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

Stem definitionDrug idCAS RN
vasopressin receptor antagonists 4110 150683-30-0

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • OPC 41061
  • jinarc
  • tolvaptan
  • samsca
  • OPC-41061
A benzazepine derivative and selective VASOPRESSIN V2 RECEPTOR antagonist that is used to treat euvolemic and hypervolemic HYPONATREMIA. It is also used in the treatment of rapidly progressing AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE to slow the rate of cyst development and renal insufficiency.
  • Molecular weight: 448.95
  • Formula: C26H25ClN2O3
  • CLOGP: 4.31
  • LIPINSKI: 0
  • HAC: 5
  • HDO: 2
  • TPSA: 69.64
  • ALOGS: -5.56
  • ROTB: 3

  • Status: OFP

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

Drug dosage:

DoseUnitRoute
30 mg O

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 2 Benet LZ, Broccatelli F, Oprea TI
S (Water solubility) 0.00 mg/mL Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine) 0 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 1.91 ┬ÁM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
Vd (Volume of distribution) 0.50 L/kg Lombardo F, Berellini G, Obach RS
CL (Clearance) 2.40 mL/min/kg Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma) 0.01 % Lombardo F, Berellini G, Obach RS
t_half (Half-life) 2.90 hours Lombardo F, Berellini G, Obach RS

Approvals:

DateAgencyCompanyOrphan
Oct. 27, 2010 PMDA Otsuka Pharmaceutical Co., Ltd
Feb. 26, 2015 EMA
May 19, 2009 FDA OTSUKA AMERICA PHARM

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Rapid correction of hyponatraemia 376.26 24.23 55 7136 86 46678785
Incorrect product administration duration 311.15 24.23 97 7094 9480 46669391
Hypernatraemia 299.78 24.23 86 7105 6315 46672556
Cardiac failure 274.54 24.23 164 7027 79784 46599087
Hepatic function abnormal 257.42 24.23 119 7072 34302 46644569
Inappropriate schedule of product administration 216.87 24.23 131 7060 64882 46613989
Thirst 215.30 24.23 76 7115 10900 46667971
Blood sodium decreased 149.56 24.23 71 7120 21655 46657216
Blood urea increased 136.25 24.23 70 7121 25282 46653589
Renal impairment 135.26 24.23 103 7088 74269 46604602
Off label use 130.39 24.23 219 6972 379622 46299249
Blood sodium increased 104.89 24.23 31 7160 2518 46676353
Wrong technique in product usage process 98.04 24.23 75 7116 54347 46624524
Liver disorder 96.34 24.23 64 7127 37182 46641689
Aspartate aminotransferase increased 81.51 24.23 79 7112 78621 46600250
Alanine aminotransferase increased 80.94 24.23 83 7108 88368 46590503
Polydipsia 77.02 24.23 26 7165 3253 46675618
Underdose 74.44 24.23 43 7148 19515 46659356
Polyuria 73.44 24.23 31 7160 7164 46671707
Nocturia 67.08 24.23 29 7162 7103 46671768
Platelet count decreased 59.36 24.23 75 7116 99949 46578922
Hospitalisation 57.07 24.23 59 7132 63326 46615545
Hepatic encephalopathy 54.38 24.23 28 7163 10129 46668742
Hyponatraemia 53.91 24.23 72 7119 101260 46577611
Renal cyst haemorrhage 53.41 24.23 9 7182 48 46678823
Gallbladder polyp 52.95 24.23 14 7177 755 46678116
Dehydration 51.71 24.23 90 7101 159450 46519421
Incorrect drug administration rate 51.57 24.23 17 7174 1976 46676895
Glomerular filtration rate decreased 50.67 24.23 28 7163 11666 46667205
Death 49.74 24.23 138 7053 335410 46343461
Blood creatinine increased 49.67 24.23 60 7131 76343 46602528
Brain natriuretic peptide increased 47.33 24.23 20 7171 4630 46674241
Inability to afford medication 47.06 24.23 14 7177 1162 46677709
Drug titration error 46.46 24.23 12 7179 590 46678281
Blood uric acid increased 45.89 24.23 19 7172 4182 46674689
Hyperuricaemia 40.52 24.23 18 7173 4699 46674172
Renal cyst ruptured 39.16 24.23 6 7185 15 46678856
Incorrect dose administered 38.48 24.23 41 7150 45509 46633362
Concomitant disease aggravated 37.27 24.23 20 7171 7862 46671009
Hepatotoxicity 35.48 24.23 30 7161 24979 46653892
Cardiac failure chronic 35.34 24.23 15 7176 3509 46675362
Pulmonary congestion 34.81 24.23 24 7167 14775 46664096
Blood pressure decreased 34.08 24.23 43 7148 57116 46621755
Ascites 32.80 24.23 34 7157 36550 46642321
Pulmonary arterial hypertension 32.53 24.23 29 7162 25899 46652972
Product use in unapproved indication 31.93 24.23 53 7138 90220 46588651
Therapy cessation 31.87 24.23 29 7162 26600 46652271
Hepatic cirrhosis 31.21 24.23 23 7168 15709 46663162
Pollakiuria 30.17 24.23 27 7164 24234 46654637
Renal cyst infection 29.35 24.23 6 7185 102 46678769
Drug ineffective 29.34 24.23 37 7154 677801 46001070
No adverse event 29.23 24.23 31 7160 34200 46644671
Pain 28.98 24.23 19 7172 476929 46201942
Concomitant disease progression 27.81 24.23 11 7180 2151 46676720
Osmotic demyelination syndrome 27.78 24.23 8 7183 592 46678279
Fatigue 27.63 24.23 32 7159 608665 46070206
Drug-induced liver injury 27.22 24.23 26 7165 25342 46653529
Cerebral infarction 27.09 24.23 25 7166 23341 46655530
Urine output increased 25.84 24.23 9 7182 1236 46677635
Upper respiratory tract inflammation 25.09 24.23 11 7180 2784 46676087

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Hypernatraemia 495.48 22.90 145 7017 7339 29937977
Rapid correction of hyponatraemia 362.17 22.90 54 7108 48 29945268
Thirst 328.60 22.90 104 7058 6845 29938471
Incorrect product administration duration 299.52 22.90 85 7077 3837 29941479
Cardiac failure 231.10 22.90 177 6985 83241 29862075
Hepatic function abnormal 191.22 22.90 121 7041 41824 29903492
Blood urea increased 156.75 22.90 96 7066 31285 29914031
Renal impairment 150.71 22.90 139 7023 84045 29861271
Inappropriate schedule of product administration 145.47 22.90 100 7062 39628 29905688
Blood sodium increased 124.23 22.90 40 7122 2771 29942545
Hepatic encephalopathy 93.49 22.90 52 7110 14140 29931176
Off label use 87.56 22.90 187 6975 249103 29696213
Osmotic demyelination syndrome 81.09 22.90 21 7141 665 29944651
Polyuria 80.87 22.90 38 7124 7268 29938048
Wrong technique in product usage process 79.17 22.90 63 7099 31092 29914224
Blood creatinine increased 74.38 22.90 100 7062 91275 29854041
Blood sodium decreased 72.73 22.90 46 7116 15810 29929506
Hyperuricaemia 68.36 22.90 34 7128 7360 29937956
Altered state of consciousness 67.79 22.90 48 7114 19871 29925445
Dehydration 59.39 22.90 106 7056 123433 29821883
Low cardiac output syndrome 58.34 22.90 14 7148 322 29944994
Hyponatraemia 53.79 22.90 73 7089 67129 29878187
Aspartate aminotransferase increased 52.44 22.90 70 7092 63352 29881964
Glomerular filtration rate decreased 52.18 22.90 33 7129 11329 29933987
Alanine aminotransferase increased 51.03 22.90 75 7087 74201 29871115
Nocturia 48.10 22.90 28 7134 8284 29937032
Cardiac failure chronic 45.60 22.90 24 7138 5839 29939477
Incorrect drug administration rate 41.48 22.90 14 7148 1122 29944194
Underdose 40.70 22.90 29 7133 12112 29933204
Death 39.46 22.90 179 6983 357104 29588212
Renal cyst infection 36.59 22.90 7 7155 51 29945265
Liver disorder 36.30 22.90 40 7122 29682 29915634
Right ventricular failure 36.05 22.90 23 7139 8013 29937303
Renal cyst haemorrhage 35.41 22.90 8 7154 140 29945176
Hospitalisation 35.20 22.90 48 7114 44271 29901045
Polydipsia 34.53 22.90 17 7145 3596 29941720
Hyperkalaemia 33.39 22.90 58 7104 65952 29879364
Drug titration error 31.38 22.90 9 7153 420 29944896
Procedural failure 29.06 22.90 6 7156 67 29945249
Toxicity to various agents 29.03 22.90 4 7158 177179 29768137
Product use issue 28.06 22.90 44 7118 45972 29899344
Cerebral infarction 27.97 22.90 33 7129 26340 29918976
Concomitant disease aggravated 26.34 22.90 16 7146 5113 29940203
Inability to afford medication 26.02 22.90 9 7153 776 29944540
Blood potassium increased 25.51 22.90 25 7137 16188 29929128
Renal cyst ruptured 25.31 22.90 4 7158 7 29945309
Urine osmolarity decreased 25.29 22.90 5 7157 44 29945272

Pharmacologic Action:

SourceCodeDescription
ATC C03XA01 CARDIOVASCULAR SYSTEM
DIURETICS
OTHER DIURETICS
Vasopressin antagonists
MeSH PA D065092 Antidiuretic Hormone Receptor Antagonists
MeSH PA D045283 Natriuretic Agents
FDA MoA N0000193178 Vasopressin V2 Receptor Antagonists
FDA EPC N0000193181 Vasopressin V2 Receptor Antagonist

Drug Use (View source of the data)

DiseaseRelationSNOMED_IDDOID
Polycystic kidney disease, adult type indication 28728008
Syndrome of inappropriate vasopressin secretion indication 55004003 DOID:3401
Hyponatremia indication 89627008
Nutritional disorder contraindication 2492009 DOID:374
Alcoholism contraindication 7200002
Hyperkalemia contraindication 14140009
Cirrhosis of liver contraindication 19943007 DOID:5082
Hypovolemia contraindication 28560003
Demyelination contraindication 32693004
Dehydration contraindication 34095006
Hepatic failure contraindication 59927004
Gastrointestinal hemorrhage contraindication 74474003

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 13.1 acidic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRouteExclusivity dateDescription
15MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2021 USE OF TOLVAPTAN TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
30MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2021 USE OF TOLVAPTAN TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
45MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2021 USE OF TOLVAPTAN TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
60MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2021 USE OF TOLVAPTAN TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
90MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2021 USE OF TOLVAPTAN TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
15MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2025 INDICATED TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
30MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2025 INDICATED TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
45MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2025 INDICATED TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
60MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2025 INDICATED TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)
90MG JYNULLRQUE OTSUKA N204441 April 23, 2018 RX TABLET ORAL April 23, 2025 INDICATED TO SLOW KIDNEY FUNCTION DECLINE IN ADULTS AT RISK OF RAPIDLY PROGRESSING AUTOSOMAL DOMINULLNT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
Vasopressin V2 receptor GPCR ANTAGONIST Ki 9 WOMBAT-PK DRUG LABEL
Vasopressin V1a receptor GPCR ANTAGONIST Ki 7.90 IUPHAR
Vasopressin V1a receptor GPCR ANTAGONIST Ki 6.50 IUPHAR
Vasopressin V2 receptor GPCR ANTAGONIST Ki 8.90 IUPHAR

External reference:

IDSource
4028789 VUID
N0000178481 NUI
D01213 KEGG_DRUG
4028789 VANDF
C2710117 UMLSCUI
CHEBI:32246 CHEBI
CHEMBL344159 ChEMBL_ID
D000077602 MESH_DESCRIPTOR_UI
7969 INN_ID
DB06212 DRUGBANK_ID
21G72T1950 UNII
216237 PUBCHEM_CID
2226 IUPHAR_LIGAND_ID
358257 RXNORM
165174 MMSL
26477 MMSL
334368 MMSL
d07447 MMSL
013121 NDDF
442901006 SNOMEDCT_US
443058000 SNOMEDCT_US

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
SAMSCA HUMAN PRESCRIPTION DRUG LABEL 1 59148-020 TABLET 15 mg ORAL NDA 33 sections
SAMSCA HUMAN PRESCRIPTION DRUG LABEL 1 59148-021 TABLET 30 mg ORAL NDA 33 sections
JYNULLRQUE HUMAN PRESCRIPTION DRUG LABEL 1 59148-082 TABLET 15 mg ORAL NDA 32 sections
JYNULLRQUE HUMAN PRESCRIPTION DRUG LABEL 1 59148-083 TABLET 30 mg ORAL NDA 32 sections
TOLVAPTAN HUMAN PRESCRIPTION DRUG LABEL 1 60505-4704 TABLET 15 mg ORAL NDA 33 sections
TOLVAPTAN HUMAN PRESCRIPTION DRUG LABEL 1 60505-4705 TABLET 30 mg ORAL NDA 33 sections
Tolvaptan Human Prescription Drug Label 1 67877-636 TABLET 30 mg ORAL ANDA 23 sections
Tolvaptan Human Prescription Drug Label 1 67877-637 TABLET 60 mg ORAL ANDA 23 sections