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

Stem definition	Drug id	CAS RN
bradycardic agents	3312	155974-00-8

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: corlanor corlentor ivabradine hydrochloride ivabradine coraxan procoralan ivabradine HCl	Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation. Molecular weight: 468.59 Formula: C27H36N2O5 CLOGP: 3.27 LIPINSKI: 0 HAC: 7 HDO: 0 TPSA: 60.47 ALOGS: -4.36 ROTB: 10 Status: ONP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

corlanor
corlentor
ivabradine hydrochloride
ivabradine
coraxan
procoralan
ivabradine HCl

Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation.

Molecular weight: 468.59
Formula: C27H36N2O5
CLOGP: 3.27
LIPINSKI: 0
HAC: 7
HDO: 0
TPSA: 60.47
ALOGS: -4.36
ROTB: 10

Status: ONP

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

Drug dosage:

Dose	Unit	Route
10	mg	O

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	1	Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine)	4 %	Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose)	0.46 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
Vd (Volume of distribution)	1.66 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	10.27 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.28 %	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company
Sept. 20, 2019	PMDA	Ono Pharmaceutical Co., Ltd.
April 15, 2015	FDA	AMGEN INC
Oct. 25, 2005	EMA	Les Laboratoires Servier

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
Off label use	470.79	17.93	454	7526	471758	52869328
Photopsia	149.79	17.93	46	7934	4389	53336697
Drug interaction	137.07	17.93	166	7814	219163	53121923
Torsade de pointes	127.59	17.93	54	7926	12951	53328135
Electrocardiogram QT prolonged	117.85	17.93	84	7896	56319	53284767
Bradycardia	100.62	17.93	84	7896	70972	53270114
Cardiac failure	98.46	17.93	90	7890	85754	53255332
First trimester pregnancy	72.21	17.93	10	7970	8	53341078
Palpitations	69.53	17.93	81	7899	102267	53238819
Syncope	63.66	17.93	81	7899	111912	53229174
Ischaemic stroke	54.99	17.93	34	7946	17959	53323127
Cardiac failure chronic	54.19	17.93	21	7959	4009	53337077
Crush syndrome	52.30	17.93	10	7970	122	53340964
Myoglobin blood increased	48.47	17.93	15	7965	1465	53339621
Ventricular tachycardia	47.87	17.93	31	7949	17731	53323355
Chest pain	47.07	17.93	94	7886	190091	53150995
Congestive cardiomyopathy	45.67	17.93	21	7959	6117	53334969
Apallic syndrome	45.66	17.93	12	7968	651	53340435
Ventricular fibrillation	45.48	17.93	26	7954	11899	53329187
Language disorder	44.71	17.93	15	7965	1896	53339190
Drug effective for unapproved indication	43.82	17.93	15	7965	2015	53339071
Dizziness	43.36	17.93	138	7842	372121	52968965
Acute kidney injury	43.17	17.93	108	7872	253760	53087326
Bundle branch block left	43.00	17.93	21	7959	6992	53334094
Sensorimotor disorder	39.08	17.93	10	7970	488	53340598
Pain	38.67	17.93	20	7960	588378	52752708
Heart rate decreased	37.05	17.93	36	7944	36911	53304175
Tachycardia	36.24	17.93	61	7919	108151	53232935
Rheumatoid arthritis	35.91	17.93	3	7977	314528	53026558
Sinus bradycardia	35.74	17.93	24	7956	14577	53326509
Dyspnoea	34.80	17.93	176	7804	586056	52755030
Angina pectoris	32.64	17.93	30	7950	28695	53312391
Heart rate increased	32.47	17.93	50	7930	82265	53258821
Pneumobilia	32.11	17.93	7	7973	169	53340917
Genital rash	29.26	17.93	8	7972	505	53340581
Hyperparathyroidism secondary	28.29	17.93	10	7970	1477	53339609
Mitral valve incompetence	27.39	17.93	23	7957	19528	53321558
Shock haemorrhagic	27.16	17.93	17	7963	9166	53331920
Drug ineffective	26.11	17.93	52	7928	817193	52523893
Hyperphosphataemia	24.70	17.93	10	7970	2139	53338947
Lactic acidosis	24.44	17.93	29	7951	37224	53303862
Visual impairment	24.26	17.93	41	7939	72871	53268215
Anaemia folate deficiency	24.09	17.93	6	7974	262	53340824
Sinus tachycardia	23.68	17.93	23	7957	23549	53317537
Second trimester pregnancy	23.42	17.93	3	7977	0	53341086
Third trimester pregnancy	23.42	17.93	3	7977	0	53341086
Lordosis	23.13	17.93	6	7974	309	53340777
Hypotension	22.38	17.93	86	7894	253990	53087096
Tuberculosis of central nervous system	21.94	17.93	6	7974	379	53340707
Gastrointestinal tract adenoma	21.92	17.93	6	7974	380	53340706
Femoral neck fracture	21.04	17.93	14	7966	8369	53332717
Atrial tachycardia	20.79	17.93	9	7971	2275	53338811
Cardiac arrest	20.42	17.93	44	7936	93623	53247463
Alopecia	20.40	17.93	5	7975	234578	53106508
Lupus myocarditis	20.09	17.93	4	7976	61	53341025
Pneumonia fungal	20.06	17.93	11	7969	4645	53336441
Orthopnoea	19.83	17.93	12	7968	6092	53334994
Oliguria	19.81	17.93	14	7966	9224	53331862
Serotonin syndrome	19.75	17.93	22	7958	26384	53314702
Osteochondrosis	19.50	17.93	7	7973	1081	53340005
Sinus arrest	19.22	17.93	8	7972	1836	53339250
Nasopharyngitis	19.02	17.93	3	7977	192292	53148794
Gastric antral vascular ectasia	19.02	17.93	6	7974	624	53340462
Personality disorder	18.46	17.93	10	7970	4121	53336965
Arrhythmia	18.37	17.93	25	7955	36754	53304332
Portal hypertensive gastropathy	18.08	17.93	6	7974	733	53340353

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
Cardiac failure	255.59	18.98	201	8144	91472	32413709
Bradycardia	107.57	18.98	111	8234	71451	32433730
Photopsia	102.12	18.98	32	8313	1887	32503294
Cardiac failure chronic	87.80	18.98	41	8304	7199	32497982
Hypotension	84.75	18.98	177	8168	215933	32289248
Computerised tomogram coronary artery abnormal	78.16	18.98	16	8329	158	32505023
Ischaemic cardiomyopathy	67.54	18.98	33	8312	6401	32498780
Sinus bradycardia	60.47	18.98	39	8306	12899	32492282
Dyspnoea	60.04	18.98	216	8129	361829	32143352
Oesophageal obstruction	58.36	18.98	15	8330	428	32504753
N-terminal prohormone brain natriuretic peptide increased	57.15	18.98	21	8324	2011	32503170
Torsade de pointes	54.68	18.98	30	8315	7385	32497796
Bezoar	51.67	18.98	16	8329	906	32504275
Angina pectoris	51.23	18.98	51	8294	31375	32473806
Venous pressure jugular increased	45.26	18.98	14	8331	790	32504391
Blood pressure systolic decreased	45.14	18.98	22	8323	4241	32500940
Hyperkalaemia	42.15	18.98	69	8276	69681	32435500
Base excess decreased	41.43	18.98	10	8335	219	32504962
Dyspnoea at rest	40.65	18.98	19	8326	3340	32501841
Acute kidney injury	40.20	18.98	165	8180	293303	32211878
Drug interaction	39.28	18.98	134	8211	218051	32287130
Brain natriuretic peptide increased	39.07	18.98	20	8325	4280	32500901
Blood potassium increased	38.51	18.98	33	8312	16771	32488410
Oxygen consumption decreased	38.16	18.98	9	8336	178	32505003
Glomerular filtration rate decreased	37.46	18.98	29	8316	12782	32492399
Ejection fraction decreased	37.10	18.98	33	8312	17625	32487556
Ventricular extrasystoles	36.87	18.98	28	8317	11998	32493183
Venous pressure jugular decreased	35.74	18.98	7	8338	54	32505127
Dermatitis exfoliative generalised	34.85	18.98	17	8328	3284	32501897
Ventricular arrhythmia	33.23	18.98	19	8326	5060	32500121
Sinus arrest	31.99	18.98	13	8332	1631	32503550
Urticaria chronic	31.82	18.98	7	8338	100	32505081
Atrial tachycardia	31.67	18.98	14	8331	2163	32503018
Left ventricular enlargement	30.91	18.98	10	8335	653	32504528
Death	29.46	18.98	33	8312	382484	32122697
Oedema peripheral	28.84	18.98	79	8266	114012	32391169
Electrocardiogram abnormal	27.98	18.98	20	8325	7810	32497371
Ventricular dysfunction	27.18	18.98	15	8330	3731	32501450
ECG signs of myocardial ischaemia	26.90	18.98	7	8338	210	32504971
Asthma-chronic obstructive pulmonary disease overlap syndrome	26.75	18.98	10	8335	1004	32504177
Blood creatinine increased	26.75	18.98	69	8276	96063	32409118
Left ventricular dilatation	26.27	18.98	9	8336	702	32504479
Hypertrophy	26.24	18.98	8	8337	430	32504751
Presyncope	26.21	18.98	27	8318	17274	32487907
Tracheal atresia	24.68	18.98	4	8341	8	32505173
Ventricular fibrillation	24.41	18.98	26	8319	17284	32487897
Syncope	24.36	18.98	64	8281	90060	32415121
Cardiomyopathy	24.27	18.98	25	8320	15988	32489193
Ventricular tachycardia	23.74	18.98	31	8314	25525	32479656
Mean cell haemoglobin decreased	23.70	18.98	10	8335	1380	32503801
Tricuspid valve incompetence	22.84	18.98	19	8326	9268	32495913
Congestive cardiomyopathy	22.58	18.98	17	8328	7185	32497996
Bronchial hyperreactivity	22.45	18.98	10	8335	1572	32503609
Large cell lung cancer metastatic	22.26	18.98	4	8341	18	32505163
Low cardiac output syndrome	21.99	18.98	7	8338	434	32504747
Blood chloride increased	21.74	18.98	12	8333	2987	32502194
Pulmonary oedema	21.73	18.98	41	8304	46226	32458955
Oesophageal haemorrhage	21.64	18.98	9	8336	1198	32503983
Lichenoid keratosis	21.35	18.98	11	8334	2385	32502796
Blood luteinising hormone increased	21.34	18.98	5	8340	96	32505085
Eosinophilia	21.23	18.98	29	8316	24929	32480252
Heart rate decreased	21.01	18.98	29	8316	25171	32480010
Contraindicated product administered	20.68	18.98	25	8320	19051	32486130
Cardiac hypertrophy	20.50	18.98	8	8337	903	32504278
Diastolic dysfunction	20.19	18.98	14	8331	5210	32499971
Blood follicle stimulating hormone increased	19.90	18.98	5	8340	130	32505051
Pulmonary function test abnormal	19.81	18.98	10	8335	2076	32503105
Carbon dioxide decreased	19.70	18.98	9	8336	1500	32503681
Off label use	19.63	18.98	140	8205	306180	32199001
Pancreatitis chronic	19.14	18.98	10	8335	2230	32502951
Haemodynamic test abnormal	18.98	18.98	4	8341	46	32505135

Pharmacologic Action:

Source	Code	Description
ATC	C01EB17	CARDIOVASCULAR SYSTEM CARDIAC THERAPY OTHER CARDIAC PREPARATIONS Other cardiac preparations
ATC	C07FX05	CARDIOVASCULAR SYSTEM BETA BLOCKING AGENTS BETA BLOCKING AGENTS, OTHER COMBINATIONS Beta blocking agents, other combinations
ATC	C07FX06	CARDIOVASCULAR SYSTEM BETA BLOCKING AGENTS BETA BLOCKING AGENTS, OTHER COMBINATIONS Beta blocking agents, other combinations
MeSH PA	D002317	Cardiovascular Agents
FDA EPC	N0000191544	Hyperpolarization-activated Cyclic Nucleotide-gated Channel Blocker
FDA MoA	N0000191546	Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists
CHEBI has role	CHEBI:38147	cardiotonic drugs

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Chronic heart failure	indication	48447003
Angina pectoris	indication	194828000

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	8.45	Basic

Orange Book patent data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Patent number	Patent expiration date	Patent use
EQ 5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7361649	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7361650	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7879842	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 7.5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7361649	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 7.5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7361650	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 7.5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7879842	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	7361649	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	7361650	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	7879842	Feb. 22, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7867996	Dec. 12, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
EQ 7.5MG BASE	CORLANOR	AMGEN INC	N206143	April 15, 2015	RX	TABLET	ORAL	7867996	Dec. 12, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	7867996	Dec. 12, 2026	A METHOD FOR TREATING HEART FAILURE IN A HUMAN USING A CRYSTALLINE FORM OF IVABRADINE HYDROCHLORIDE

Orange Book exclusivity data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Exclusivity date	Description
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	April 22, 2022	NEW PRODUCT
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	Oct. 22, 2022	PEDIATRIC EXCLUSIVITY
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	April 22, 2026	INDICATED FOR THE TREATMENT OF STABLE SYMPTOMATIC HEART FAILURE DUE TO DILATED CARDIOMYOPATHY (DCM) IN PEDIATRIC PATIENTS AGED 6 MONTHS AND OLDER, WHO ARE IN SINUS RHYTHM WITH AN ELEVATED HEART RATE
5MG/5ML (1MG/ML)	CORLANOR	AMGEN INC	N209964	April 22, 2019	RX	SOLUTION	ORAL	Oct. 22, 2026	PEDIATRIC EXCLUSIVITY

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Ion channel	O60741	HCN1_HUMAN	BLOCKER	IC50	5.70	IUPHAR	DRUG LABEL
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2	Ion channel	Q9UL51	HCN2_HUMAN	BLOCKER			UNKNOWN	DRUG LABEL
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3	Ion channel	Q9P1Z3	HCN3_HUMAN	BLOCKER	IC50	5.70	IUPHAR	DRUG LABEL
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	Ion channel	Q9Y3Q4	HCN4_HUMAN		EC50	5.37	CHEMBL
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Ion channel		HCN1_MOUSE		EC50	5.35	CHEMBL
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2	Ion channel		HCN2_MOUSE		EC50	5.34	CHEMBL

External reference:

ID	Source
D07165	KEGG_DRUG
148849-67-6	SECONDARY_CAS_RN
4034416	VANDF
C0257190	UMLSCUI
CHEBI:85969	CHEBI
CHEMBL471737	ChEMBL_ID
CHEMBL2145077	ChEMBL_ID
D000077550	MESH_DESCRIPTOR_UI
DB09083	DRUGBANK_ID
2357	IUPHAR_LIGAND_ID
7523	INN_ID
3H48L0LPZQ	UNII
132999	PUBCHEM_CID
1649479	RXNORM
20884	MMSL
233849	MMSL
d05706	MMSL
011156	NDDF
011157	NDDF
420906000	SNOMEDCT_US
421228002	SNOMEDCT_US
421692002	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Corlanor	HUMAN PRESCRIPTION DRUG LABEL	1	55513-800	TABLET, FILM COATED	5 mg	ORAL	NDA	31 sections
Corlanor	HUMAN PRESCRIPTION DRUG LABEL	1	55513-810	TABLET, FILM COATED	7.50 mg	ORAL	NDA	31 sections
Corlanor	HUMAN PRESCRIPTION DRUG LABEL	1	55513-813	SOLUTION	5 mg	ORAL	NDA	31 sections
Corlanor	HUMAN PRESCRIPTION DRUG LABEL	1	70518-3309	TABLET, FILM COATED	5 mg	ORAL	NDA	33 sections