agents
MeSH PA	D004791	Enzyme Inhibitors
MeSH PA	D018373	Peripheral Nervous System Agents
MeSH PA	D018689	Sensory System Agents
MeSH PA	D059005	Topoisomerase II Inhibitors
CHEBI has role	CHEBI:23240	chromophores
CHEBI has role	CHEBI:37958	dyes
CHEBI has role	CHEBI:76924	plant metabolites
CHEBI has role	CHEBI:35610	cytostatic

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Acute myeloid leukemia, disease	indication	91861009
Relapsing remitting multiple sclerosis	indication	426373005	DOID:2378
Metastatic Prostate Carcinoma	indication
Follicular non-Hodgkin's lymphoma	off-label use	308121000
Metastatic Breast Carcinoma	off-label use
Progressive Diffuse Large B-Cell Lymphoma	off-label use
Mycosis	contraindication	3218000	DOID:1564
Viral disease	contraindication	34014006	DOID:934
Chronic heart failure	contraindication	48447003
Hepatic failure	contraindication	59927004
Acute infectious disease	contraindication	63171007
Leukopenia	contraindication	84828003	DOID:615
Left heart failure	contraindication	85232009
Bacterial infectious disease	contraindication	87628006
Radiation oncology AND/OR radiotherapy	contraindication	108290001
Acute disease of cardiovascular system	contraindication	128487001
Seizure disorder	contraindication	128613002
Disease of liver	contraindication	235856003	DOID:409
Anemia	contraindication	271737000	DOID:2355
Pregnancy, function	contraindication	289908002
Thrombocytopenic disorder	contraindication	302215000	DOID:1588
Neutropenic disorder	contraindication	303011007	DOID:1227
Bone marrow depression	contraindication	307762000
Breastfeeding (mother)	contraindication	413712001

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	9.37	acidic
pKa2	10.7	acidic
pKa3	9.13	Basic
pKa4	8.52	Basic
pKa5	4.01	Basic
pKa6	1.49	Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
DNA topoisomerase 2-alpha	Enzyme	P11388	TOP2A_HUMAN	INHIBITOR	IC90	5.96	WOMBAT-PK	CHEMBL
Potassium voltage-gated channel subfamily H member 2	Ion channel	Q12809	KCNH2_HUMAN		Ki	5.53	DRUG MATRIX
Sodium-dependent noradrenaline transporter	Transporter	P23975	SC6A2_HUMAN		Ki	5.31	DRUG MATRIX
5-hydroxytryptamine receptor 2C	GPCR	P28335	5HT2C_HUMAN		Ki	5.73	DRUG MATRIX
Muscarinic acetylcholine receptor M1	GPCR	P11229	ACM1_HUMAN		Ki	6.74	DRUG MATRIX
Muscarinic acetylcholine receptor M2	GPCR	P08172	ACM2_HUMAN		Ki	7.11	DRUG MATRIX
Muscarinic acetylcholine receptor M4	GPCR	P08173	ACM4_HUMAN		Ki	7.05	DRUG MATRIX
Epidermal growth factor receptor	Kinase	P00533	EGFR_HUMAN		IC50	5.27	DRUG MATRIX
Tyrosine-protein kinase Fyn	Kinase	P06241	FYN_HUMAN		IC50	5.90	DRUG MATRIX
Receptor tyrosine-protein kinase erbB-2	Kinase	P04626	ERBB2_HUMAN		IC50	5.69	DRUG MATRIX
ATP-binding cassette sub-family G member 2	Transporter	Q9UNQ0	ABCG2_HUMAN		Kact	5.15	WOMBAT-PK
Multidrug resistance-associated protein 1	Transporter	P33527	MRP1_HUMAN		IC50	6.29	WOMBAT-PK
Canalicular multispecific organic anion transporter 1	Transporter	Q92887	MRP2_HUMAN				WOMBAT-PK
Multidrug resistance protein 1	Transporter	P08183	MDR1_HUMAN		IC50	5.84	WOMBAT-PK
Solute carrier family 22 member 3	Transporter	O75751	S22A3_HUMAN		IC50	4.22	CHEMBL
Solute carrier family 22 member 1	Transporter	O15245	S22A1_HUMAN		IC50	4.36	CHEMBL
Solute carrier family 22 member 2	Transporter	O15244	S22A2_HUMAN		IC50	4.13	CHEMBL
Tyrosine-protein kinase BTK	Kinase	Q06187	BTK_HUMAN		IC50	6	CHEMBL
Serine/threonine-protein kinase pim-1	Kinase	P11309	PIM1_HUMAN		IC50	7.29	CHEMBL
Multidrug and toxin extrusion protein 2	Transporter	Q86VL8	S47A2_HUMAN		IC50	6.28	CHEMBL
Multidrug and toxin extrusion protein 1	Transporter	Q96FL8	S47A1_HUMAN		IC50	6.72	CHEMBL
DNA-3-methyladenine glycosylase	Enzyme	P29372	3MG_HUMAN		IC50	5.60	CHEMBL
Arachidonate 15-lipoxygenase	Enzyme		LOX15_RABIT		IC50	5.75	DRUG MATRIX
Integrase	Enzyme		Q7ZJM1_9HIV1		IC50	5.42	CHEMBL
Dual specificity tyrosine-phosphorylation-regulated kinase 1A	Unclassified		DYR1A_RAT		AC50	5.02	CHEMBL

External reference:

ID	Source
4019842	VUID
N0000147929	NUI
D02166	KEGG_DRUG
70476-82-3	SECONDARY_CAS_RN
4019527	VANDF
4019842	VANDF
C0026259	UMLSCUI
CHEBI:37484	CHEBI
MIX	PDB_CHEM_ID
CHEMBL58	ChEMBL_ID
CHEMBL1417019	ChEMBL_ID
CHEMBL1200827	ChEMBL_ID
D008942	MESH_DESCRIPTOR_UI
DB01204	DRUGBANK_ID
4212	PUBCHEM_CID
7242	IUPHAR_LIGAND_ID
4922	INN_ID
BZ114NVM5P	UNII
203129	RXNORM
5124	MMSL
81184	MMSL
d00306	MMSL
002676	NDDF
004828	NDDF
108791001	SNOMEDCT_US
386913001	SNOMEDCT_US
412249002	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
mitoXANTRONE	HUMAN PRESCRIPTION DRUG LABEL	1	0703-4680	INJECTION, SOLUTION, CONCENTRATE	2 mg	INTRAVENOUS	ANDA	24 sections
mitoXANTRONE	HUMAN PRESCRIPTION DRUG LABEL	1	0703-4685	INJECTION, SOLUTION, CONCENTRATE	2 mg	INTRAVENOUS	ANDA	24 sections
mitoXANTRONE	HUMAN PRESCRIPTION DRUG LABEL	1	0703-4686	INJECTION, SOLUTION, CONCENTRATE	2 mg	INTRAVENOUS	ANDA	24 sections
Mitoxantrone	HUMAN PRESCRIPTION DRUG LABEL	1	61703-343	INJECTION, SOLUTION, CONCENTRATE	2 mg	INTRAVENOUS	ANDA	28 sections
Mitoxantrone	HUMAN PRESCRIPTION DRUG LABEL	1	63323-132	INJECTION, SOLUTION	2 mg	INTRAVENOUS	ANDA	15 sections