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Amlodipine

PubChem CID
2162
Structure
Amlodipine_small.png
Amlodipine_3D_Structure.png
Molecular Formula
Synonyms
  • amlodipine
  • 88150-42-9
  • Norvasc
  • Amlocard
  • Coroval
Molecular Weight
408.9 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-11
Description
Amlodipine is a fully substituted dialkyl 1,4-dihydropyridine-3,5-dicarboxylate derivative, which is used for the treatment of hypertension, chronic stable angina and confirmed or suspected vasospastic angina. It has a role as an antihypertensive agent, a calcium channel blocker and a vasodilator agent. It is a dihydropyridine, a member of monochlorobenzenes, an ethyl ester, a methyl ester and a primary amino compound.
Amlodipine, initially approved by the FDA in 1987, is a popular antihypertensive drug belonging to the group of drugs called dihydropyridine calcium channel blockers. Due to their selectivity for the peripheral blood vessels, dihydropyridine calcium channel blockers are associated with a lower incidence of myocardial depression and cardiac conduction abnormalities than other calcium channel blockers. Amlodipine is commonly used in the treatment of high blood pressure and angina. Amlodipine has antioxidant properties and an ability to enhance the production of nitric oxide (NO), an important vasodilator that decreases blood pressure. The option for single daily dosing of amlodipine is an attractive feature of this drug.
Amlodipine is a Dihydropyridine Calcium Channel Blocker and Calcium Channel Blocker. The mechanism of action of amlodipine is as a Calcium Channel Antagonist and Cytochrome P450 3A Inhibitor.
See also: Amlodipine Besylate (has salt form); Amlodipine Maleate (has salt form); Amlodipine Benzoate (active moiety of) ... View More ...

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Amlodipine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C20H25ClN2O5/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21/h5-8,17,23H,4,9-11,22H2,1-3H3
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

HTIQEAQVCYTUBX-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CCOC(=O)C1=C(NC(=C(C1C2=CC=CC=C2Cl)C(=O)OC)C)COCCN
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C20H25ClN2O5
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Amlodipine
  • Amlodipine Besylate
  • Amlodipine Maleate
  • Amlodipine Maleate (1:1)
  • Amlodipine, (+-)-Isomer
  • Amlodipine, (+-)-Isomer, Maleate (1:1)
  • Amlodipine, (R)-Isomer
  • Amlodipine, (S)-Isomer, Maleate (1:1)
  • Amlodis
  • Amlor
  • Astudal
  • Istin
  • Norvasc

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
408.9 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
3
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
10
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
408.1451996 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
408.1451996 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
99.9 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
28
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
647
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Boiling Point

3.2.3 Melting Point

3.2.4 Solubility

slightly soluble in water
FDA label

3.2.5 LogP

3
AUSTIN,RP ET AL. (1995)
log Kow = 3.00
Austin RP et al; J Pharm Sci 84: 1180-83 (1995)
3.00
AUSTIN,RP ET AL. (1995)

3.2.6 Stability / Shelf Life

Stable under recommended storage conditions. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html

3.2.7 Decomposition

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), sulfur oxides, hydrogen chloride gas. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
When heated to decomposition it emits toxic vapors of /nitric oxides/ and /hydrogen chloride/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 228

3.2.8 Dissociation Constants

Basic pKa
9.26
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037

3.2.9 Collision Cross Section

188 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

3.2.10 Other Experimental Properties

Mol wt 524.95. White crystals from ethyl acetate, mp 178-179 °C /Amlopidine maleate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 87
MW: 567.06. White crystalline powder. Slightly soluble in water; sparingly soluble in ethanol /Amlodipine benzenesulfonate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 87

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals -> Antihypertensives
S57 | GREEKPHARMA | Suspect Pharmaceuticals from the National Organization of Medicine, Greece | DOI:10.5281/zenodo.3248883
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents
Human drug -> Prescription
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664
Antihypertensive medicines
3.3.1.2 Animal Drugs
Veterinary drugs -> Calcium channel blockers -> Veterinary pharmacotherapeutic group -> EMA Drug Category
Pharmaceuticals -> UK Veterinary Medicines Directorate List
S104 | UKVETMED | UK Veterinary Medicines Directorate's List | DOI:10.5281/zenodo.7802119

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
Water
pH
7.00
Shifts [ppm]:Intensity
7.26:5.11, 3.25:10.76, 7.19:7.68, 3.61:100.00, 7.29:4.87, 7.20:6.35, 7.36:10.13, 4.62:9.19, 2.29:79.87, 7.47:9.67, 4.71:5.62, 7.18:2.47, 4.09:15.90, 4.71:5.79, 1.17:60.24, 3.26:15.91, 7.49:8.92, 7.18:3.90, 7.19:7.52, 3.81:14.00, 4.10:5.13, 3.80:9.26, 4.68:12.20, 7.27:8.64, 4.64:16.26, 7.37:8.38, 7.36:9.49, 3.82:8.63, 3.80:8.95, 1.15:27.49, 7.26:5.82, 4.06:5.52, 3.82:8.91, 5.34:19.55, 1.18:28.75, 3.81:13.68, 7.48:10.55, 7.28:9.54, 7.20:6.32, 3.27:13.38, 4.10:4.99, 7.19:7.15, 4.06:4.78, 3.26:15.77, 4.07:15.59, 7.29:4.65, 7.37:8.64, 4.09:16.67, 7.19:8.19, 7.49:8.81, 7.18:4.45, 4.08:17.57
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4.1.2 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 2D NMR Spectra

4.2.1 1H-13C NMR Spectra

2D NMR Spectra Type
1H-13C HSQC
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
Water
pH
7.00
Shifts [ppm] (F2:F1):Intensity
4.08:64.07:0.33, 7.27:130.46:0.23, 3.61:54.11:1.00, 3.26:41.65:0.47, 7.48:133.79:0.27, 4.63:69.72:0.05, 7.19:130.81:0.26, 5.34:40.16:0.51, 1.16:15.93:0.10, 7.36:132.12:0.24, 2.29:20.58:0.16, 3.81:69.05:0.58, 4.69:69.72:0.03
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4.3 Mass Spectrometry

4.3.1 GC-MS

1 of 4
View All
NIST Number
247418
Library
Main library
Total Peaks
263
m/z Top Peak
297
m/z 2nd Highest
208
m/z 3rd Highest
254
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2 of 4
View All
NIST Number
335276
Library
Replicate library
Total Peaks
125
m/z Top Peak
297
m/z 2nd Highest
208
m/z 3rd Highest
44
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4.3.2 MS-MS

1 of 6
View All
Spectra ID
Instrument Type
LC-ESI-QTOF
Ionization Mode
positive
Top 5 Peaks

238.0632 100

294.0898 52.72

208.0606 52.50

206.0366 47.79

377.1277 34.11

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Notes
instrument=Bruker maXis Impact
2 of 6
View All
Spectra ID
Ionization Mode
positive
Top 5 Peaks

238.0634 100

294.089539 76.76

377.126556 54.20

240.059662 46.71

296.086182 26.79

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Notes
instrument=qTof

4.3.3 LC-MS

1 of 38
View All
Authors
Nikiforos Alygizakis, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
RAMP 23.8-35.7 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
8.589 min
Precursor m/z
409.1525
Precursor Adduct
[M+H]+
Top 5 Peaks

238.0632 999

294.0898 526

208.0606 524

206.0366 477

377.1277 340

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License
CC BY
2 of 38
View All
Authors
Nihon Waters K.K.
Instrument
ZQ, Waters
Instrument Type
LC-ESI-Q
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ESI
Column Name
2.1 mm id - 3. 5{mu}m XTerra C18MS
Retention Time
15.430 min
Top 5 Peaks

148 999

149 815

180 807

102 803

176 780

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License
CC BY-NC

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Amlodipine may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of the following conditions: • Hypertension • Coronary artery disease • Chronic stable angina • Vasospastic angina (Prinzmetal’s or Variant angina) • Angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40%
Treatment of systemic arterial hypertension in cats.

7.2 LiverTox Summary

Amlodipine besylate is a second generation calcium channel blocker that is used in the therapy of hypertension and angina pectoris. Amlodipine has been linked to a low rate of serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents
Cardiovascular Agents

7.4 WHO Essential Medicines

Drug
Drug Classes
Antihypertensive medicines
Formulation
Oral - Solid: 5 mg (as maleate, mesylate or besylate)
Indication
Essential hypertension

7.5 FDA National Drug Code Directory

7.6 Drug Labels

Drug and label
Active ingredient and drug

7.7 Clinical Trials

7.7.1 ClinicalTrials.gov

7.7.2 EU Clinical Trials Register

7.7.3 NIPH Clinical Trials Search of Japan

7.8 EMA Drug Information

Medicine
Category
Veterinary drugs
Active Substance
Amlodipine besilate
INN/Common name
amlodipine
Pharmacotherapeutic Classes
Calcium channel blockers
Status
Refused
Company
Le Vet Beheer B.V.

7.9 Therapeutic Uses

Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents
National Library of Medicine's Medical Subject Headings. Amlodipine. Online file (MeSH, 2016). Available from, as of October 28, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
Norvasc is indicated for the treatment of hypertension, to lower blood pressure. ... Norvasc may be used alone or in combination with other antihypertensive agents. /Included in US product label/
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
Norvasc is indicated for the symptomatic treatment of chronic stable angina. Norvasc may be used alone or in combination with other antianginal agents. /Included in US product label/
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
Norvasc is indicated for the treatment of confirmed or suspected vasospastic angina. Norvasc may be used as monotherapy or in combination with other antianginal agents. /Included in US product label/
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
For more Therapeutic Uses (Complete) data for AMLODIPINE (6 total), please visit the HSDB record page.

7.10 Drug Warnings

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2008
In patients with hepatic impairment, amlodipine clearance is decreased and AUC is increased by about 40-60%. A reduced initial dosage of the drug is recommended, and subsequent dosage should be titrated slowly.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2008
When amlodipine is used in fixed combination with other drugs (e.g., other antihypertensive agents, atorvastatin), cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with amlodipine. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) also should be considered for each drug in the fixed combination.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2008
Although some calcium-channel blockers have been shown to worsen the clinical status of patients with heart failure, no evidence of worsening heart failure (based on exercise tolerance, New York Heart Association (NYHA) class, symptoms, or left ventricular ejection fraction) and no adverse effects on overall survival and cardiac morbidity were observed in controlled studies of amlodipine in patients with heart failure. Cardiac morbidity and overall mortality rates in these studies were similar in patients receiving amlodipine and those receiving placebo. In patients with moderate to severe heart failure, amlodipine clearance is decreased and area under the concentration-time curve (AUC) is increased by about 40-60%.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2008
For more Drug Warnings (Complete) data for AMLODIPINE (15 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

**General pharmacodynamic effects** Amlodipine has a strong affinity for cell membranes, modulating calcium influx by inhibiting selected membrane calcium channels. This drug's unique binding properties allow for its long-acting action and less frequent dosing regimen,. **Hemodynamic effects** After the administration of therapeutic doses of amlodipine to patients diagnosed with hypertension, amlodipine causes vasodilation, which results in a reduction of supine and standing blood pressure. During these blood pressure reductions, there are no clinically significant changes in heart rate or plasma catecholamine levels with long-term use. Acute intravenous administration of amlodipine reduces arterial blood pressure and increases heart rate in patients with chronic stable angina, however, chronic oral administration of amlodipine in clinical studies did not cause clinically significant alterations in heart rate or blood pressures in patients diagnosed with angina and normal blood pressure. With long-term, once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. **Electrophysiologic effects** Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in animals or humans. In patients who were diagnosed with chronic stable angina, the intravenous administration of 10 mg of amlodipine did not cause clinically significant alterations A-H and H-V conduction and sinus node recovery time after cardiac pacing. Patients administered amlodipine with concomitant beta-blockers produced similar results. In clinical trials in which amlodipine was given in combination with beta-blockers to patients diagnosed with hypertension or angina, no adverse effects on electrocardiographic parameters were noted. In clinical studies comprised of angina patients alone, amlodipine did not change electrocardiographic intervals or produce high degrees of AV block. **Effects on angina** Amlodipine relieves the symptoms of chest pain associated with angina. In patients diagnosed with angina, daily administration of a single amlodipine dose increases total exercise time, the time to angina onset, and the time to 1 mm ST-segment depression on ECG studies, decreases anginal attack frequency, and decreases the requirement for nitroglycerin tablets.

8.2 MeSH Pharmacological Classification

Antihypertensive Agents
Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)
Vasodilator Agents
Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)
Calcium Channel Blockers
A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
1J444QC288
Active Moiety
AMLODIPINE
Pharmacological Classes
Mechanisms of Action [MoA] - Calcium Channel Antagonists
Pharmacological Classes
Established Pharmacologic Class [EPC] - Dihydropyridine Calcium Channel Blocker
Pharmacological Classes
Established Pharmacologic Class [EPC] - Calcium Channel Blocker
Pharmacological Classes
Chemical Structure [CS] - Dihydropyridines
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors
FDA Pharmacology Summary
Amlodipine is a Dihydropyridine Calcium Channel Blocker and Calcium Channel Blocker. The mechanism of action of amlodipine is as a Calcium Channel Antagonist and Cytochrome P450 3A Inhibitor.
2 of 2
Non-Proprietary Name
AMLODIPINE
Pharmacological Classes
Cytochrome P450 3A Inhibitors [MoA]; Dihydropyridines [CS]; Calcium Channel Blocker [EPC]; Dihydropyridine Calcium Channel Blocker [EPC]; Calcium Channel Antagonists [MoA]

8.4 ATC Code

QC08CA01
S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

C - Cardiovascular system

C08 - Calcium channel blockers

C08C - Selective calcium channel blockers with mainly vascular effects

C08CA - Dihydropyridine derivatives

C08CA01 - Amlodipine

8.5 Absorption, Distribution and Excretion

Absorption
Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food.
Route of Elimination
Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing. Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure,.
Volume of Distribution
21 L/kg,.
Clearance
Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers,. Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required.
/MILK/ The aims of this study were to evaluate the plasma concentration of amlodipine and its passage into breast milk in lactating women with pregnancy-induced hypertension and to estimate the risk for breastfeeding infants. Thirty-one lactating women receiving oral amlodipine once daily for pregnancy-induced hypertension were enrolled. Pre-dose plasma and milk concentrations of amlodipine were determined at day 6 or later after starting the medication. Relative infant dose (RID) as an infant risk for breastfeeding was calculated by dividing the infant dose via milk by the maternal dose. The mean maternal dose of amlodipine was 6.0 mg. The medians of the plasma and milk concentrations of amlodipine were 15.5 and 11.5 ng/mL, respectively. Interindividual variation was observed in the amlodipine dose and body weight-adjusted milk concentrations (interquartile range [IQR], 96.7-205 ng/mL per mg/kg). The median and IQR of the amlodipine concentration ratio of milk to plasma were 0.85 and 0.74 to 1.08, respectively. The medians of infant birth weight and daily amlodipine dose via milk were 2170 g and 4.2 ug/kg, respectively. The median of the RID of amlodipine was 4.2% (IQR, 3.1%-7.3%). Lactating women with pregnancy-induced hypertension had higher plasma concentrations of amlodipine during the early postpartum period. Oral amlodipine transferred into breast milk at the same level as that of plasma. However, the RID of amlodipine in most patients was less than 10%.
Naito T et al; J Hum Lact 31 (2): 301-6 (2015)
After oral administration of therapeutic doses of Norvasc, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Norvasc is not altered by the presence of food.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. ... Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
Amlodipine is a dihydropyridine calcium antagonist drug with distinctive pharmacokinetic characteristics which appear to be attributable to a high degree of ionization. Following oral administration, bioavailability is 60 to 65% and plasma concentrations rise gradually to peak 6 to 8 hr after administration. Amlodipine is extensively metabolized in the liver (but there is no significant presystemic or first-pass metabolism) and is slowly cleared with a terminal elimination half-life of 40 to 50 hr. Volume of distribution is large (21 L/kg) and there is a high degree of protein binding (98%). There is some evidence that age, severe hepatic impairment and severe renal impairment influence the pharmacokinetic profile leading to higher plasma concentrations and longer half-lives. There is no evidence of pharmacokinetic drug interactions. Amlodipine shows linear dose-related pharmacokinetic characteristics and, at steady-state, there are relatively small fluctuations in plasma concentrations across a dosage interval. Thus, although structurally related to other dihydropyridine derivatives, amlodipine displays significantly different pharmacokinetic characteristics and is suitable for administration in a single daily dose.
Meredith PA et al; Clin Pharmacokinet 22(1): p.22-31 (1992)
... A randomized, 2-way crossover study was conducted in 18 healthy male volunteers to compare the pharmacokinetics and pharmacodynamics of these two forms, i.e. amlodipine nicotinate (test) and amlodipine besylate (reference), after administration of a single dose of 5 mg of each drug and a washout period between doses of 4 weeks. Blood samples for the pharmacokinetic analysis of amlodipine were obtained over the 144-hour period after administration. Systolic and diastolic blood pressures and pulse rates were recorded immediately prior to each blood sampling. All participants completed both treatment periods, and no serious adverse events occurred during the study period. After administering a single dose of each formulation, mean AUC0-infinity and Cmax values were 190.91+/-60.49 ng x hr/mL and 3.87+/-1.04 ng/mL for the test formulation and 203.15+/-52.05 ng x hr/mL and 4.01+/-0.60 ng/mL for the reference formulation, respectively. The 90% confidence intervals of test/reference mean ratios for AUC0- infinity and Cmax fell within the predetermined equivalence range of 80 - 125%. Pharmacodynamic profiles including systolic and diastolic blood pressures and pulse rates exhibited no significant differences between the two formulations. The two amlodipine formulations showed similar pharmacokinetic and pharmacodynamic characteristics and the new amlodipine formulation, amlodipine nicotinate, was found to be equivalent for pharmacokinetics to the currently available amlodipine besylate with respect to the rate and extent of amlodipine absorption.
Park JY et al; Int J Clin Pharmacol Ther 44 (12): 641-7 (2006)

8.6 Metabolism / Metabolites

Amlodipine is heavily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites found excreted in the urine. _Ex vivo_ studies have shown that about 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Characteristics that add to amlodipine's unique pharmacologic profile include nearly complete absorption, late-peak plasma concentrations, high bioavailability, and slow hepatic breakdown.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
Metabolism of the dihydropyridine calcium antagonist (R,S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbony l-5- methoxycarbonyl- 6 -methyl- 1,4-dihydropyridine (amlodipine) has been studied in animals and man using (14)C-labelled drug. The metabolite patterns are complex; 18 metabolites have been isolated from rat, dog and human urine. Based on chromatographic and mass-spectral evidence, structures have been proposed for the main metabolites and confirmed by synthesis of unambiguous reference compounds. Comparison of all reference compounds and isolated metabolites was made by gas chromatography-mass spectrometry pressure liquid chromatography on-line thermospray-mass spectrometry of underivatised compounds directly in urine. The metabolites are largely pyridine derivatives. The methods used in structure designation are presented, along with the proposed route of metabolism, which indicates that the metabolic pattern for amlodipine in man has features in common with those of both rat and dog.
Beresford AP et al; Arzneimittelforschung 39 (2): 201-9 (1989)
... Objectives of this study were to determine the metabolite profile of amlodipine (a racemic mixture and S-isomer) in human liver microsomes (HLM), and to identify the cytochrome P450 (P450) enzyme(s) involved in the M9 formation. Liquid chromatography/mass spectrometry analysis showed that amlodipine was mainly converted to M9 in HLM incubation. M9 underwent further O-demethylation, O-dealkylation, and oxidative deamination to various pyridine derivatives. This observation is consistent with amlodipine metabolism in humans. Incubations of amlodipine with HLM in the presence of selective P450 inhibitors showed that both ketoconazole (an inhibitor of CYP3A4/5) and CYP3cide (an inhibitor of CYP3A4) completely blocked the M9 formation, whereas chemical inhibitors of other P450 enzymes had little effect. Furthermore, metabolism of amlodipine in expressed human P450 enzymes showed that only CYP3A4 had significant activity in amlodipine dehydrogenation. Metabolite profiles and P450 reaction phenotyping data of a racemic mixture and S-isomer of amlodipine were very similar. The results from this study suggest that CYP3A4, rather than CYP3A5, plays a key role in metabolic clearance of amlodipine in humans.
Zhu Y et al; Drug Metab Dispos 42 (2): 245-9 (2014)
In the present study, the metabolic profile of amlodipine, a well-known calcium channel blocker, was investigated employing liquid chromatography-mass spectrometric (LC/MS) techniques. Two different types of mass spectrometers - a triple-quadrupole (QqQ) and a quadrupole time-of-flight (Q-TOF) mass spectrometer - were utilized to acquire structural information on amlodipine metabolites. The metabolites were produced by incubation of amlodipine with primary cultures of rat hepatocytes. Incubations from rat hepatocytes were analyzed with LC-MS/MS, and 21 phase I and phase II metabolites were detected. Their product ion spectra were acquired and interpreted, and structures were proposed. Accurate mass measurement using LC-Q-TOF was used to determine the elemental composition of metabolites and thus to confirm the proposed structures of these metabolites. Mainly phase I metabolic changes were observed including dehydrogenation of the dihydropyridine core, as well as reactions of side chains, such as hydrolysis of ester bonds, hydroxylation, N-acetylation, oxidative deamination, and their combinations. The only phase II metabolite detected was the glucuronide of a dehydrogenated, deaminated metabolite of amlodipine. /Investigators/ propose several in vitro metabolic pathways of amlodipine in rat, based on our analysis of the metabolites detected and characterized.
Suchanova B et al; Eur J Pharm Sci 33 (1): 91-9 (2008)

8.7 Biological Half-Life

The terminal elimination half-life of about 30–50 hours. Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment.
Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
... Following oral administration, /amlodipine has/ a terminal elimination half-life of 40 to 50 hr. ....
Meredith PA et al; Clin Pharmacokinet 22(1): p.22-31 (1992)

8.8 Mechanism of Action

**Mechanism of action on blood pressure** Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both _dihydropyridine_ and _nondihydropyridine_ binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells. Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure. **Mechanism of action in angina** The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold: Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements. Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking.
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
Recent studies have suggested that cytokines are capable of modifying cardiovascular function and that drugs used in the treatment of heart failure have various modulating properties on the production of cytokines. More recently, we have found that ouabain induces the production of cytokines. This study was performed to examine the effects of calcium channel blockers on the production of cytokines induced by a cardiac glycoside. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured in 0.1, 1, 10, and 30 umol/L amlodipine, diltiazem, and nifedipine in presence of 1 umol/L ouabain. After 24 hr of incubation, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were measured in the culture supernatants by enzyme-linked immunosorbent assay. Ouabain induced the production of IL-1alpha, IL-1beta and IL-6, but not of TNF-alpha. Induction of IL-1beta was most prominent. The production of IL-1alpha, and IL-6 was inhibited by amlodipine in a concentration-dependent manner and was significantly decreased at a concentration of 10 umol/L. IL-1beta production was also inhibited by 30 umol/L amlodipine. In contrast, neither diltiazem nor nifedipine inhibited the production of these cytokines. The unique property of amlodipine to inhibit the production of IL-1alpha, IL-1beta and IL-6 may contribute to its beneficial effects in heart failure patients.
Matsumori A et al; Cytokine 12(3): p.294-297 (2000)
Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, /investigators/ demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. /Investigators/ show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.
Ziesche R et al; FASEB J 18 (13): 1516-23 (2004)
Calcium channel blockers (CCBs) are widely used in the therapy of cardiovascular diseases. Recent studies have shown that several CCBs exerted distinct anti-inflammatory effect in myocardial dysfunction models. The purpose of the present study was to evaluate therapeutic effect and possible mechanism of action of amlodipine, one of the widely used CCBs, on rat cardiac dysfunction during sepsis induced by lipopolysaccharide (LPS). Pretreatment of the rats with amlodipine (10 or 30 mg/kg, i.v.) delayed the fall of mean arterial blood pressure caused by LPS. Amlodipine also significantly inhibited the elevation of plasma tumor necrosis factor alpha (TNF-alpha) and decreased levels of inducible nitric oxide synthase (iNOS) in response to LPS challenge. To investigate the mechanism of the action of amlodipine, neonatal rat cardiomyocytes were used as a model. Amlodipine concentration-dependently decreased the release of TNF-alpha and iNOS protein expression, and suppressed the degradation and phosphorylation of inhibitor of kappaB-alpha (IkappaB-alpha) in LPS-activated neonatal rat cardiomyocytes. Further studies revealed that amlodipine markedly activated phosphatidylinositiol 3-kinase (PI3K) and Akt, downstream of the PI3K signal cascade. Application of PI3K inhibitors, wortmannin and LY294002 attenuated the depression of TNF-alpha and iNOS expression by amlodipine in LPS-induced cardiomyocytes. These findings may explain some cardioprotective effects of amlodipine in LPS-mediated sepsis and suggest that the inhibition of TNF-alpha and iNOS expression by amlodipine is, at least in part, dependent on PI3K/Akt signaling pathway.
Li XQ et al; Int Immunopharmacol 9 (9): 1032-41 (2009)

8.9 Human Metabolite Information

8.9.1 Tissue Locations

Epidermis

8.9.2 Metabolite Pathways

9 Use and Manufacturing

9.1 Uses

MEDICATION (VET)
MEDICATION
Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents
National Library of Medicine's Medical Subject Headings. Amlodipine. Online file (MeSH, 2016). Available from, as of October 28, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html

Use (kg; approx.) in Germany (2009): >7500

Use (kg) in USA (2002): 7610

Use (kg) in France (2004): 2013

Consumption (g per capita; approx.) in Germany (2009): 0.0916

Consumption (g per capita) in the USA (2002): 0.027

Consumption (g per capita) in France (2004): 0.0333

Excretion rate: 0.38

Calculated removal (%): 30.4

9.1.1 Use Classification

Veterinary drugs -> Calcium channel blockers -> Veterinary pharmacotherapeutic group -> EMA Drug Category
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

... 2-Chlorobenzaldehyde can be reacted with methyl acetoacetate to afford methyl 2-(2-chlorobenzylidene) acetoacetate, which upon reaction with the enamine, prepared by heating ethyl 4-(2-azidoethoxy)acetoacetate with ammonium acetate in ethanol under reflux, yields the desired intermediate of amlodipine.
Kleemann A; Cardiovascular Drugs. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2016). NY, NY: John Wiley & Sons. Online Posting Date: January 15, 2008
Preparation: S.F. Campbell et al., European Patent Office patent 89167; eidem, United States of America patent 4572909 (1983, 1986 both to Pfizer).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 88

9.3 Formulations / Preparations

Table: Amlodipine Besylate Preparations
Route
Oral
Dosage Form
Tablets
Strength
2.5 mg (of amlodipine)
Brand (Manufacturer)
Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route
Oral
Dosage Form
Tablets
Strength
2.5 mg (of amlodipine)
Brand (Manufacturer)
Norvasc (Pfizer)
Route
Oral
Dosage Form
Tablets
Strength
5 mg (of amlodipine)
Brand (Manufacturer)
Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route
Oral
Dosage Form
Tablets
Strength
5 mg (of amlodipine)
Brand (Manufacturer)
Norvasc (Pfizer)
Route
Oral
Dosage Form
Tablets
Strength
10 mg (of amlodipine)
Brand (Manufacturer)
Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route
Oral
Dosage Form
Tablets
Strength
10 mg (of amlodipine)
Brand (Manufacturer)
Norvasc (Pfizer)
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2009
Table: Amlodipine Besylate Combinations Preparations
Route of Administration
Oral
Dosage Form
Capsules
Strength
2.5 mg (of amlodipine) with Benazepril Hydrochloride 10 mg
Brand or Generic Form (Manufacturer)
Amlodipine Besylate and Benazepril Hydrochloride Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Capsules
Strength
2.5 mg (of amlodipine) with Benazepril Hydrochloride 10 mg
Brand or Generic Form (Manufacturer)
Lotrel (Novartis)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of amlodipine) with Benazepril Hydrochloride 10 mg
Brand or Generic Form (Manufacturer)
Amlodipine Besylate and Benazepril Hydrochloride Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of amlodipine) with Benazepril Hydrochloride 10 mg
Brand or Generic Form (Manufacturer)
Lotrel (Novartis)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of amlodipine) with Benazepril Hydrochloride 20 mg
Brand or Generic Form (Manufacturer)
Amlodipine Besylate and Benazepril Hydrochloride Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of amlodipine) with Benazepril Hydrochloride 20 mg
Brand or Generic Form (Manufacturer)
Lotrel (Novartis)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of amlodipine) with Benazepril Hydrochloride 40 mg
Brand or Generic Form (Manufacturer)
Amlodipine Besylate and Benazepril Hydrochloride Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Capsules
Strength
5 mg (of amlodipine) with Benazepril Hydrochloride 40 mg
Brand or Generic Form (Manufacturer)
Lotrel (Novartis)
Route of Administration
Oral
Dosage Form
Capsules
Strength
10 mg (of amlodipine) with Benazepril Hydrochloride 20 mg
Brand or Generic Form (Manufacturer)
Amlodipine Besylate and Benazepril Hydrochloride Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Capsules
Strength
10 mg (of amlodipine) with Benazepril Hydrochloride 20 mg
Brand or Generic Form (Manufacturer)
Lotrel (Novartis)
Route of Administration
Oral
Dosage Form
Capsules
Strength
10 mg (of amlodipine) with Benazepril Hydrochloride 40 mg
Brand or Generic Form (Manufacturer)
Amlodipine Besylate and Benazepril Hydrochloride Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Capsules
Strength
10 mg (of amlodipine) with Benazepril Hydrochloride 40 mg
Brand or Generic Form (Manufacturer)
Lotrel (Novartis)
Route of Administration
Oral
Dosage Form
Tablets
Strength
2.5 mg (of amlodipine) with Perindopril Arginine 3.5 mg
Brand or Generic Form (Manufacturer)
Prestalia (Symplmed)
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg (of amlodipine) with Olmesartan Medoxomil 20 mg
Brand or Generic Form (Manufacturer)
Azor (Daiichi-Sankyo)
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg (of amlodipine) with Olmesartan Medoxomil 40 mg
Brand or Generic Form (Manufacturer)
Azor (Daiichi-Sankyo)
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg (of amlodipine) with Perindopril Arginine 7 mg
Brand or Generic Form (Manufacturer)
Prestalia (Symplmed)
Route of Administration
Oral
Dosage Form
Tablets
Strength
10 mg (of amlodipine) with Olmesartan Medoxomil 20 mg
Brand or Generic Form (Manufacturer)
Azor (Daiichi-Sankyo)
Route of Administration
Oral
Dosage Form
Tablets
Strength
10 mg (of amlodipine) with Olmesartan Medoxomil 40 mg
Brand or Generic Form (Manufacturer)
Azor (Daiichi-Sankyo)
Route of Administration
Oral
Dosage Form
Tablets
Strength
10 mg (of amlodipine) with Perindopril Arginine 14 mg
Brand or Generic Form (Manufacturer)
Prestalia (Symplmed)
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2009
Table: Amlodipine Besylate Combinations Preparations
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2.5 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2.5 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2.5 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2.5 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2.5 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2.5 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Aliskiren Hemifumarate 150 mg (of aliskiren)
Brand or Generic Form (Manufacturer)
Tekamlo (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Aliskiren Hemifumarate 150 mg (of aliskiren) and Hydrochlorothiazide 12.5 mg
Brand or Generic Form (Manufacturer)
Amturnide (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren)
Brand or Generic Form (Manufacturer)
Tekamlo (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 12.5 mg
Brand or Generic Form (Manufacturer)
Amturnide (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 25 mg
Brand or Generic Form (Manufacturer)
Amturnide (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 80 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Atorvastatin Calcium 80 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Olmesartan Medoxomil 20 mg
Brand or Generic Form (Manufacturer)
Tribenzor (Daiichi Sankyo)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Olmesartan Medoxomil 40 mg
Brand or Generic Form (Manufacturer)
Tribenzor (Daiichi Sankyo)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Exforge HCT (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Olmesartan Medoxomil 40 mg
Brand or Generic Form (Manufacturer)
Tribenzor (Daiichi Sankyo)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Exforge HCT (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Valsartan Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Exforge (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Valsartan 320 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Valsartan Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg (of amlodipine) with Valsartan 320 mg
Brand or Generic Form (Manufacturer)
Exforge (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Aliskiren Hemifumarate 150 mg (of aliskiren)
Brand or Generic Form (Manufacturer)
Tekamlo (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren)
Brand or Generic Form (Manufacturer)
Tekamlo (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 12.5 mg
Brand or Generic Form (Manufacturer)
Amturnide (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Aliskiren Hemifumarate 300 mg (of aliskiren) and Hydrochlorothiazide 25 mg
Brand or Generic Form (Manufacturer)
Amturnide (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 10 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 20 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 40 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 80 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate and Atorvastatin Calcium Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Atorvastatin Calcium 80 mg (of atorvastatin)
Brand or Generic Form (Manufacturer)
Caduet (Pfizer)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Olmesartan Medoxomil 40 mg
Brand or Generic Form (Manufacturer)
Tribenzor (Daiichi Sankyo)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 12.5 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Exforge HCT (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Olmesartan Medoxomil 40 mg
Brand or Generic Form (Manufacturer)
Tribenzor (Daiichi Sankyo)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 160 mg
Brand or Generic Form (Manufacturer)
Exforge HCT (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 320 mg
Brand or Generic Form (Manufacturer)
Generic Name: Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg (of amlodipine) with Hydrochlorothiazide 25 mg and Valsartan 320 mg
Brand or Generic Form (Manufacturer)
Exforge HCT (Novartis)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
5 mg (of amlodipine) with Telmisartan 40 mg
Brand or Generic Form (Manufacturer)
Generic Name: Telmisartan and Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
5 mg (of amlodipine) with Telmisartan 40 mg
Brand or Generic Form (Manufacturer)
Twynsta (Boehringer Ingelheim)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
5 mg (of amlodipine) with Telmisartan 80 mg
Brand or Generic Form (Manufacturer)
Generic Name: Telmisartan and Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
5 mg (of amlodipine) with Telmisartan 80 mg
Brand or Generic Form (Manufacturer)
Twynsta (Boehringer Ingelheim)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
10 mg (of amlodipine) with Telmisartan 40 mg
Brand or Generic Form (Manufacturer)
Generic Name: Telmisartan and Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
10 mg (of amlodipine) with Telmisartan 40 mg
Brand or Generic Form (Manufacturer)
Twynsta (Boehringer Ingelheim)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
10 mg (of amlodipine) with Telmisartan 80 mg
Brand or Generic Form (Manufacturer)
Generic Name: Telmisartan and Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, multilayer
Strength
10 mg (of amlodipine) with Telmisartan 80 mg
Brand or Generic Form (Manufacturer)
Twynsta (Boehringer Ingelheim)
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2009

10 Identification

10.1 Analytic Laboratory Methods

A gas chromatography assay with electron capture has a limit of detection 0.2 ug/L. A gas chromatography-mass spectrometry method has also been described to assay amlodipine and its major metabolites.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 564

10.2 Clinical Laboratory Methods

Gas chromatography determination in plasma.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 88

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 5
View All
Pictogram(s)
Corrosive
Acute Toxic
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

H314 (33.3%): Causes severe skin burns and eye damage [Danger Skin corrosion/irritation]

H318 (66.7%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H341 (33.3%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

H373 (66.7%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]

H400 (66.7%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

H410 (66.7%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

H411 (33.3%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P264, P264+P265, P270, P273, P280, P301+P316, P301+P330+P331, P302+P361+P354, P304+P340, P305+P354+P338, P316, P317, P318, P319, P321, P330, P363, P391, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 3 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 3 (100%)

Eye Dam. 1 (66.7%)

STOT RE 2 (66.7%)

Aquatic Acute 1 (66.7%)

Aquatic Chronic 1 (66.7%)

Acute Tox. 3 (100%)

Skin Irrit. 2 (25%)

Eye Dam. 1 (100%)

STOT RE 2 (100%)

Aquatic Acute 1 (100%)

Aquatic Chronic 1 (100%)

11.2 Fire Fighting

11.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3 Accidental Release Measures

11.3.1 Cleanup Methods

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.3 Preventive Measures

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
For more Preventive Measures (Complete) data for AMLODIPINE (6 total), please visit the HSDB record page.

11.4 Handling and Storage

11.4.1 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Store bottles at controlled room temperature, 59 deg to 86 °F (15 deg to 30 °C) and dispense in tight, light-resistant containers.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed

11.5 Exposure Control and Personal Protection

11.5.1 Personal Protective Equipment (PPE)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html

11.6 Stability and Reactivity

11.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents. /Amlodipine besylate/
Sigma-Aldrich; Safety Data Sheet for Amlodipine besylate. Product Number: A5605, Version 4.5 (Revision Date 06/13/2016). Available from, as of November 15, 2016: https://www.sigmaaldrich.com/safety-center.html

11.7 Regulatory Information

REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
Amlodipine: Does not have an individual approval but may be used under an appropriate group standard

11.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including amlodipine besylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amlodipine besylate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of November 8, 2016: https://www.fda.gov/cder/ob/

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Amlodipine is calcium channel blocker used as antihypertensive and vasodilator agent. HUMAN EXPOSURE AND TOXICITY: One patient ingested 250 mg amlodipine and was asymptomatic. Another patient ingested 120 mg, underwent gastric lavage, and remained normotensive. A third patient took 105 mg and had hypotension (90/50 mmHG), which normalized following plasma expansion. A 19-month old ingested 30 mg (2 mg/kg) and had no evidence of hypotension but had a heart rate of 180 bpm. Children who ingested > 10 mg were 4.4 times more likely to develop clinically important responses than those ingesting < or = 5 mg. Hypotension may occur in children with amlodipine doses as low as 2.5 mg. ANIMAL STUDIES: Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. Amlodipine has been shown to prolong the duration of labor in rats. No evidence of teratogenicity or other embryo/fetal toxicity was observed in rats or rabbits given up to 10 mg/kg during periods of major organogenesis. However, the number of intrauterine deaths increased about five-fold, and rat litter size was decreased by 50%. Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

12.1.2 Hepatotoxicity

Chronic therapy with amlodipine is associated with a low rate of serum enzyme elevations at rates that are similar to matched control populations. The enzyme elevations are usually mild, transient and asymptomatic and may resolve even during continued therapy. Clinically apparent liver injury from amlodipine is rare and described only in isolated case reports. In the few idiosyncratic cases reported, the latency period to onset of liver injury was usually 4 to 12 weeks, but examples with prolonged latency have also been published (10 months and several years). The latency period is shorter with recurrence on reexposure, including several instances of recurrence after liver injury due to other calcium channel blockers. The pattern of serum enzyme elevations is usually mixed or cholestatic. Rash, fever and eosinophilia have not been described and autoantibodies are not typical.

Likelihood score: C (probable but rare cause of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
amlodipine
DILI Annotation
Less-DILI-Concern
Severity Grade
5
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information indicates that milk levels of amlodipine are usually low and plasma levels in breastfed infants are undetectable. Maternal use of amlodipine during breastfeeding has not caused any adverse effects in breastfed infants. If the mother requires amlodipine, it is not a reason to discontinue breastfeeding.

◉ Effects in Breastfed Infants

A woman took amlodipine for hypertension 5 mg daily beginning 2 weeks postpartum. Her exclusively breastfed infant was examined regularly and at 3 months of age was healthy and had normal physical and neurological development.

One woman received amlodipine 2.5 mg orally twice daily during pregnancy for hypertension associated with glomerulonephritis. The dose was increased to 5 mg twice daily on day 2 postpartum. Her exclusively breastfed infant's growth was normal throughout the first year of life and no adverse effects were noted.

A preterm infant of 32 weeks gestation was breastfed exclusively from day 7 to day 20 postpartum. The infant's mother was taking amlodipine and labetalol in unspecified dosages for hypertension. The infant had apnea episodes unrelated to amlodipine. Growth at 2 months of age was slightly low.

Thirty-one women with pregnancy-induced hypertension postpartum received amlodipine 5 mg daily by mouth, with the dosage increased as needed to maintain blood pressure of 140/90 mm Hg or less. Their breastfed (extent not stated) infants exhibited no observed adverse cardiovascular effects within 3 weeks postpartum, although exact measurement methods were not stated.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.5 Acute Effects

12.1.6 Interactions

This open-label, crossover study was performed to establish if there is evidence for interaction between telmisartan, an angiotensin II antagonist, and amlodipine, a class II (dihydropyridine) calcium channel antagonist, on the basis of pharmacokinetics and safety. In a two-way crossover trial, 12 healthy Caucasian males were randomized to receive once daily for 9 days oral amlodipine 10 mg with or without oral telmisartan 120 mg. After a washout period of > or = 13 days, the subjects were switched to the other medication regimen. The geometric means of the primary pharmacokinetic parameters at steady state (day 9) for amlodipine when given alone were the following: maximum plasma concentration (Cmax) 17.7 ng/mL, area under the plasma concentration-time curve (AUC) 331 ng.hr/mL, and renal clearance 39.5 mL/min, with 8% of the total amlodipine dose being excreted. When concomitant telmisartan was given, the respective values were 18.7 ng/mL, 352 ng.hr/mL, and 43.0 mL/min, with 9.4% of the total amlodipine dose being excreted renally. The limits of the 90% confidence intervals (CIs) for the ratios of these steady-state parameters were 0.97 to 1.14 for Cmax and 0.98 to 1.16 for AUC; both were within the predefined reference range (0.8 to 1.25) for bioequivalence. The high intersubject variability in urinary amlodipine excretion resulted in bioequivalence not being demonstrated for renal clearance. Adverse effects were few, mild to moderate in intensity, and transient whether amlodipine was given alone or with telmisartan. Vital signs, except for blood pressure, and clinical laboratory values were unaffected by either medication. The findings of this study show that concomitant telmisartan and amlodipine may be administered as there is no clinically significant variation in primary pharmacokinetic parameters of amlodipine in the presence of telmisartan, and the safety of the combination is comparable to that of amlodipine alone.
Stangier J et al; J Clin Pharmacol 40(12): p.1347-1354 (2000)
Amlodipine is a representative calcium channel blocker that is frequently prescribed for the treatment of hypertension. In this study, the possibility of drug-drug interactions between amlodipine and coadministered antibiotics (ampicillin) was investigated in rats; thus, changes in the metabolic activities of gut microflora and the consequent pharmacokinetic pattern of amlodipine following ampicillin treatment were characterized. In human and rat fecalase incubation samples, amlodipine was metabolized to yield a major pyridine metabolite. The remaining amlodipine decreased and the formation of pyridine metabolite increased with incubation time, indicating the involvement of gut microbiota in the metabolism of amlodipine. Pharmacokinetic analyses showed that systemic exposure of amlodipine was significantly elevated in antibiotic-treated rats compared with controls. These results showed that antibiotic intake might increase the bioavailability of amlodipine by suppressing gut microbial metabolic activities, which could be followed by changes in therapeutic potency. Therefore, coadministration of amlodipine with antibiotics requires caution and clinical monitoring.
Yoo HH et al; J Hypertens 34 (1): 156-62 (2016)
1. The antinociceptive effects of amlodipine, administered subcutaneously (sc), intracerebroventricularly (icv) and intrathecally (it) were examined with the acetic acid writhing and tail-flick tests in mice. Amlodipine was also tested in combination with morphine and ketorolac. Isobolographic analyses were used to define the nature of functional interactions between amlodipine and morphine or ketorolac. 2. The s.c. (0.1, 1.25, 2.5, 5 and 10 mg/kg), icv (2.5, 5, 10 and 20 ug/mice) and it (2.5, 5, 10 and 20 ug/mice) administration of amlodipine exhibited a dose-dependent antinociceptive effect in the writhing test but had no effect on the tail-flick latency. Isobolographic analyses revealed an additive interaction between amlodipine and morphine or ketorolac in the writhing test. 3. These results suggest that amlodipine induces antinociception and increases antinociceptive action of morphine and ketorolac, possibly through a decrease in cellular calcium availability.
Dogrul A et al; Gen Pharmacol 29(5): p.839-845 (1997)
...The purpose of this study was to investigate drug interactions between amlodipine and simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4 weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak concentration (C(max)) of HMG-CoA reductase inhibitors from 9.6 +/- 3.7 ng/mL to 13.7 +/- 4.7 ng/mL (p < 0.05) and the area under the concentration-time curve (AUC) from 34.3 +/- 16.5 ng h/mL to 43.9 +/- 16.6 ng h/mL (p < 0.05) without affecting the cholesterol-lowering effect of simvastatin. ...
Nishio S et al; Hypertens Res 28 (3): 223-7 (2005)
For more Interactions (Complete) data for AMLODIPINE (13 total), please visit the HSDB record page.

12.1.7 Antidote and Emergency Treatment

The purpose of this study was to investigate the effect of activated charcoal on the absorption of amlodipine, with special reference to delayed charcoal administration. Thirty-two healthy volunteers, eight subjects in four parallel groups, ingested 10 mg of amlodipine on an empty stomach. Activated charcoal (25 g in 300 mL of water) was ingested either immediately afterwards or 2 hr or 6 hr after amlodipine, or amlodipine was ingested with 300 mL of water only (control). Plasma concentrations and the cumulative excretion of amlodipine into urine were measured by GC-MS for 96 h and 72 hr, respectively. In addition, adsorption of amlodipine to charcoal was studied in vitro. Activated charcoal administered immediately after amlodipine reduced the amlodipine AUC(0.96 hr) and the 72-hr urinary excretion by 99% (P < 0.0005). After a delay of 2 hr in charcoal administration the AUC(0.96 hr) was reduced by 49% (P = 0.001), but after a delay of 6 hr the reduction was 15% only (P = NS). At a charcoal:drug ratio of 5:1, about 90% of amlodipine was adsorbed by charcoal in vitro; at ratios of 10:1 and 20:1, adsorption was practically complete. Activated charcoal almost completely prevented amlodipine absorption when administered immediately after amlodipine ingestion. Charcoal also markedly reduced amlodipine absorption when given 2 hr after amlodipine; in amlodipine overdose, administration of charcoal may be beneficial even later. Administration of activated charcoal is the method of choice to prevent absorption of amlodipine in amlodipine overdose.
Laine K et al; BrJ Clin Pharmacol 43(1): p.29-33 (1997)
This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines.
Adams BD et al; Am J Emerg Med 16(5): p.527-528 (1998)
The objective of this study was to report a use of hyperinsulinemia euglycemia therapy in severe amlodipine intoxication. Intoxication with 420 mg of amlodipine caused severe hypotension in a 20-year-old female patient. The patient was initially treated with fluids, calcium gluconate, and epinephrine without effect. She was then given hyperinsulinemia euglycemia therapy. /Investigators/ observed a rise in blood pressure (BP) approximately 30 min after insulin was given and the BP was subsequently responsive to epinephrine. The patient was weaned from pressors 5 hr after insulin therapy. The trachea was extubated 24 hr after ingesting amlodipine, and the patient was transferred for psychiatric treatment 3 days later. This possible positive inotropic effect of insulin therapy in patients with calcium channel blocker intoxication supports previous findings. It is suggested that hyperinsulinemia euglycemia therapy may be considered as a first-line therapy in amlodipine intoxication.
Azendour H et al; J Emerg Med 38 (1): 33-5 (2010)
/EXPERIMENTAL/ A case of a serious poisoning with the calcium entry blocker amlodipine is described, which was treated effectively with 4-aminopyridine. Calcium is suggested as general treatment of poisoning with calcium entry blockers in many guidelines. The use of intravenous 4-aminopyridine is theoretically useful to treat poisoning from calcium entry blockers and was demonstrated in this case report.
Wilffert B et al; J Clin Pharm Ther 32 (6): 655-7 (2007)
For more Antidote and Emergency Treatment (Complete) data for AMLODIPINE (12 total), please visit the HSDB record page.

12.1.8 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
/SIGNS AND SYMPTOMS/ Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Norvasc is limited.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
/CASE REPORTS/ A 35-year-old woman with a 9-year history of Grave's disease delivered a male infant weighing 2,210 g at 32 weeks of gestation by cesarean section. The neonate developed thyrotoxicosis and, at the age of 24 hr, was treated with oral carbimazole (500 ug every 8 hr) and propranolol (2 mg/kg/day in two divided doses). He subsequently developed hypertension on day 4, which required therapy with amlodipine (0.1 mg once daily). Severe hypotension developed within 24 hr and required discontinuation of amlodipine, with initiation of intravenous inotropic support with dopamine and dobutamine (at a rate of 20 ug/kg/min). The blood pressure rapidly normalized, and both dopamine and dobutamine infusions were stopped within 36 hr. A Naranjo assessment score of 6 was calculated, indicating that the severe hypotension was a probable adverse drug reaction caused by the combination of amlodipine and propranolol therapy.
Khassawneh M et al; Drug Saf Case Rep 2 (1): 2 (2015)
/CASE REPORTS/ Amlodipine is a relatively new agent that has the longest half-life of all calcium channel blockers. This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines.
Adams BD et al; Am J Emerg Med 16(5): p.527-528 (1998)
For more Human Toxicity Excerpts (Complete) data for AMLODIPINE (26 total), please visit the HSDB record page.

12.1.9 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /Investigators/ examined whether amlodipine, an L-type calcium channel blocker (CCB), has an inhibitory effect on oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E-deficient (ApoEKO) mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with or without oral administration of amlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions of NADPH oxidase subunits (p47(phox) and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10 weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the proximal aorta. In the atherosclerotic lesion, superoxide production, the expression of NADPH oxidase subunits, and NADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant with HCD administration, with no significant change in blood pressure and plasma cholesterol level. /Investigators/ also observed that treatment with amlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of oxidative stress and inflammatory response.
Yoshii T et al; Hypertens Res 29 (6): 457-66 (2006)
Yoshii T et al; Hypertens Res 29 (6): 457-66 (2006)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... /The purpose of this study was/ to investigate the effects of high doses of dihydropyridines on preproendothelin-1 expression in the ventricles and aorta of normotensive rats. Sprague-Dawley rats were treated with amlodipine 5 or 20 mg/kg per day (Amlo 5 or Amlo 20) in drinking water for 5 days or 5 weeks. Systolic blood pressure and heart rate were measured by tail-cuff plethysmography. Gene expression was examined by reverse transcriptase polymerase chain reaction. Amlo 5 increased heart rate during the first week only and had no effect on blood pressure and ventricular weight and gene expression. Amlo 20 reduced blood pressure transiently and increased heart rate consistently. It did not change relative left ventricular weight (corrected for body weight) after 5 days, but increased it after 5 weeks; it increased relative right ventricular weight at both time points. Aorta weight (mg/mm) was decreased after 5 weeks of treatment with both dosages of amlodipine. Preproendothelin-1 mRNA levels were increased by Amlo 20 in the ventricles and aorta and, concomitantly, renin mRNA was increased in the kidney. Less consistently, interleukin-6 mRNA also increased in ventricles, whereas cardiotrophin-1 mRNA remained unchanged. The sensitivity of isolated aorta to the contractile effect of noradrenaline was decreased by Amlo 5, but not by Amlo 20. In Sprague-Dawley rats, high-dose amlodipine, while promoting neurohormonal activation, induced overexpression of preproendothelin-1 mRNA in the ventricles and aorta. Endothelin-1 overexpression could contribute to the lack of inhibitory effect of high-dose amlodipine on ventricular mass in normotensive rats.
Krenek P et al; J Hypertens 22 (4): 827-35 (2004)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/sq m basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.
NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of October 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc53-db1c652505ed
For more Non-Human Toxicity Excerpts (Complete) data for AMLODIPINE (10 total), please visit the HSDB record page.

12.1.10 Populations at Special Risk

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2008

12.1.11 Protein Binding

About 98%,.

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Amlodipine's production and administration as a medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C indicates amlodipine will exist solely in the particulate phase in the atmosphere. Particulate-phase amlodipine will be removed from the atmosphere by wet and dry deposition. Amlodipine contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, amlodipine is expected to have slight mobility based upon an estimated Koc of 3200. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.9X10-17 atm-cu m/mole. Amlodipine is not expected to volatilize from dry soil surfaces based upon its vapor pressure. A biodegradation of 3% in 28 days using an aqueous ready biodegradability test suggests that biodegradation is not an important environmental fate process in soil and water. If released into water, amlodipine is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 44 suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to be an important environmental fate process since this class of compounds hydrolyze very slowly under environmental conditions (pH 5 to 9). Occupational exposure to amlodipine may occur through inhalation and dermal contact with this compound at workplaces where amlodipine is produced or used. Limited monitoring data indicate that the general population may be exposed to amlodipine via ingestion of contaminated water. Use data indicate exposure will occur to those being administered the drug. (SRC)

12.2.2 Artificial Pollution Sources

Amlodipine's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).
(1) NIH; DailyMed. Current Medication Information for Norvasc (Amlodipine Besylate) Tablet (Updated: April 2016). Available from, as of Oct 31, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd6a2ca-40c2-485c-bc5 3-db1c652505ed

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3200(SRC), determined from a structure estimation method(2), indicates that amlodipine is expected to have slight mobility in soil(SRC). Volatilization of amlodipine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.9X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Amlodipine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A biodegradation of 3% in 28 days using an aqueous ready biodegradability test(4) suggests that biodegradation is not an important environmental fate process in soil(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 9, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(4) ECHA; Search for Chemicals. 3-Ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedic arboxylate (88150-42-9) Registered Substances Dossier. European Chemical Agency. Available from, as of Nov 9, 2016: https://echa.europa.eu/
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3200(SRC), determined from a structure estimation method(2), indicates that amlodipine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.9X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 44(SRC), from its log Kow of 3.00(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). A biodegradation of 3% in 28 days using an aqueous ready biodegradability test(7) suggests that biodegradation is not an important environmental fate process in water(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 4, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
(6) Austin RP et al; J Pharm Sci 84: 1180-83 (1995)
(7) ECHA; Search for Chemicals. 3-Ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedic arboxylate (88150-42-9) Registered Substances Dossier. European Chemical Agency. Available from, as of Nov 9, 2016: https://echa.europa.eu/
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), amlodipine, which has an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase amlodipine may be removed from the air by wet and dry deposition(SRC). Amlodipine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 9, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.4 Environmental Biodegradation

AEROBIC: Amlodipine reached 3% degradation in 28 days using a ready biodegradability test in water(1).
(1) ECHA; Search for Chemicals. 3-Ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedic arboxylate (88150-42-9) Registered Substances Dossier. European Chemical Agency. Available from, as of Nov 9, 2016: https://echa.europa.eu/

12.2.5 Environmental Abiotic Degradation

A base-catalyzed second-order hydrolysis rate constant of 4.0X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(1); this corresponds to half-lives of 55 and 5.5 years at pH values of 7 and 8, respectively(1). Amlodipine contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). A photodegradation half-life of 8.8 minutes has been measured for amlodipine exposed to xenon irradiation. Solar irridiation half-lives were as follows (days, matrix): 0.4, wastewater influent; 0.2, wastewater effluent; 0.3, river water; 0.4, untreated water; 1.3, methanol; 2.2, ultrapure water pH 3; 0.7, ultrapure water, pH 10. Sixteen photodegradation products were identified(3).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 9, 2016: https://www2.epa.gov/tsca-screening-tools
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)
(3) Jakimska A et al; PLoS One 2014 Oct 3: 9, iss 10: e109206 (2014). Available from, as of Jan 16, 2017: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184881/

12.2.6 Environmental Bioconcentration

An estimated BCF of 44 was calculated in fish for amlodipine(SRC), using a log Kow of 3.00(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).
(1) Austin RP et al; J Pharm Sci 84: 1180-83 (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 9, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of amlodipine can be estimated to be 3200(SRC). According to a classification scheme(2), this estimated Koc value suggests that amlodipine is expected to have slight mobility in soil. Amlodipine has the potential to adsorb to wastewater treatment plant biosolids(3).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 9, 2016: https://www2.epa.gov/tsca-screening-tools
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Xia K et al; J Environ Qual 34: 91-104 (2005)

12.2.8 Volatilization from Water / Soil

The Henry's Law constant for amlodipine is estimated as 2.9X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that amlodipine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Amlodipine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Nov 9, 2016: https://www2.epa.gov/tsca-screening-tools

12.2.9 Environmental Water Concentrations

DRINKING WATER: Amlodipine was detected at a mean concentration of 1 ng/L in raw water (5 samples) entering a drinking water treatment plant operation located on the Llobregat River in northeast Spain that serves over 1 million people. It was tested for but not detected in subsequent samples from prechlorination, clarification, groundwater, ozonation, GAC filtration treatments and finished water; sampling was conducted October 2008 to January 2009(1).
(1) Huerta-Fontela M et al; Water Res 45(3): 1432-1442 (2011)

12.2.10 Probable Routes of Human Exposure

Occupational exposure to amlodipine may occur through inhalation and dermal contact with this compound at workplaces where amlodipine is produced or used. Limited monitoring data indicate that the general population may be exposed to amlodipine via ingestion of contaminated water. Use data indicate exposure will occur to those being administered the drug. (SRC)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

  • Avoid grapefruit products.
  • Avoid natural licorice.
  • Take with or without food. The absorption is unaffected by food.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Target-based Classification of Drugs

18.6 KEGG: Drug Groups

18.7 WHO ATC Classification System

18.8 FDA Pharm Classes

18.9 ChemIDplus

18.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.11 ChEMBL Target Tree

18.12 UN GHS Classification

18.13 NORMAN Suspect List Exchange Classification

18.14 CCSBase Classification

18.15 EPA DSSTox Classification

18.16 FDA Drug Type and Pharmacologic Classification

18.17 EPA Substance Registry Services Tree

18.18 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
  2. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  5. Therapeutic Target Database (TTD)
    Amlodipine/ irbesartan fixed-dose combination
    https://idrblab.net/ttd/data/drug/details/D02NZO
  6. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  7. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  8. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  9. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    3-ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate
    https://chem.echa.europa.eu/100.102.428
    3,5-Pyridinedicarboxylic acid, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-, 3-ethyl 5-methyl ester
    https://echa.europa.eu/substance-information/-/substanceinfo/100.125.844
    3,5-Pyridinedicarboxylic acid, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-, 3-ethyl 5-methyl ester (EC: 618-119-7)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/97610
    3-ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (EC: 425-820-1)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/111819
  10. FDA Global Substance Registration System (GSRS)
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  11. Hazardous Substances Data Bank (HSDB)
  12. Human Metabolome Database (HMDB)
    LICENSE
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    http://www.hmdb.ca/citing
  13. New Zealand Environmental Protection Authority (EPA)
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    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  14. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  15. ChEBI
  16. FDA Pharm Classes
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  17. LiverTox
  18. NCI Thesaurus (NCIt)
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    https://www.cancer.gov/policies/copyright-reuse
  19. Open Targets
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    https://platform-docs.opentargets.org/licence
  20. ChEMBL
    LICENSE
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    http://www.ebi.ac.uk/Information/termsofuse.html
  21. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  22. DailyMed
  23. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. European Medicines Agency (EMA)
    LICENSE
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    https://www.ema.europa.eu/en/about-us/legal-notice
  25. Drugs and Lactation Database (LactMed)
  26. Drugs@FDA
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  27. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    AMLODIPINE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  28. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  29. EU Clinical Trials Register
  30. Hazardous Chemical Information System (HCIS), Safe Work Australia
  31. Regulation (EC) No 1272/2008 of the European Parliament and of the Council
    LICENSE
    The copyright for the editorial content of this source, the summaries of EU legislation and the consolidated texts, which is owned by the EU, is licensed under the Creative Commons Attribution 4.0 International licence.
    https://eur-lex.europa.eu/content/legal-notice/legal-notice.html
  32. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.whocc.no/copyright_disclaimer/
  33. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  34. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  35. Japan Chemical Substance Dictionary (Nikkaji)
  36. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  37. MassBank Europe
  38. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  39. Metabolomics Workbench
  40. NIPH Clinical Trials Search of Japan
  41. SpectraBase
    AMLODIPINE;3-ETHYL-5-METHYL-2-[2-(AMINOETHOXYMETHYL)-4-(2-CHLOROPHENYL)-1,4-DIHYDRO-6-METHYL-3,5-PYRIDINE-DICARBOXYLATE
    https://spectrabase.com/spectrum/KLPlDiH4OYw
  42. NLM RxNorm Terminology
    LICENSE
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  43. PharmGKB
    LICENSE
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    https://www.pharmgkb.org/page/policies
  44. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  45. Protein Data Bank in Europe (PDBe)
  46. Springer Nature
  47. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  48. Wikidata
  49. Wikipedia
  50. Wiley
  51. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
  52. PubChem
  53. GHS Classification (UNECE)
  54. EPA Substance Registry Services
  55. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  56. PATENTSCOPE (WIPO)
  57. NCBI
CONTENTS