Amlodipine - C20H25ClN2O5 - PubChem PDF

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Amlodipine  Cite this Record
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PubChem CID: 2162
Chemical Names: Amlodipine; 88150-42-9; Norvasc; Amlodis; Amlodipino; Amlodipinum More...
Molecular Formula: C20H25ClN2O5

Molecular Weight: 408.879 g/mol
InChI Key: HTIQEAQVCYTUBX-UHFFFAOYSA-N
Drug Information: Drug Indication Therapeutic Uses Clinical Trials FDA Orange Book FDA UNII
Safety Summary: Laboratory Chemical Safety Summary (LCSS)
Amlodipine is a long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of ANGINA PECTORIS
and HYPERTENSION.
 from MeSH
Amlodipine is a synthetic dihydropyridine and a calcium channel blocker with antihypertensive and antianginal properties.
Amlodipine inhibits the influx of extracellular calcium ions into myocardial and peripheral vascular smooth muscle cells,
thereby preventing vascular and myocardial contraction. This results in a dilatation of the main coronary and systemic
arteries, decreased myocardial contractility, increased blood flow and oxygen delivery to the myocardial tissue, and
decreased total peripheral resistance. This agent may also modulate multi-drug response (MDR) activity through inhibition
of the p-glycoprotein efflux pump.
 Pharmacology from NCIt
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.
 LiverTox Summary from LiverTox
PUBCHEM  COMPOUND  AMLODIPINE Modify Date: 2018-06-02; Create Date: 2005-03-25

1 2D Structure
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 from PubChem
2 3D Conformer
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 Show Hydrogens  Show Atoms  Interact
 from PubChem
3 Names and Identifiers
3.1 Computed Descriptors
3.1.1 IUPAC Name

3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
 from PubChem
3.1.2 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
 from PubChem
3.1.3 InChI Key

HTIQEAQVCYTUBX-UHFFFAOYSA-N
 from PubChem
3.1.4 Canonical SMILES

CCOC(=O)C1=C(NC(=C(C1C2=CC=CC=C2Cl)C(=O)OC)C)COCCN
 from PubChem
3.2 Molecular Formula

C20H25ClN2O5
 from PubChem
3.3 Other Identifiers
3.3.1 CAS
88150-42-9
 from ChemIDplus, DrugBank, EPA DSStox, European Chemicals Agency (ECHA), Human Metabolome Database (…
3.3.2 EC Number
425-820-1
 from European Chemicals Agency (ECHA)
618-119-7
3.3.3 UNII
1J444QC288
 from DrugBank
3.3.4 Wikipedia
Title amlodipine mesylate
Description chemical compound
Title amlodipine
Description medication used to treat high blood pressure and coronary artery disease
 from Wikipedia
3.4 Synonyms
3.4.1 MeSH Entry Terms
1. Amlodipine 11. Astudal

2. Amlodipine Besylate 12. Istin
3. Amlodipine Maleate 13. Norvasc
4. Amlodipine Maleate (1:1)
5. Amlodipine, (+-)-Isomer
6. Amlodipine, (+-)-Isomer, Maleate (1:1)
7. Amlodipine, (R)-Isomer
8. Amlodipine, (S)-Isomer, Maleate (1:1)
9. Amlodis
10. Amlor
 from MeSH
3.4.2 Depositor-Supplied Synonyms
ylate 41. UK-48,340

oxylate 42. Amlodipin
43. Intervask
5-methyl ester 44. Amlodipine/
oxylate 45. R,S)-Amlodipine
oxylate 46. Dailyvasc (TN)
xylate 47. Perivasc (TN)
48. 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydr
49. 2-[2-aminoethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro
50. Amlodipine (INN)
 from PubChem
4 Chemical and Physical Properties
4.1 Computed Properties
Property Name Property Value
Molecular Weight 408.879 g/mol
Hydrogen Bond Donor Count 2
Hydrogen Bond Acceptor Count 7
Rotatable Bond Count 10
Complexity 647
AAADceB7OAAEAAAAAAAAAAAAAAAAAAAAAAAwQAA
AAAAAAAABAAAAHgIQAAAADQrhmCYyCILABACIAiTSS
CACTVS Substructure Key Fingerprint
AACAAAgBQAIiIEAAsgKJDKBMxCDMAAkkACYqUeI7uiOg
AAAAAABAAAAAAAAAAIAAAAAAAAAAA==
Topological Polar Surface Area 99.9 A^2
Monoisotopic Mass 408.145 g/mol
Exact Mass 408.145 g/mol
XLogP3 3
Compound Is Canonicalized true
Formal Charge 0
Heavy Atom Count 28
Defined Atom Stereocenter Count 0
Undefined Atom Stereocenter Count 1
Defined Bond Stereocenter Count 0
Undefined Bond Stereocenter Count 0
Isotope Atom Count 0
Covalently-Bonded Unit Count 1
 from PubChem
4.2 Experimental Properties
4.2.1 Physical Description

Solid
 from Human Metabolome Database (HMDB)
4.2.2 Melting Point

178-179 °C
 from DrugBank
4.2.3 Solubility
Water Solubility
75.3 mg/L
 from DrugBank
In water, 75.3 mg/L at 25 deg C (est)

US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Nov 7, 2016: http://www2.epa.gov/tsca-
screening-tools
 from HSDB
4.2.4 Vapor Pressure

1.19X10-9 mm Hg at 25 deg C (est)
US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Nov 7, 2016: http://www2.epa.gov/tsca-
screening-tools
 from HSDB
4.2.5 LogP
3
AUSTIN,RP ET AL. (1995)
 from DrugBank
log Kow = 3.00

Abstract: PubMed
Austin RP et al; J Pharm Sci 84: 1180-83 (1995)
 from HSDB
3.00
AUSTIN,RP ET AL. (1995)
4.2.6 Stability
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: http://www.sigmaaldrich.com/safety-center.html
 from HSDB
4.2.7 Decomposition
Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), sulfur oxides,
hydrogen chloride gas. /Amlodipine besylate/
 from HSDB
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
 from HSDB
4.2.8 Dissociation Constants

pKa = 9.4 (amine) (est)
ACE; ACE and JChem acidity and basicity calculator. ACE UKY-4.0. 2005-2015. Marvin JS. ChemAxon. Available from, as of Nov 7, 2016:
https://epoch.uky.edu/ace/public/pKa.jsp
 from HSDB
4.3 Spectral Properties
4.3.1 1D NMR Spectra
1D NMR Spectra: 1 of 2 (1H NMR Spectra)
1H NMR Spectra 1D NMR Spectrum 2020 - Bruker 600 MHz 1H NMR
1D NMR Spectra: 2 of 2 (13C NMR Spectra)
Copyright Copyright © 2016 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
 from SpectraBase
4.3.2 2D NMR Spectra
2D NMR Spectra: 1 of 1 (1H-13C NMR Spectra)

2D NMR Spectra: 1 of 1 (1H-13C NMR Spectra)
1H-13C NMR Spectra 2D NMR Spectrum 1955 - Bruker 600 MHz 1H-13C HSQC
4.3.3 Mass Spectrometry
4.3.3.1 General MS
General MS: 1 of 11 (MS)
MoNA ID AU154406
MS Type Chromatography identified as LC-MS
MS Level MS2
Precursor Type [M+H]+
precursor m/z 409.1525
Instrument Bruker maXis Impact
Instrument Type LC-ESI-QTOF
Ionization ESI
Ionization Mode positive
Collision Energy RAMP 23.8-35.7 eV
Retention Time 8.589 min
Splash splash10-0a4u-0192000000-988fbef9dd83defbfbe0
Thumbnail
Submitter Nikolaos Thomaidis, University of Athens
 from MassBank of North America (MoNA)
MoNA ID CCMSLIB00000078338
MS Level MS2
Precursor Type [M+H]
Instrument qTof
Splash splash10-002o-1392000000-3e9bc5dcf61b0f4cae6a
Thumbnail
Submitter GNPS Collaboration, University of California, San Diego
MoNA ID FiehnHILIC000194
MS Level MS2
Instrument Thermo Q Exactive HF
Instrument Type LC-ESI-QFT
Collision Energy HCD (NCE 20-30-40%)
Splash splash10-052u-0091000000-b77e9f75b93751060979
Thumbnail
Submitter Megan Showalter, University of California, Davis

View All 11 General MS
4.3.3.2 GC-MS
GC-MS Spectrum 16864 - GC-MS Ei Predicted by CFMID-EI, energy0

  1 of 2  
NIST Number 247418
Library Main library
Total Peaks 263
m/z Top Peak 297
m/z 2nd Highest 208
m/z 3rd Highest 254
Thumbnail
 from NIST
4.3.3.3 MS-MS
1. MS-MS Spectrum 245253 - 10V Positive Predicted by CFM-ID

4. MS-MS Spectrum 265200 - 10V Negative Predicted by CFM-ID
7. MS-MS Spectrum 441085 - LC-ESI-QTOF positive instrument=Bruker maXis Impact
8. MS-MS Spectrum 450768 - positive instrument=qTof
MS-MS: 1 of 1 (MS-MS Fields)
NIST Number 1163510
Instrument Type IT/ion trap
Collision Energy 0
Spectrum Type MS2
Precursor m/z 409.1525
Total Peaks 46
m/z Top Peak 238
m/z 2nd Highest 294
m/z 3rd Highest 392.1
Thumbnail
 from NIST
5 Related Records
 Download
Chemical Information Ingenuity Pathways Analysis
Chemical Information Side effects of amlodipine - SIDER Side Effect Resource
 from NCBI
5.1 Related Compounds with Annotation
 Download
Medications (2) Literature (8) 3D Structure (1) Bioactivities (85) Patents (485)
Felodipine Amlodipine maleate
 from PubChem
5.2 Related Compounds
Same Tautomer 26 records
Same Connectivity 20 records
Same Stereo 15 records
Same Isotope 3 records
Same Parent, Tautomer 198 records
Same Parent, Connectivity 189 records
Same Parent, Stereo 118 records
Same Parent, Isotope 162 records
Same Parent, Exact 94 records
Mixtures, Components, and

246 records
Neutralized Forms
Similar Compounds 742 records

Similar Conformers 237 records
 from PubChem
5.3 Substances
5.3.1 Related Substances
All 887 records
Same 174 records
Mixture 713 records
 from PubChem
5.3.2 Substances by Category
 Download
 Chemical Vendors (73)
 Curation Efforts (20)
 Governmental Organizations (15)
 Journal Publishers (3)
 NIH Initiatives (19)
 Research and Development (54)

 from PubChem
 Subscription Services (10)
5.4 Entrez Crosslinks
PubMed 188 records
Taxonomy 4 records
OMIM 31 records
Gene 67 records
 from PubChem
6 Chemical Vendors
 Refine/Analyze  Download
Vendor/Supplier Purchasable Chemical PubChem SID
Molepedia M90526504P 252427344
Bide Pharmatech Ltd. BD42079 252072439
AB347494 316537898
abcr GmbH
AB384789 316571287
Boerchem BC203909 196106494
 from PubChem
7 Drug and Medication Information
7.1 Drug Indication

For the treatment of hypertension and chronic stable angina.
 from DrugBank
FDA Label
 from DrugBank
Hypertension
|Chronic stable angina pectoris
|Vasospastic (Prinzmetal's) angina
 from EU Community Register of Medicinal Products
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.
 from LiverTox
7.3 Drug Classes

Cardiovascular Agents
 from LiverTox
7.4 FDA Orange Book
7.4.1 Prescription Drug Products
Prescription Drug Products: 1 of 2 (RX Drug Ingredient)
Drug Ingredient AMLODIPINE BESYLATE
Proprietary Name NORVASC
Applicant PFIZER (Application Number: N019787)
 from FDA Orange Book
Prescription Drug Products: 2 of 2 (RX Drug Ingredient)
Drug Ingredient AMLODIPINE BESYLATE; ATORVASTATIN CALCIUM
Proprietary Name CADUET
Applicant PFIZER (Application Number: N021540. Patent: 6455574)

7.4.2 Discontinued Drug Products
Discontinued Drug Products: 1 of 1 (DISCN Drug Ingredient)
Drug Ingredient AMLODIPINE MALEATE
Proprietary Name AMVAZ
Applicant DR REDDYS LABS INC (Application Number: N021435)
7.5 Drugs at PubMed Health
Drugs at PubMed Health: 1 of 3 (PubMed Health Drug Name)
Drug Name Amlodipine (By mouth)
Treats high blood pressure and angina (chest pain). This medicine is a calcium
Description
channel blocker.
Drug Classes Antianginal, Antihypertensive, Cardiovascular Agent
 from PubMed Health
Drug Name Caduet
Notes See Amlodipine/Atorvastatin (By mouth)
Drug Name Norvasc
Notes See Amlodipine (By mouth)
7.6 Clinical Trials
 Download
1 to 5 of 233 View More
Record ID Title Status Phase
NCT03489317 Gut Microbiomes in Patients With Metabolic Syndrome Recruiting

Record ID Title Status Phase
Not yet
NCT03461003 N-of-1 Trials In Children With Hypertension 4
recruiting
A Study on Molecular Genetics of Drug Responsiveness in Essential

NCT03276598 Completed 4
Hypertension
Intervention for High-normal or Borderline-elevated Blood Pressure in Adults Not yet

NCT03264352 4
With Type 2 Diabetes recruiting
Bioequivalence Trial of Concor AM® vs Bisoprolol and Amlodipine in

NCT03226275 Completed 1
Chinese Subjects
 from ClinicalTrials.gov
7.7 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
 from HSDB
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
 from HSDB
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/
 from HSDB
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/
 from HSDB
In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, Norvasc
is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization
procedure. /Included in US product label/
 from HSDB
VET: In cats and dogs, it is used to treat systematic hypertension (high blood pressure). Amlodipine is considered the
drug of choice by many clinicians for treating hypertension in cats. By comparison, angiotensin-converting enzyme (ACE)
inhibitors are less effective in cats. Amlodipine may improve survival in cats with hypertensive kidney disease. In cats,
addition of a beta blocker to slow heart rate may also be beneficial.
Papich, M.G. Saunders Handbook of Veterinary Drugs Small and Large Animal. 3rd ed. St. Louis, MO: Elsevier Saunders, 2011, p. 34
 from HSDB
7.8 Drug Warning

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
 from HSDB
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.
 from HSDB
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.
 from HSDB
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%.
 from HSDB
Worsening of angina or acute myocardial infarction can occur, particularly in patients with severe obstructive coronary
artery disease, upon initiation of amlodipine therapy or an increase in amlodipine dosage.
 from HSDB
Symptomatic hypotension may occur in patients receiving amlodipine, particularly in individuals with severe aortic
stenosis; however, acute hypotension is unlikely because of the gradual onset of action of the drug.
 from HSDB
Adverse effects reported in 1% or more of patients receiving amlodipine include edema, dizziness, flushing, palpitations,
fatigue, nausea, abdominal pain, and somnolence. Edema, flushing, palpitations, and somnolence may occur more
commonly in women than in men. Edema is dose related and may be less frequent with concomitant use of an
angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist.
 from HSDB
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.
 from HSDB
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and
animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given
during pregnancy; but the potential benefits may outweigh the potential risk./
 from HSDB
Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Efficacy of
amlodipine (2.5-5 mg daily) for the treatment of hypertension has been established in pediatric patients 6-17 years of
age. Safety and efficacy of amlodipine in fixed combination with aliskiren (with or without hydrochlorothiazide),
atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), perindopril, telmisartan, or valsartan (with or
without hydrochlorothiazide) have not been established in children.
 from HSDB
It is not known whether amlodipine is distributed into milk; the manufacturer recommends discontinuance of nursing if
amlodipine is used.
 from HSDB
VET: Use cautiously in animals with poor cardiac reserve and that are prone to hypotensin. Do not use in dehydrate
animals.
 from HSDB
VET: Because of amlodipine's relatively slow onset of action, hypotension and inappetence is usually absent in cats.
Infrequently, cats may develop azotemia, lethargy, hypokalemia, reflex tachycardia, and weight loss.
Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 71
 from HSDB
VET: In dogs, reversible gingival hyperplasia has been reported when amlodipine has been used long term; incidence in
the retrospective study was 8.5%. Gingival hyperplasia could also occur in cats, but is apparently quite rare.
Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 71
 from HSDB
VET: Adverse effects can include hypotension and bradycardia. In dogs, gingival hyperplasia has been observed but
through an unknown mechanism.
 from HSDB
8 Pharmacology and Biochemistry
8.1 Pharmacology
Amlodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class
of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was
widely accepted that DHP CCBs target L-type calcium channels, the major channel in muscle cells that mediate
contraction; however, some studies have indicated that amlodipine also binds to and inhibits N-type calcium channels
(see references in Targets section). Similar to other DHP CCBs, amlodipine binds directly to inactive L-type calcium
channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than
cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the
alpha-1 subunit of the channel gives amlodipine additional arterial selectivity. At therapeutic sub-toxic concentrations,
amlodipine has little effect on cardiac myocytes and conduction cells.
 from DrugBank
Amlodipine is a synthetic dihydropyridine and a calcium channel blocker with antihypertensive and antianginal properties.
Amlodipine inhibits the influx of extracellular calcium ions into myocardial and peripheral vascular smooth muscle cells,
thereby preventing vascular and myocardial contraction. This results in a dilatation of the main coronary and systemic
arteries, decreased myocardial contractility, increased blood flow and oxygen delivery to the myocardial tissue, and
decreased total peripheral resistance. This agent may also modulate multi-drug response (MDR) activity through
inhibition of the p-glycoprotein efflux pump.
 from NCIt
8.2 MeSH Pharmacological Classification
Calcium Channel Blockers

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.
See a list of PubChem compounds matching this category.
 from MeSH
Vasodilator Agents
Drugs used to cause dilation of the blood vessels.
 from MeSH
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.
 from MeSH
8.3 ATC Code

C - Cardiovascular system
C08 - Calcium channel blockers
C08C - Selective calcium channel blockers with mainly vascular effects
C08CA - Dihydropyridine derivatives
C08CA01 - Amlodipine
More information...
 from WHO ATC
8.4 Absorption, Distribution and Excretion
Absorption
Amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations are
reached 6-12 hour following oral administration. Its estimated bioavailability is 64-90%. Absorption is not affected by
food.
 from DrugBank
Route of Elimination
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.
 from DrugBank
/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%.
Abstract: PubMed
Naito T et al; J Hum Lact 31 (2): 301-6 (2015)
 from HSDB
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.
 from HSDB
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.
 from HSDB
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)
 from HSDB
... 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.
Abstract: PubMed
Park JY et al; Int J Clin Pharmacol Ther 44 (12): 641-7 (2006)
 from HSDB
8.5 Metabolism/Metabolites
Metabolism
Hepatic. Metabolized extensively (90%) to inactive metabolites via the cytochrome P450 3A4 isozyme.
 from DrugBank
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.
 from HSDB
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.
Abstract: PubMed
Beresford AP et al; Arzneimittelforschung 39 (2): 201-9 (1989)
 from HSDB
... 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.
Abstract: PubMed
Zhu Y et al; Drug Metab Dispos 42 (2): 245-9 (2014)
 from HSDB
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.
Abstract: PubMed
Suchanova B et al; Eur J Pharm Sci 33 (1): 91-9 (2008)
 from HSDB
8.6 Biological Half-Life

30-50 hours
 from DrugBank
Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours.
 from HSDB
... 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)
 from HSDB
8.7 Mechanism of Action
Amlodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of
calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin.
Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the
phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is
achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of
the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation.
The vasodilatory effects of amlodipine result in an overall decrease in blood pressure. Amlodipine is a long-acting CCB
that may be used to treat mild to moderate essential hypertension and exertion-related angina (chronic stable angina).
Another possible mechanism is that amlodipine inhibits vascular smooth muscle carbonic anhydrase I activity causing
cellular pH increases which may be involved in regulating intracelluar calcium influx through calcium channels.
 from DrugBank
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.
 from HSDB
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)
 from HSDB
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.
Abstract: PubMed
Ziesche R et al; FASEB J 18 (13): 1516-23 (2004)
 from HSDB
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.
Abstract: PubMed
Li XQ et al; Int Immunopharmacol 9 (9): 1032-41 (2009)
 from HSDB
8.8 Human Metabolite Information
8.8.1 Metabolite Description
Description
Amlodipine is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina. As
other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing peripheral
resistance and hence improving blood pressure; in angina it improves blood flow to the myocardium. It was developed
under the direction of Dr. Simon Campbell; A long acting dihydropyridine calcium channel blocker. It is effective in the
treatment of angina pectoris and hypertension; in angina it improves blood flow to the myocardium. Amlodipine (as
besylate, mesylate or maleate) is a long-acting calcium channel blocker used as an anti hypertensive and in the treatment
of angina. Amlodipine is marketed as Norvasc in North America and as Istin in the United Kingdom as well as under
various other names. As other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial
wall, decreasing peripheral resistance and hence improving blood pressure; Amlodipine (as besylate, mesylate or
maleate) is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina.
Amlodipine is marketed as Norvasc in North America and as Istin in the United Kingdom as well as under various other
names. As other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing
peripheral resistance and hence improving blood pressure; in angina it improves blood flow to the myocardium. It was
developed under the direction of Dr. Simon Campbell.
8.8.2 Tissue Locations

Skin
8.8.3 Metabolite Pathways
Amlodipine Action Pathway
9 Use and Manufacturing
9.1 Uses
EU Pharmaceutical Product Classes

Human drug
 from EU Community Register of Medicinal Products
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
 from HSDB
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
 from HSDB
9.3 Formulations/Preparations
Dosage
Route Strength Brand (Manufacturer)
Form
2.5 mg (of Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor,
Oral Tablets
amlodipine) and/or repackager by generic (nonproprietary) name)
2.5 mg (of
Oral Tablets Norvasc (Pfizer)
amlodipine)
5 mg (of Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor,
Oral Tablets
5 mg (of
amlodipine)
10 mg (of Amlodipine Besylate Tablets (Available from one or more manufacturer, distributor,
Oral Tablets
10 mg (of
amlodipine)
 from HSDB
Route of Dosage Strength Brand or Generic Form (Manufacturer)
Administration Form
2.5 mg (of
Amlodipine Besylate and Benazepril Hydrochloride Capsules
amlodipine) with
Oral Capsules (Available from one or more manufacturer, distributor, and/or
Benazepril
repackager by generic (nonproprietary) name)
Hydrochloride 10 mg
2.5 mg (of
amlodipine) with
Oral Capsules Lotrel (Novartis)
Benazepril
Hydrochloride 10 mg
5 mg (of amlodipine) Amlodipine Besylate and Benazepril Hydrochloride Capsules

Oral Capsules with Benazepril (Available from one or more manufacturer, distributor, and/or
Hydrochloride 10 mg repackager by generic (nonproprietary) name)
5 mg (of amlodipine)
Oral Capsules with Benazepril Lotrel (Novartis)
Hydrochloride 10 mg

Hydrochloride 20 mg

Hydrochloride 40 mg
10 mg (of
amlodipine) with
Benazepril
Hydrochloride 20 mg
10 mg (of
amlodipine) with
Benazepril
Hydrochloride 20 mg
10 mg (of
amlodipine) with
Benazepril
Hydrochloride 40 mg
10 mg (of
amlodipine) with
Benazepril
Hydrochloride 40 mg
2.5 mg (of
amlodipine) with
Oral Tablets Prestalia (Symplmed)
Perindopril Arginine
3.5 mg
Oral Tablets 5 mg (of amlodipine) Azor (Daiichi-Sankyo)
with Olmesartan
Medoxomil 20 mg
Oral Tablets with Olmesartan Azor (Daiichi-Sankyo)
Medoxomil 40 mg
Oral Tablets with Perindopril Prestalia (Symplmed)
Arginine 7 mg
10 mg (of
amlodipine) with
Oral Tablets Azor (Daiichi-Sankyo)
Olmesartan
Medoxomil 20 mg
10 mg (of
amlodipine) with
Oral Tablets Azor (Daiichi-Sankyo)
Olmesartan
Medoxomil 40 mg
10 mg (of
amlodipine) with
Oral Tablets Prestalia (Symplmed)
Perindopril Arginine
14 mg
 from HSDB
Route of Dosage
Strength Brand or Generic Form (Manufacturer)
Administration Form
Generic Name: Amlodipine Besylate and Atorvastatin

Tablets, 2.5 mg (of amlodipine) with
Calcium Tablets (Available from one or more
Oral film- Atorvastatin Calcium 10 mg
manufacturer, distributor, and/or repackager by generic
coated (of atorvastatin)
(nonproprietary) name)

Oral film- Atorvastatin Calcium 10 mg Caduet (Pfizer)




Oral Tablets, 5 mg (of amlodipine) with Tekamlo (Novartis)
film- Aliskiren Hemifumarate 150
coated mg (of aliskiren)
5 mg (of amlodipine) with

Tablets,
Aliskiren Hemifumarate 150
Oral film- Amturnide (Novartis)
mg (of aliskiren) and
coated
Hydrochlorothiazide 12.5 mg
Tablets, 5 mg (of amlodipine) with

Oral film- Aliskiren Hemifumarate 300 Tekamlo (Novartis)

Tablets,
coated

Tablets,
coated
Hydrochlorothiazide 25 mg








Oral Tablets, 5 mg (of amlodipine) with Tribenzor (Daiichi Sankyo)

film- Hydrochlorothiazide 12.5 mg
coated
and Olmesartan Medoxomil
20 mg

Tablets,
Oral film- Tribenzor (Daiichi Sankyo)
coated
40 mg
Generic Name: Amlodipine Besylate, Valsartan, and

Hydrochlorothiazide Tablets (Available from one or
Oral film- Hydrochlorothiazide 12.5 mg
more manufacturer, distributor, and/or repackager by
coated and Valsartan 160 mg
generic (nonproprietary) name)

Oral film- Hydrochlorothiazide 12.5 mg Exforge HCT (Novartis)

Tablets,
coated
40 mg

Oral film- Hydrochlorothiazide 25 mg

Oral film- Hydrochlorothiazide 25 mg Exforge HCT (Novartis)
Generic Name: Amlodipine Besylate and Valsartan

Tablets,
5 mg (of amlodipine) with Tablets (Available from one or more manufacturer,
Oral film-
Valsartan 160 mg distributor, and/or repackager by generic
coated
Tablets,
Oral film- Exforge (Novartis)
Valsartan 160 mg
coated
Generic Name: Amlodipine Besylate and Valsartan

Tablets,
5 mg (of amlodipine) with Tablets (Available from one or more manufacturer,
Oral film-
Valsartan 320 mg distributor, and/or repackager by generic
coated
Tablets,
Oral film- Exforge (Novartis)
Valsartan 320 mg
coated



Tablets,
coated
Oral Tablets, 10 mg (of amlodipine) with Amturnide (Novartis)
film- Aliskiren Hemifumarate 300
coated mg (of aliskiren) and









Tablets,
coated
40 mg

Oral film- Hydrochlorothiazide 12.5 mg

Oral film- Hydrochlorothiazide 12.5 mg Exforge HCT (Novartis)

Tablets,
coated
40 mg
Oral Tablets, 10 mg (of amlodipine) with Generic Name: Amlodipine Besylate, Valsartan, and
film- Hydrochlorothiazide 25 mg Hydrochlorothiazide Tablets (Available from one or
coated and Valsartan 160 mg more manufacturer, distributor, and/or repackager by


Oral film- Hydrochlorothiazide 25 mg

Generic Name: Telmisartan and Amlodipine Besylate

Tablets, 5 mg (of amlodipine) with Tablets (Available from one or more manufacturer,
Oral
multilayer Telmisartan 40 mg distributor, and/or repackager by generic

Oral Twynsta (Boehringer Ingelheim)
multilayer Telmisartan 40 mg

Oral


Oral


Oral

 from HSDB
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
 from HSDB
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
 from HSDB
11 Safety and Hazards
11.1 Hazards Identification
11.1.1 GHS Classification
Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 3 companies from 2 notifications to the ECHA C&L Inventory. Each notification
may be associated with multiple companies.
H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

H314 (66.67%): Causes severe skin burns and eye damage [Danger Skin corrosion/irritation]
H318 (100%): Causes serious eye damage [Danger Serious eye damage/eye irritation]
H341 (66.67%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]
H373 (100%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity,
repeated exposure]
H400 (100%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]
H410 (100%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-
term hazard]
H411 (66.67%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]
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.
Precautionary Statement Codes

P201, P202, P260, P264, P270, P273, P280, P281, P301+P310, P301+P330+P331, P303+P361+P353, P304+P340,
P305+P351+P338, P308+P313, P310, P314, P321, P330, P363, P391, P405, and P501
(The corresponding statement to each P-code can be found here.)
View all (4) GHS Classification entries
11.2 Fire Fighting Measures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Amlodipine
besylate/
 from HSDB
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Amlodipine besylate/
 from HSDB
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/
 from HSDB
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.
 from HSDB
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/
 from HSDB
11.3.3 Other Preventative 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/
 from HSDB
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/
 from HSDB
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/
 from HSDB
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/
 from HSDB
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion
of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is
both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the
local ventilation moves the contaminant away from the worker.
 from HSDB
/Wear/ chemically compatible safety glasses or goggles. Protect exposed skin.

United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Amlodipine Besylate; Catalog
Number: 1029501; (Revision Date: March 16, 2006)
 from HSDB
11.4 Handling and Storage
11.4.1 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. /Amlodipine besylate/
 from HSDB
Store bottles at controlled room temperature, 59 deg to 86 deg F (15 deg to 30 deg C) and dispense in tight, light-resistant
containers.
 from HSDB
11.5 Exposure Control and Personal Protection
11.5.1 Protective Equipment and Clothing

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/
 from HSDB
Skin protection: Handle with gloves. /Amlodipine besylate/
 from HSDB
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/
 from HSDB
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/
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11.6 Stability and Reactivity
11.6.1 Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents. /Amlodipine besylate/
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11.7 Regulatory Information
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: http://www.fda.gov/cder/ob/
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12 Toxicity
12.1 Toxicological Information
12.1.1 Heptatoxicity
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.
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12.1.2 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)
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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.
Abstract: PubMed
Yoo HH et al; J Hypertens 34 (1): 156-62 (2016)
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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)
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...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. ...
Abstract: PubMed
Nishio S et al; Hypertens Res 28 (3): 223-7 (2005)
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... Forty-two patients were given atorvastatin 20mg/day and placebo, atorvastatin 20mg/day and amlodipine 10mg/day,
or amlodipine 10mg/day and placebo during each 2-month treatment period of a randomized, single-blind, placebo-
controlled cross-over trial with two 2-month washout periods. Atorvastatin combined with amlodipine or amlodipine
alone significantly reduced blood pressure to a greater extent than atorvastatin alone (all P < 0.001 by ANOVA).
Atorvastatin combined with amlodipine significantly reduced plasma malondialdehyde and improved flow-mediated
dilation to a greater extent than atorvastatin or amlodipine alone (all P < 0.001 by ANOVA). Atorvastatin therapy
significantly increased insulin levels (P = 0.004) and decreased plasma adiponectin levels (P = 0.016) and insulin
sensitivity (determined by QUICKI; P = 0.026) relative to baseline measurements. Amlodipine therapy significantly
decreased insulin levels (P = 0.001) and increased adiponectin levels (P < 0.001) and insulin sensitivity (P = 0.003)
relative to baseline measurements. Atorvastatin combined with amlodipine therapy significantly increased adiponectin
levels (P < 0.001) and insulin sensitivity (P = 0.034) relative to baseline measurements. Effects of all three therapeutic
arms on adiponectin levels and insulin sensitivity were statistically significant (P < 0.001 by ANOVA). Atorvastatin
combined with amlodipine therapy improves endothelial function and increases adiponectin levels and insulin sensitivity
to a greater extent than monotherapy with either drug in hypertensive patients.
Abstract: PubMed
Koh KK et al; Int J Cardiol 146 (3): 319-25 (2011)
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Concomitant administration of sildenafil with amlodipine did not alter systemic exposure to amlodipine; however,
additional reductions in blood pressure are possible with such concomitant use. Patients receiving sildenafil
concomitantly with amlodipine should be monitored for hypotension.
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Concomitant use of tacrolimus and amlodipine may result in increased systemic exposure to tacrolimus. If concomitant
use is required, tacrolimus concentrations should be monitored frequently and tacrolimus dosage adjusted as needed. In
healthy Chinese individuals who expressed the CYP3A5 isoenzyme, concomitant administration of amlodipine with
tacrolimus resulted in a 2.5- to 4-fold increase in tacrolimus exposure compared with tacrolimus alone; this finding was
not observed in individuals who did not express CYP3A5. However, in a renal transplant patient who did not express
CYP3A5, a threefold increase in systemic exposure to tacrolimus was observed following initiation of amlodipine therapy
for posttransplantation hypertension; reduction in tacrolimus dosage was required. Irrespective of CYP3A5 genotype, the
possibility of an interaction between tacrolimus and amlodipine cannot be excluded.
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Concomitant use of cyclosporine and amlodipine may result in increased systemic exposure to cyclosporine.
Concomitant use of amlodipine with cyclosporine in renal allograft recipients resulted in a 40% increase in trough
concentrations of the immunosuppressant. If concomitant use is required, cyclosporine concentrations should be
monitored frequently and cyclosporine dosage adjusted as needed.
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Concomitant administration of amlodipine (multiple 10-mg doses) with simvastatin (80 mg) resulted in a 77% increase in
simvastatin exposure compared with simvastatin alone. In patients receiving amlodipine, simvastatin dosage should not
exceed 20 mg daily.
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The manufacturer states that concomitant administration of grapefruit juice with amlodipine did not alter systemic
exposure to amlodipine. Although there is some evidence from healthy individuals that concomitant administration with
grapefruit juice may increase oral bioavailability of the drug compared with concomitant administration with water, there
currently is no evidence of altered amlodipine pharmacodynamics by concurrent ingestion of grapefruit juice in healthy
individuals. Concomitant oral administration of other 1,4-dihydropyridine-derivative calcium-channel blocking agents (e.g.,
felodipine, nifedipine, nisoldipine) with grapefruit juice has resulted in potentially clinically important increases in the
hemodynamic effects of these drugs.
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Concomitant use of diltiazem hydrochloride (180 mg daily) with amlodipine (5 mg) in geriatric patients with hypertension
resulted in a 60% increase in amlodipine exposure.
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Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine
for treating senile hypertension in clinic. The aim of this study was to study the pharmacokinetics of amlodipine after oral
administration of amlodipine and GLT and to investigate the potential for pharmacokinetic herb-drug interactions
between GLT and amlodipine in rats. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method
was developed for quantification of amlodipine in rat plasma. The accuracy, precision, linearity, selectivity and recovery
were all within an acceptable range. Male Sprague-Dawley rats were randomly assigned to two groups: amlodipine group
and amlodipine + GLT group. Plasma concentrations of amlodipine were determined at the designated time points after
oral administration by using the developed LC-MS/MS method, and the main pharmacokinetic parameters were
calculated and compared. As ginkgolides A, ginkgolides B, bilobalide, quercetin and kaempferol were the main
components of GLT, the effects of these ingredients in GLT on metabolism of amlodipine were further investigated in rat
liver microsomes. The pharmacokinetic parameters, maximum plasma concentration (C max), time to reach C max (T
max), area under the concentration-time curve (AUC), area under the first moment plasma concentration-time curve
(AUMC) and elimination half-life (t 1/2), of amlodipine were significantly increased in amlodipine + GLT group, which
suggested that GLT may influence the pharmacokinetic behavior after oral co-administration with amlodipine. Amlodipine
is metabolized by cytochrome P450 (CYP) 3A4, so it was speculated that GLT may change the pharmacokinetic
parameters of amlodipine through modulating the metabolism of CYP3A4 enzymes. When ginkgolides B, bilobalide, or
quercetin and amlodipine were co-incubated in the rat liver microsomes, the metabolic rate of amlodipine was prolonged
to 533.1, 216.1 and 407.6 min, respectively, from 73.7 min. These results suggested that these components in GLT inhibit
the metabolism of amlodipine. So it can be speculated that the herb-drug interactions between GLT and amlodipine
resulted from inhibiting the metabolism of amlodipine by GLT when they were co-administered.[Wang R et al; Eur J Drug
Metab Pharmacokinet. 2015 Dec 9.
Abstract: PubMed
Epub ahead of print]
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12.1.3 Toxicity Summary
Toxicity
Gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and
probably prolonged systemic hypotension up to an including shock with fatal outcome have been reported.
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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.
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12.1.4 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)
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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)
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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.
Abstract: PubMed
Azendour H et al; J Emerg Med 38 (1): 33-5 (2010)
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/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.
Abstract: PubMed
Wilffert B et al; J Clin Pharm Ther 32 (6): 655-7 (2007)
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If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure
measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the
extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative
measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and
urine output. As Norvasc is highly protein bound, hemodialysis is not likely to be of benefit.
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Emergency and supportive measures: Maintain on open airway and assist ventilation if necessary. Treat coma,
hypotension, and bradyarrhythmias if they occur. ... Atropine and cardiac pacing, although having variable success, can be
considered for bradyarrhythmias that are contributing to hypotension. Monitor the vital signs and ECG for at least 6 hours
after alleged ingestion of immediate-released compounds. Sustained-release products ... require a longer observation
period (... 18 hours). Admit symptomatic patients for at least 24 hours. /Calcium channel antagonists/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 155
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Specific drugs and antidotes: 1. Calcium reverses the depression of cardiac contractility in some patients, but it does not
affect sinus node depression or peripheral vasodilation and has variable effects on the AV nodal conduction. ... Calcium
chloride would be given only via a central line or secure peripheral IV line owing to the potential for skin necrosis. 2.
Hyperinsulinemia/euglycemia (HIE) therapy is effective in animal models of severe intoxication and has been successful
in multiple human case reports. The putative mechanism is correction of calcium antagonist-induced hypoinsulinemia,
leading to improved cell carbohydrate metabolism, which in turn increases myocardial contractility. Like calcium, HIE
treatment is not likely to reverse calcium antagonist-induced vasodilation, conduction block, or bradycardia. ... 3.
Intravenous lipid emulsion (ILE) therapy has shown promise in recent animal studies and a few case reports of severe
verapamil poisoning. ... 4. Epinephrine has both alpha-adrenergic and beta-adrenergic effects and may relieve
hypotension and bradycardia. ... 5. Glucagon is reported to increase blood pressure in patients with refractory
hypotension and may also help with bradyarrhythmias. ... /Calcium channel antagonists/
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Decontamination factor: Administer activated charcoal orally if conditions are appropriate. For large ingestions of a
sustained-release preparation, consider whole-bowl irrigation in addition to repeated doses of charcoal. /Calcium channel
antagonists/
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Enhanced elimination: Owing to extensive protein binding and large volumes of distribution, dialysis and hemoperfusion
are not effective. /Calcium channel antagonists/
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/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start
artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained.
Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If
vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open
airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention.
/Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier
Mosby, St. Louis, MO 2007, p. 160
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/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if
necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by
nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and
treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with
water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse
mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and
does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Mosby, St. Louis, MO 2007, p. 160
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/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is
unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques
with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering
a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary
... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's
(LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch
for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist
eye irrigation ... . /Poisons A and B/
Mosby, St. Louis, MO 2007, p. 160-1
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12.1.5 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.
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/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.
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/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)] Full text: PMC4982473
Abstract: PubMed
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/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)
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/CASE REPORTS/ ... A 42-year-old woman with a history of hypertension reported ingesting 50-100 mg amlodipine
besylate and at least 40 ounces of beer in a suicide attempt. The patient's symptoms were mild; BP ranged from 79/50 to
113/76 mm Hg and HR from 92 to 129 beats/min (sinus tachycardia). Laboratory studies revealed normoglycemia, mild
metabolic acidosis, mild hypocalcemia, blood ethanol concentration of 263 mmol/L, and a serum amlodipine
concentration of 88 ng/mL (normal 3-11) 2.5 hours after ingestion. Therapy included activated charcoal, whole bowel
irrigation, and intravenous NaCl 0.9%. After receiving 1.5 L of NaCl 0.9%, the patient developed signs of mild pulmonary
edema that resolved over several hours without intervention. A serum amlodipine concentration obtained 35 hours later
was 79 mg/mL. The patient was discharged on day 2 in good condition. ...
Stanek EJ et al; AnnPharmacother 31(7-8): 853-856 (1997)
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/CASE REPORTS/ A 14-year-old boy was admitted for gingival swelling. He had received a renal transplant for focal
segmental glomerulosclerosis in 2005. He also had a history of hypertension, which he had been treating with oral
amlodipine (10 mg twice daily) for the past 3 years. His mother said that he had been suffering from increasing gum
swelling for 2 years. There was no history of any other prescription drug use during this time. Examination of the oral
cavity revealed substantial diffuse gingival hypertrophy of both the upper and lower gums. The hypertrophic gingiva were
painless, and there was no sign of inflammation or ulceration. He brushed his teeth regularly and his oral hygiene was
normal. The rest of the physical examination findings and laboratory test results were normal. After excluding other
potential causes, /investigators/ considered the diagnosis of amlodipine-induced massive gingival hypertrophy. ... An
angiotensin receptor blocker /was substituted/ for the amlodipine, and within 6 months the gingival hypertrophy had
regressed completely.[Sucu M et al; Can Fam Physician 57 (4): 436-7 (2011)] Full text: PMC3076474
Abstract: PubMed
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/CASE REPORTS/ ... A 69-year-old white man presented with a diffuse conjunctival mass on his left eye. Examination
revealed extensive bulbar conjunctival dependent chemosis of his left eye without injection, pruritus, discharge, or pain.
Bipedal pitting edema was found. History revealed that the features were noted 3 months after starting amlodipine
besylate (Norvasc) for essential hypertension. Evaluation was unrevealing for allergic or contact irritants and systemic
conditions, and the findings were attributed to the previously described side effects of the calcium channel blocker
amlodipine besylate with resolution 6 months after cessation. ...
Abstract: PubMed
Say EA et al; Cornea 30 (5): 604-7 (2011)
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/CASE REPORTS/ ... A 79-year-old African American man with stage 4 chronic kidney disease and coronary artery disease
was admitted with acute on chronic renal failure secondary to volume depletion from diuretics. The patient's home
medication on presentation included aspirin, carvedilol, furosemide, simvastatin, spironolactone, and valsartan. His
admission blood pressure was 139/58 mm Hg, and serum electrolytes were normal except for increased potassium (6.9
mEq/L; normal = 3.5-5.0 mEq/L), blood urea nitrogen (77 mg/dL; normal = 8-20 mg/dL), and creatinine (4.0 mg/dL;
normal = 0.5-1.5 mg/dL). On admission, spironolactone and valsartan were withheld. On days 2 and 3, the patient's
systolic blood pressure increased to the 160 to 180 mm Hg range and treatment with amlodipine 2.5 mg daily was begun.
On day 4, his blood pressure remained elevated and amlodipine was increased to 10 mg daily. On day 5, the patient
developed involuntary, repetitive jerking of both his upper and lower extremities, consistent with myoclonus. Serum
potassium at that time remained slightly elevated (5.3 mEq/L), but blood urea nitrogen (39 mg/dL) and creatinine (2.3
mg/dL) had returned to the patient's baseline levels. Amlodipine was withheld secondary to literature reports of calcium
channel blocker-induced myoclonus. Within 24 hours of discontinuing the amlodipine and no other intervention, the
patient's myoclonic jerking resolved. He continued to have problems with hypertension, and treatment with clonidine 0.1
mg twice per day was added. On day 8, with a blood pressure of 131/56 mm Hg and potassium (5.3 mEq/L) and
creatinine (2.2 mg/dL) levels remaining at baseline, the patient was then discharged to a skilled nursing home without
any further recurrence of myoclonus. Our patient exhibited signs and symptoms consistent with myoclonus, as previously
reported with other calcium channel blockers. Although he was receiving carvedilol, which also has been reported to
cause myoclonus, we believe that the myoclonus experienced by this patient was secondary to amlodipine therapy on the
basis of the temporal association of administration, the response to increasing dosage, and both a Naranjo score of 7
(probable) and "probable likely" by the World Health Organization causality scale. ...
Abstract: PubMed
Wallace EL et al; Am J Med 122 (4): e7 (2009)
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/CASE REPORTS/ Drug-induced gingival overgrowth occurs in genetically susceptibIe individuals as a side effect of
various drugs. There is a gross disfiguring enlargement of gingiva mostly in the anterior region leading to difficulty in
mastication, speech and maintenance of oral hygiene. In this case report, amlodipine-induced gingival enlargement and
its management are discussed. Drug substituion, appropriate non-surgical and surgical treatment along with excellent
plaque control lead to the regression and prevention of recurrence of drug-induced gingival overgrowth.
Abstract: PubMed
Banthia R et al; J Mich Dent Assoc 94 (9): 48-51 (2012)
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/CASE REPORTS/ ... A 50-year-old female experienced angioedema during hospitalization for a right thalamic
hemorrhagic stroke. She had no past history of angioedema and all of her medications were assessed for risk of
angioedema. After careful evaluation, case reports linking calcium channel blockers (CCBs) and angioedema led to
further examination of amlodipine as a cause. Amlodipine therapy had been initiated 24 hours prior to the development of
angioedema, which then resolved 72 hours after discontinuation of the drug. In total, the patient experienced
oropharyngeal swelling for 10 days. In determining a cause for the patient's angioedema /investigators/ eliminated
genetic, allergic, physically induced, thyroid autoimmune disease-associated, and medication-induced causes. The onset
and resolution of symptoms in /this/ patient were very similar to those seen in other case reports. Application of the
Naranjo probability scale found a probable link between amlodipine and angioedema. ...
Abstract: PubMed
Southward J et al; Ann Pharmacother 43 (4): 772-6 (2009)
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/CASE REPORTS/ ... This study describes a girl aged 2 years 9 months with end-stage renal disease resulting from
crescent glomerulonephritis and severe interstitial nephritis who developed leukocytosis with a predominance of
lymphocytes in the dialysate effluent, and in whom the effluent cell count normalized 1 week after discontinuation of
amlodipine besylate therapy. Rechallenge confirmed that amlodipine was the offending agent causing effluent
leukocytosis.
Abstract: PubMed
Lee F, Yu MC; Am J Kidney Dis 53 (3): e1-3 (2009)
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/CASE REPORTS/ ... A previously well and normotensive 6-year-old girl presented with a generalized vasculitis of
unknown origin and severe hypertension. Large vessels predominantly affecting the neck, chest, and abdomen were
found to be involved, resulting in abnormal arterial circulation and significant blood pressure differences between the
upper and lower extremities. Multiple antihypertensive agents were initially required to control blood pressure. She was
stabilized and discharged on amlodipine 10 mg each evening, atenolol 50 mg/day, and warfarin. Three days later she was
noted to have facial and bilateral upper extremity pitting edema. Laboratory and radiologic assessments for possible
etiologies were negative. Discontinuation of amlodipine resulted in resolution of edema. ... According to the Naranjo
probability scale, amlodipine was a probable cause of bilateral upper extremity edema in this child. ...
Abstract: PubMed
Ganeshalingham A, Wong W; Ann Pharmacother 41 (9): 1536-8 (2007)
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/CASE REPORTS/ /Investigators/ report the case of attempted suicide with amlodipine, chlorthalidone and mefenamic
acid and subsequent medical intensive care measures which resulted in total recovery of a 42-year-old male. After
admission to the medical intensive care unit the intoxicated patient was deeply hypotensive and needed fluid
replacement, dobutamine and norepinephrine. Additionally insulin and calcium gluconate were given. Since hypotension
persisted and the patient developed oliguria, terlipressin was applied and finally showed an effect on blood pressure and
on urinary output. A volume overload of 7 L in the first 24 hr resulted in a pulmonary edema. The patient was started on
non-invasive ventilation with continuous positive airway pressure (CPAP) and frusemide was added to the therapy with
good success. Quantitative determination of amlodipine in plasma samples was performed by liquid chromatography-
tandem mass spectrometry (LC-MS/MS). The highest amlodipine concentrations was measured in the plasma sample
collected approximately 8 hr after ingestion of the drug, and was 393 ug/L. Four days later, it was possible to stop the
treatment with catecholamines, at that time the amlodipine plasma concentration had declined to 132 ug/L, still tenfold
higher than therapeutic (5-18 ug/L). Elimination half-life of amlodipine is approximately 55 hr. After 6 days in the intensive
care unit the patient was transferred to psychiatric treatment.
Abstract: PubMed
Vogt S et al; Forensic Sci Int 161 (2-3): 216-20 (2006)
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/CASE REPORTS/ A case of acute poisoning with amlodipine with deep hypotension, transient oliguria and clinical signs
of acute heart failure was described. A woman of 23 years swallowed intentionally 60 tablets of amlodipine (600 mg).
After eleven hours of ingestion she was admitted to Warsaw Poison Control Centre. She was in severe clinical condition;
tachycardia and deep hypotension were the prominent signs of poisoning. There was no CNS depression. Intensive
treatment with i.v. catecholamines (dopamine, norepinephrine), crystalloids (with continuous control of central venous
pressure), and i.v. calcium salts (with control of plasma calcium concentration) was started immediately. The patient did
not improve but got worse. Acute heart failure developed, especially of left ventricle, so i.v. crystalloids were stopped and
dubutamin, morphine, nitroglycerin and glucagon were introduced. Because of oliguria and insufficient effect of high
doses of furosemide four-hours hemodiafiltration was set in. The patient's condition slowly improved after third and
fourth day of hospitalization. The systolic blood pressure rose, heart work was really better and on sixth day--the
stabilization of diastolic blood pressure was definitely achieved. The patient was discharge in good condition with heart
ejection fraction of 65% measured echocardiographically.
Abstract: PubMed
Feldman R, Glinska-Serwin M; Pol Arch Med Wewn 105 (6): 495-9 (2001)
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/CASE REPORTS/ Two fatal overdoses of the calcium channel blocker amlodipine are described. Postmortem samples
were screened for volatiles and therapeutic and abused drugs. Amlodipine was measured by liquid chromatography-
atmospheric pressure photoionization-mass spectrometry. The heart blood amlodipine concentrations for the two cases
were 2.4 and 0.95 mg/L, and amlodipine was quantified in all other tissues. In the first case, venlafaxine and
norvenlafaxine were also found, and the angiotensin receptor antagonist olmesartan was tentatively identified. The
concentrations of amlodipine are compared with previously reported fatal and nonfatal overdoses. The medical
examiners ruled in both cases that the manner of death was suicide and the causes of death were mixed drug
intoxication and amlodipine intoxication.
Abstract: PubMed
Sklerov JH et al; J Anal Toxicol 30 (5): 346-51 (2006)
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/CASE REPORTS/ ... A 77-year-old woman with essential hypertension who had not been treated with any other drug was
prescribed amlodipine 10 mg/day to control her blood pressure. She developed anasarca edema soon after amlodipine
treatment was initiated. Laboratory test results for possible etiologies were negative. Discontinuation of amlodipine
resulted in dramatic improvement. ... Pretibial edema is the most common adverse effect of amlodipine. Periocular and
perioral edema have occurred less frequently, but anasarca edema has not emerged as a problem. An objective causality
assessment revealed amlodipine to be a probable cause of anasarca edema. ...
Abstract: PubMed
Sener D et al; Ann Pharmacother 39 (4): 761-3 (2005)
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/CASE REPORTS/ Drug-induced thrombocytopenia is a serious, but rare, side-effect of treatment with a number of drugs.
In this report, /the authors/ investigate the suspicion that amlodipine, a calcium-channel blocker, was responsible for
immune thrombocytopenia in a 79-year-old patient. /This/ patient experienced two attacks of thrombocytopenic purpura
after 10 years of treatment with amlodipine. Antibodies to platelets were tested by standard methods. Initially, the platelet
count increased owing to treatment with prednisolone and intravenous immunoglobulin G, but decreased shortly after
discontinuation of this treatment. The patient's serum was found to contain amlodipine-dependent antibodies to
platelets, and he recovered after stopping the drug. Amlodipine can induce immune thrombocytopenia, which may
strongly resemble autoimmune thrombocytopenia.
Abstract: PubMed
Garbe E et al; Vox Sang 86 (1): 75-6 (2004)
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/CASE REPORTS/ ... A 64-year-old Caucasian female developed a granuloma annulare-like reaction 13 days after starting
amlodipine and cleared within 3 months after drug cessation. The eruption consisted of multiple erythematous pruritic
papules, distributed symmetrically over the lateral aspects of the legs and thighs, as well as on both palms. Histology
showed focal collagen degeneration and significant interstitial histiocytic dermal infiltrate suggestive of granuloma
annulare. ...
Abstract: PubMed
Lim AC et al; Australas J Dermatol 43 (1): 24-7 (2002)
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/CASE REPORTS/ ... A 52-year-old white woman with asthma and newly diagnosed hypertension was initiated on
zafirlukast therapy for asthma and amlodipine therapy for hypertension. Two months later, the patient reported severe,
generalized muscle and joint pain, muscle stiffness, and weakness. The zafirlukast was discontinued without resolution
of symptoms. Laboratory tests revealed an elevated C-reactive protein. The amlodipine dosage was increased. Her
symptoms persisted and further laboratory tests revealed a positive anti-nuclear antibody screen, and negative single-
and double-stranded DNA antibody tests. After another amlodipine dosage increase, the patient experienced a sudden
onset of left-sided facial numbness, facial weakness, and a severe headache.The patient was admitted to rule out a
possible cerebrovascular event or a metabolic neurologic process. Magnetic resonance imaging showed no
abnormalities. The patient discontinued the amlodipine and reported complete resolution of the neurologic symptoms
after 4 days. One month later, zafirlukast was reinitiated without a return of symptoms. Amlodipine was not initially
suspected as a cause of these symptoms because these effects are not commonly associated with amlodipine therapy.
However, due to the temporal relationship and progression of symptoms with increasing amlodipine dosage, drug-related
causes were eventually explored. Review of the medical literature suggests myalgias and arthralgias may be adverse
effects common to dihydropyridine calcium-channel antagonists.
Abstract: PubMed
Phillips BB, Muller BA; Ann Pharmacother 32 (11): 1165-7 (1998)
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/CASE REPORTS/ ... A 71-year-old diabetic and hypertensive woman had been noted to have worsened renal dysfunction
and hyperkalemia attributed to enalapril, thus a trial of amlodipine was begun. On day 12 of amlodipine therapy, the
patient developed a pruritic maculopapular rash on her hands for which she sought medical attention. On day 16, she
presented again to the emergency department now with hives and small blisters involving the trunk and arms with about
25% /total body surface area (TBSA)/ involvement warranting transfer to a regional burn treatment center. The rash
progressed after admission to 48.5% TBSA and included conjunctival sloughing. The patient's hospital course was
uneventful, and she was discharged after 8 days. Drug-induced dermatotoxicity presenting as toxic epidermal necrolysis
is often caused by antibiotics and antiepileptic medications; however, calcium channel blockers are an uncommon cause.
The Naranjo assessment yielded a score of 5, and the SCORTEN was 4 with a predicted mortality of 58%. ...
Abstract: PubMed
Baetz BE et al; J Burn Care Res 32 (5): e158-60 (2011)
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/CASE REPORTS/ A 59-year-old male patient was diagnosed as having essential hypertension and was prescribed
amlodipine 2.5 mg 6 years ago; this was increased to 5 mg 2 years ago. The patient is an alcoholic. Physical and
laboratory examination was essentially normal. He had no other concurrent illness or signs of vitamin deficiency. About a
month ago he developed loss of taste sensation and numbness in the anterior two-thirds of the tongue. It was sudden in
onset. One week later the patient ran out of amlodipine supply and did not refill it. At the time he reported return of taste
sensation. After 10 days he started taking amlodipine again, following which he had loss of taste sensation. After this he
consulted the physician and was told that this medication was probably the cause of his loss of taste. ... A large
postmarketing surveillance did not reveal any taste loss with the calcium channel blockers. The causal relationship in this
case is strengthened by the de-challenge and re-challenge which the patient had inadvertently done himself. The only
inexplicable factor is the delay in onset of dysgeusia. ...[Sadasivam B, Jhaj R; Br J Clin Pharmacol 63 (2): 253 (2007)] Full
text: PMC2000565
Abstract: PubMed
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/CASE REPORTS/ ... A 34-year-old patient was admitted for worsening gastrointestinal graft versus host disease 100
days after an allogeneic stem cell transplant and treated with high-dose systemic steroids. Amlodipine was started for
steroid-induced hypertension; 11 days after its initiation, alanine aminotransferase and aspartate aminotransferase
peaked at 630 and 421 IU/L, respectively. Total bilirubin and alkaline phosphatase remained normal. A liver biopsy
interpreted the liver injury as being possibly drug induced. Amlodipine, the most recently added medication, was
discontinued, and transaminases trended down to normal within 2 weeks. Allogeneic stem cell transplant patients are
often prescribed many medications that carry the risk of hepatotoxicity. Amlodipine, ondansetron, and tacrolimus all have
literature support for hepatotoxicity. Amlodipine, however, was the only agent for which initiation and discontinuation
followed the acute rise and fall of liver transaminases. An objective causality assessment for liver toxicity, the RUCAM,
revealed that the elevation in transaminases was "possible" drug toxicity caused by amlodipine. The package insert and
other case reports of amlodipine hepatotoxicity suggest that it can occur both in the acute and chronic setting, and the
injury is characterized as either cholestatic or hepatocellular. ...
Abstract: PubMed
Hammerstrom AE; Ann Pharmacother 49 (1): 135-9 (2015)
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/CASE REPORTS/ /The purpose of this study was/ to assess the fetal outcome of three hypertensive women exposed to
amlodipine 5 mg/day, in the first trimester of pregnancy. CASE 1: The patient was treated with amlodipine until 7 weeks of
gestation. She was also exposed to levosulpiride, aluminum hydroxide gel, magnesium carbonate, and Ginkgo biloba. At
38(+3) weeks of pregnancy, she delivered a 3750 g healthy female baby, and restarted taking amlodipine, 5 mg/day, while
exclusively breastfeeding her daughter. At three months of age, the infant was healthy. CASE 2: The patient was treated
with amlodipine from 2(+2) to 3(+4) weeks of pregnancy. Her treatment was modified to atenolol until the week 6(+4
weeks), when she declined any antihypertensive treatment. At 39(+4) weeks of pregnancy, the patient delivered a 2600 g
baby. At 20 months old, the baby presented with intellectual delay and weakness in the left arm and hand grasp. These
neurological alterations were not attributed to her exposure to amlodipine early in utero. CASE 3: The patient was treated
with amlodipine from 7(+6) to 12 weeks of pregnancy. She was also taking sucralfate and lorazepam. At 12 weeks of
amenorrhea, ultrasound revealed a 15.3 mm, single fetal pole in the gestational sac without cardiac activity. She
underwent dilatation and evacuation of a dead embryo.
Abstract: PubMed
Ahn HK et al; Hypertens Pregnancy 26 (2): 179-87 (2007)
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/EPIDEMIOLOGY STUDIES/ Drug-induced gingival overgrowth (DIGO) is one of the unwanted side effects of amlodipine
therapy, but the pathogenesis still remains unclear. Apoptosis, which plays a ubiquitous role in tissue homeostasis,
including gingiva, may be involved in the development of gingival enlargement. /The purpose of this research was/: (i) To
study the distribution of Bcl-2 in healthy and overgrown gingival tissues. (ii) To compare and correlate the Bcl-2
expression in gingival samples from subjects on amlodipine therapy to the findings in healthy controls. A total of 25
subjects were recruited for the study - 15 hypertensive patients and 10 systemically healthy subjects. Both the groups
were analyzed for Bcl-2 expression using immunohistochemistry. Few of the control specimens showed weak positivity
to Bcl-2 antibody, with the distribution limited to the basal cell layers alone, whereas 10 hyperplastic specimens
expressed Bcl-2 and, unlike the control group, the distribution pattern was seen in both basal and suprabasal layers. The
results indicate that the pathogenesis of amlodipine-induced gingival overgrowth might involve inhibition of apoptosis,
especially with morphogenesis of hyperplastic gingival epithelia.
Abstract: PubMed
Arunachalam LT, Rao S; Indian J Dent Res 24 (2): 255-60 (2013)
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/SURVEILLANCE/ The purposes of this study were to describe amlodipine poisoning in children and to determine whether
a dose-response relationship could be detected in this population using standardized call data from United States (US)
poison centers. 1251 amlodipine-only ingestions in children < 6 years of age were reviewed. Cases with doses coded as
"Exact" or "Estimated" and with dose, age, and medical outcome were analyzed (n = 678). Ingestions reported as a "taste
or lick" (n = 53) were included as a dose of 1/10 of the dosage form involved. A clinically important response was defined
as bradycardia, hypotension, dysrhythmia, conduction disturbance, or hyperglycemia. The risk of such responses was
examined over four dosage intervals (< 2.5 mg, 2.5-5 mg, 5.1-10 mg, and > 10 mg). The median estimated dose ingested
was 5 mg (range 0.25-200 mg). Clinically important responses developed in 27 patients (3.98%), and the prevalence of
such response significantly increased from 0% for the lowest to 11.1% for the highest dose interval (p = 0.001). The
smallest dose to produce a clinically important response was 2.5 mg (0.15 mg/kg). 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. The National Poison Data System might provide useful insights
regarding dose-response.
Abstract: PubMed
Benson BE et al; J Emerg Med 39 (2): 186-93 (2010)
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/OTHER TOXICITY INFORMATION/ Recent studies have questioned the safety of calcium antagonists in general, and
short-acting dihydropyridine derivatives in particular. Reasons include excessive catecholamine stimulation after stress.
We therefore wanted to assess whether amlodipine, a second generation dihydropyridine with a prolonged plasma half-
life, would show a more favorable hemodynamic and biochemical profile after strenuous exercise. For this purpose, we
studied 9 healthy volunteers in a double-blind, randomized, placebo-controlled trial. After 10 days of amlodipine, 5 mg
orally daily or placebo therapy, volunteers performed a treadmill effort test; the sequence was repeated after a 2-week
washout period. Amlodipine caused a significant increase in mean resting heart rate (HR) (from 65 +/- 3 to 70 +/- 3
beats/min, p < 0.05), without changing systolic or diastolic blood pressure (SBP, DBP). Post-exercise hemodynamic
responses were similar while on amlodipine or placebo therapy. Amlodipine did not alter the normal profile of resting or
exercise-induced metabolic [plasma glucose, serum K+, serum free fatty acid (FFA)] and hormonal [plasma cortisol,
growth hormone, prolactin, insulin, epinephrine (EPI) and norepinephrine (NE)] responses--although plasma EPI
concentrations dropped significantly lower (p < 0.05) at 5 min and 15 min post-exercise while on the calcium antagonist.
We conclude that amlodipine has a largely neutral effect on the physiological profile after brisk exercise in healthy young
subjects and that this may prove to be a useful property for a vasodilator drug.
Stankovis S et al; Cardiovasc Drugs Ther 13(6): p.513-517 (1999)
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12.1.6 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.
Abstract: PubMed
Yoshii T et al; Hypertens Res 29 (6): 457-66 (2006)
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/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.
Abstract: PubMed
Krenek P et al; J Hypertens 22 (4): 827-35 (2004)
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/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.
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No evidence of teratogenicity or other embryo/fetal
toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg
amlodipine/kg/day (respectively, 8 times 2 and 23 times 2 the maximum recommended human dose of 10 mg on a
mg/sq m basis) during their respective periods of major organogenesis. However, litter size was significantly decreased
(by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving
amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating
and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats
at this dose.
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ There was no effect on the fertility of rats treated
orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg
amlodipine/kg/day (8 times the maximum recommended human dose of 10 mg/day on a mg/sq m basis).
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Thirty male rats were divided into two groups A and
B each containing 15 rats. Group A rats were given distilled water (vehicle) whereas group B rats were given amlodipine
by oral gavage for 50 days. After 50 days, amlodipine/distilled water was withdrawn. The rats were left for recovery to
take place for another 50 days of drug withdrawal period. Testes were removed in all the rats and sectioned. The sections
were stained with hematoxylin and eosin and examined microscopically. ... Fifty days after drug withdrawal, there were
statistically insignificant differences in mean tubular diameter and height of germinal epithelium between amlodipine
treated and vehicle treated groups. Spermatogenesis in amlodipine treated rats does not differ significantly from
spermatogenesis in vehicle treated rats after 50 days of drug withdrawal period.
Abstract: PubMed
Latif R et al; J Ayub Med Coll Abbottabad 21 (1): 25-7 (2009)
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/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The purpose of the present study was to investigate
whether treatment of male rats with the calcium antagonist amlodipine, used in the treatment of hypertension and
angina, interferes with the reproductive function of male rats. Amlodipine treatment (0.04 mg amlodipine
besylate/rat/day for 30 days) decreased plasma follicle-stimulating hormone and testosterone but not luteinizing
hormone or prolactin concentrations (measured by double-antibody radioimmuno-assay). A significant reduction (23%)
was observed in sperm density (sperm suspension collected from the cauda epididymidis) as well as in the amount of
mature spermatids (14%) and Sertoli cells (9%) counted in seminiferous tubule cross-sections (400 x magnification). The
results reveal the deleterious effects of subacute amlodipine treatment on the reproductive function of male rats.
Abstract: PubMed
Almeida SA et al; Exp Toxicol Pathol 52(4): 353-356 (2000)
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/GENOTOXICITY/ Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the
gene or chromosome level.
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ The effects of long-acting calcium channel blockers on pressure overload-induced
cardiac hypertrophy have been little studied in experimental animals and the underlying mechanisms are not fully
understood. /Investigators/ previously reported that cardiomyocyte hypertrophy could be induced via phosphorylation of
the epidermal growth factor receptor (EGFR). In this study, /the authors/ investigated whether amlodipine attenuates
cardiac hypertrophy by inhibiting EGFR phosphorylation. /Investigators/ found that amlodipine dose-dependently
inhibited epinephrine-induced protein synthesis and EGFR phosphorylation in cultured neonatal rat cardiomyocytes.
/This/ in vivo study revealed that amlodipine could ameliorate myocardial hypertrophy induced by transverse aortic
constriction (TAC) in C57/B6 mice. One week after TAC, amlodipine treatment (3 mg/kg/day) significantly reduced the
heart-to-body weight ratio (6.04 +/- 0.16 mg/g vs. 6.90 +/- 0.45 mg/g in untreated TAC mice, P < 0.01). These results
indicate that amlodipine ameliorates cardiomyocyte hypertrophy via inhibition of EGFR phosphorylation.
Abstract: PubMed
Liao Y et al; Biochem Biophys Res Commun 327 (4): 1083-7 (2005)
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12.1.7 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.
 from HSDB
12.1.8 Protein Binding

97.5%
 from DrugBank
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 deg 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)
 from HSDB
12.2.2 Artificial 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
 from HSDB
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 deg
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: http://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:
http://echa.europa.eu/
 from HSDB
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: http://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: http://echa.europa.eu/
 from HSDB
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 deg 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: http://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)
 from HSDB
12.2.4 Biodegredation
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:
http://echa.europa.eu/
 from HSDB
12.2.5 Abiotic Degredation

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: http://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/
 from HSDB
12.2.6 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: http://www2.epa.gov/tsca-screening-tools (3) Franke C et al; Chemosphere 29: 1501-14 (1994)
 from HSDB
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: http://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)
 from HSDB
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: http://www2.epa.gov/tsca-screening-tools
 from HSDB
12.2.9 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)
 from HSDB
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)
 from HSDB
13 Literature
13.1 Depositor Provided PubMed Citations
LOADING... PLEASE WAIT...
 from PubChem
13.2 NLM Curated PubMed Citations
 from PubChem
13.3 Synthesis References

Kim, Seok-Chan; Choi, Kwan-Min; Cheong, Chan-Seong. Synthesis of amlodipine using aza Diels-Alder reaction. Bulletin of
the Korean Chemical Society (2002), 23(1), 143-144.
13.4 General References
General Reference
Nayler WG, Gu XH: The unique binding properties of amlodipine: a long-acting calcium antagonist. J Hum Hypertens.
1991 Aug;5 Suppl 1:55-9.
Abstract: PubMed
 from DrugBank
General Reference
van Zwieten PA: Amlodipine: an overview of its pharmacodynamic and pharmacokinetic properties. Clin Cardiol. 1994
Sep;17(9 Suppl 3):III3-6.
Abstract: PubMed
 from DrugBank
13.5 Metabolite References
 Download
1 to 2 of 2
PMID Reference
Iabichella ML, Dell'Omo G, Melillo E, Pedrinelli R: Calcium channel blockers blunt postural cutaneous
9052891
vasoconstriction in hypertensive patients. Hypertension. 1997 Mar;29(3):751-6.
Pedrinelli R, Dell'Omo G, Nuti M, Menegato A, Balbarini A, Mariani M: Heterogeneous effect of calcium

14508205 antagonists on leg oedema: a comparison of amlodipine versus lercanidipine in hypertensive patients. J
Hypertens. 2003 Oct;21(10):1969-73.
13.6 Springer Nature References
 from Springer Nature
13.7 Chemical Co-Occurrences in Literature
View More Chemical-Chemical Co-Occurrences and Evidence for Amlodipine

 from PubChem
14 Patents
1. CA2170278 11. US8475839
2. US6162802 12. US8613949
3. US5969156 13. US8618174
4. US6294197 14. US8183295
5. US5559111 15. US7846961
6. US6395728 16. US6696481
7. US6828339
8. US5616599
9. US6455574
10. US8101599
 from DrugBank
14.1 Depositor-Supplied Patent Identifiers
 from PubChem
14.2 FDA Orange Book Patents
FDA Orange Book Patents: 1 of 1 (FDA Orange Book Patent ID)
Patent 6455574
Expiration Aug 11, 2018
Applicant PFIZER
1. N021540 (Prescription Drug: CADUET. Ingredients: AMLODIPINE BESYLATE

2. ATORVASTATIN CALCIUM)
Drug Application
3. N021540 (Prescription Drug: CADUET. Ingredients: AMLODIPINE BESYLATE
4. ATORVASTATIN CALCIUM)

15 Biomolecular Interactions and Pathways
15.1 DrugBank Interactions
Target Voltage-dependent L-type calcium channel subunit alpha-1C
Action inhibitor
PubChem
Protein Q13936
Target
PubChem
Gene CACNA1C
Target
General
Voltage-gated calcium channel activity
Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are
also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or
neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C
gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage
Specific activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines,
Function and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA
(omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C
subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display
marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same
regulatory sites results in an opposit effects on the channel function.
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
Reference
Abstract: PubMed
Striessnig, J. (2004). Ca 2+ channel blockers. In Encyclopedic reference of molecular pharmacology (pp.

Reference
201-207). Berlin: Springer.
 from DrugBank
Target Voltage-dependent calcium channel subunit alpha-2/delta-1
Action inhibitor
PubChem
Protein P54289
Target
PubChem
Gene CACNA2D1
Target
General
Function
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and
Specific
activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction
Function
coupling (By similarity).
Reference Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
Abstract: PubMed
Reference
 from DrugBank
Target Voltage-dependent L-type calcium channel subunit beta-2
Action inhibitor
PubChem
Protein Q08289
Target
PubChem
Gene CACNB2
Target
General
Function
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium
Specific
channel by increasing peak calcium current, shifting the voltage dependencies of activation and
Function
inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting.
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
Reference
Abstract: PubMed

Reference
 from DrugBank
View all (21) DrugBank Interactions entries
16 Biological Test Results
16.1 BioAssay Results
 from PubChem
17 Classification
17.1 Ontologies
17.1.1 MeSH Tree
 from MeSH
17.1.2 ChEBI Ontology
 from ChEBI
17.1.3 KEGG: USP
 from KEGG
17.1.4 KEGG: ATC
 from KEGG
17.1.5 KEGG: Target-based Classification of Drugs
 from KEGG
17.1.6 WHO ATC Classification System
 from WHO ATC
17.1.7 WIPO IPC

 from WIPO
17.1.8 ChemIDplus
 from ChemIDplus
17.1.9 Guide to PHARMACOLOGY Target Classification
 from IUPHAR/BPS Guide to PHARMACOLOGY
17.1.10 ChEMBL Target Tree

 from ChEMBL
18 Information Sources
1. ChemIDplus /source/ChemIDplus
Amlodipine [INN:BAN]
https://chem.nlm.nih.gov/chemidplus/sid/0088150429 https://chem.nlm.nih.gov/chemidplus/sid/0088150429
ChemIDplus Chemical Information Classification
https://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp https://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp
2. DrugBank /source/DrugBank
Amlodipine
http://www.drugbank.ca/drugs/DB00381 http://www.drugbank.ca/drugs/DB00381
http://www.drugbank.ca/drugs/DB00381#targets http://www.drugbank.ca/drugs/DB00381#targets
http://www.drugbank.ca/drugs/DB00381#enzymes http://www.drugbank.ca/drugs/DB00381#enzymes
http://www.drugbank.ca/drugs/DB00381#transporters http://www.drugbank.ca/drugs/DB00381#transporters
3. EPA DSStox /source/EPA DSStox

Amlodipine
https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID7022596
https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID7022596
4. European Chemicals Agency (ECHA) /source/European Chemicals Agency (ECHA)

3-ethyl 5-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate
https://echa.europa.eu/substance-information/-/substanceinfo/100.102.428 https://echa.europa.eu/substance-
information/-/substanceinfo/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 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
https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/97610 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
https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/111819 https://echa.europa.eu/information-
on-chemicals/cl-inventory-database/-/discli/details/111819
5. Human Metabolome Database (HMDB) /source/Human Metabolome Database (HMDB)

Amlodipine
http://www.hmdb.ca/metabolites/HMDB0005018 http://www.hmdb.ca/metabolites/HMDB0005018
6. ClinicalTrials.gov /source/ClinicalTrials.gov
amlodipine
https://clinicaltrials.gov/ https://clinicaltrials.gov/
7. LiverTox /source/LiverTox
Amlodipine
https://livertox.nlm.nih.gov/Amlodipine.htm https://livertox.nlm.nih.gov/Amlodipine.htm
8. NCIt /source/NCIt
Amlodipine
https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C61635
https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C61635
9. EU Community Register of Medicinal Products /source/EU Community Register of Medicinal

Products
amlodipine
https://ec.europa.eu/health/documents/community-register/html/ho21223.htm https://ec.europa.eu/health/documents/community-
register/html/ho21223.htm
10. HSDB /source/HSDB
AMLODIPINE
https://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+88150-42-9 https://toxnet.nlm.nih.gov/cgi-
bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+88150-42-9
11. EU REGULATION (EC) No 1272/2008 /source/EU REGULATION (EC) No 1272/2008

3-ethyl 5-methyl...
http://ec.europa.eu/growth/sectors/chemicals/classification-labelling/index_en.htm
http://ec.europa.eu/growth/sectors/chemicals/classification-labelling/index_en.htm
12. Safe Work Australia - HCIS /source/Safe Work Australia - HCIS

88150-42-9
http://hcis.safeworkaustralia.gov.au/HazardousChemical/Details?chemicalID=1936
http://hcis.safeworkaustralia.gov.au/HazardousChemical/Details?chemicalID=1936
13. FDA Orange Book /source/FDA Orange Book

Patent:6455574
https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
14. MassBank of North America (MoNA) /source/MassBank of North America (MoNA)

Amlodipine
http://mona.fiehnlab.ucdavis.edu/spectra/browse?inchikey=HTIQEAQVCYTUBX-UHFFFAOYSA-N
http://mona.fiehnlab.ucdavis.edu/spectra/browse?inchikey=HTIQEAQVCYTUBX-UHFFFAOYSA-N
15. SpectraBase /source/SpectraBase

https://spectrabase.com/compound/GJdexa3plPh#KnIno72CxOU https://spectrabase.com/compound/GJdexa3plPh#KnIno72CxOU
https://spectrabase.com/compound/GJdexa3plPh#20fVinVpQjs https://spectrabase.com/compound/GJdexa3plPh#20fVinVpQjs
https://spectrabase.com/compound/GJdexa3plPh#1qWZFTQjuTS https://spectrabase.com/compound/GJdexa3plPh#1qWZFTQjuTS
https://spectrabase.com/compound/GJdexa3plPh#2DsrcoDxcBE https://spectrabase.com/compound/GJdexa3plPh#2DsrcoDxcBE
https://spectrabase.com/compound/GJdexa3plPh#HdVYCs3ug0f https://spectrabase.com/compound/GJdexa3plPh#HdVYCs3ug0f
https://spectrabase.com/compound/GJdexa3plPh#7hhG9j7nJeK https://spectrabase.com/compound/GJdexa3plPh#7hhG9j7nJeK
https://spectrabase.com/compound/GJdexa3plPh#1Z0UOuiVdQs https://spectrabase.com/compound/GJdexa3plPh#1Z0UOuiVdQs
https://spectrabase.com/compound/GJdexa3plPh#KJETXE4Cjd8 https://spectrabase.com/compound/GJdexa3plPh#KJETXE4Cjd8
https://spectrabase.com/compound/GJdexa3plPh#KLPlDiH4OYw https://spectrabase.com/compound/GJdexa3plPh#KLPlDiH4OYw
16. NIST /source/NIST

Amlodipine
http://www.nist.gov/srd/nist1a.cfm http://www.nist.gov/srd/nist1a.cfm
17. PubMed Health /source/PubMed Health

Norvasc
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008948/ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008948/
Caduet
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008955/ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008955/
18. Springer Nature /source/Springer Nature

Literature references related to scientific contents from Springer Nature journals and books. Read more ... https://link.springer.com/
19. WHO ATC /source/WHO ATC

https://www.whocc.no/atc/ https://www.whocc.no/atc/
ATC Code
https://www.whocc.no/atc_ddd_index/ https://www.whocc.no/atc_ddd_index/
20. Wikipedia /source/Wikipedia

amlodipine mesylate
https://www.wikidata.org/wiki/Q27254365 https://www.wikidata.org/wiki/Q27254365
amlodipine
https://en.wikipedia.org/wiki/Amlodipine https://en.wikipedia.org/wiki/Amlodipine
21. PubChem
Data deposited in or computed by PubChem
https://pubchem.ncbi.nlm.nih.gov https://pubchem.ncbi.nlm.nih.gov
22. MeSH /source/MeSH

Amlodipine
https://www.ncbi.nlm.nih.gov/mesh/68017311 https://www.ncbi.nlm.nih.gov/mesh/68017311
MeSH Tree
http://www.nlm.nih.gov/mesh/meshhome.html http://www.nlm.nih.gov/mesh/meshhome.html
Calcium Channel Blockers
Vasodilator Agents
Antihypertensive Agents
23. ChEBI /source/ChEBI

ChEBI Ontology
http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
24. KEGG /source/KEGG

USP drug classification
http://www.genome.jp/kegg-bin/get_htext?br08302.keg http://www.genome.jp/kegg-bin/get_htext?br08302.keg
Anatomical Therapeutic Chemical (ATC) classification
Target-based classification of drugs
25. WIPO /source/WIPO

International Patent Classification
http://www.wipo.int/classifications/ipc/ http://www.wipo.int/classifications/ipc/
26. ChEMBL /source/ChEMBL

Target Tree
https://www.ebi.ac.uk/chembl/target/browser https://www.ebi.ac.uk/chembl/target/browser
27. IUPHAR/BPS Guide to PHARMACOLOGY /source/IUPHAR/BPS Guide to PHARMACOLOGY

Target Classification
http://www.guidetopharmacology.org/ http://www.guidetopharmacology.org/
28. NCBI
LinkOut is a service that allows one to link directly from NCBI databases to a wide range of information and services beyond NCBI
systems.
https://www.ncbi.nlm.nih.gov/projects/linkout https://www.ncbi.nlm.nih.gov/projects/linkout

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Amlodipine - C20H25ClN2O5 - PubChem PDF

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NIH U.S.

National Library of Medicine National Center for Biotechnology Information

Amlodipine  Cite this Record

PubChem CID: 2162

Chemical Names: Amlodipine; 88150-42-9; Norvasc; Amlodis; Amlodipino; Amlodipinum More...

Molecular Formula: C20H25ClN2O5

Safety Summary: Laboratory Chemical Safety Summary (LCSS)

PUBCHEM  COMPOUND  AMLODIPINE Modify Date: 2018-06-02; Create Date: 2005-03-25

3.1 Computed Descriptors

3.1.1 IUPAC Name

3.1.3 InChI Key

3.1.4 Canonical SMILES

3.2 Molecular Formula

3.3 Other Identiﬁers

Title amlodipine mesylate

Description chemical compound

3.4.1 MeSH Entry Terms

1. Amlodipine 11. Astudal

3.4.2 Depositor-Supplied Synonyms

ylate 41. UK-48,340

4.1 Computed Properties

Property Name Property Value

Molecular Weight 408.879 g/mol

Hydrogen Bond Donor Count 2

Hydrogen Bond Acceptor Count 7

Rotatable Bond Count 10

Topological Polar Surface Area 99.9 A^2

Monoisotopic Mass 408.145 g/mol

Exact Mass 408.145 g/mol

Compound Is Canonicalized true

Heavy Atom Count 28

Deﬁned Atom Stereocenter Count 0

Undeﬁned Atom Stereocenter Count 1

Deﬁned Bond Stereocenter Count 0

Undeﬁned Bond Stereocenter Count 0

Isotope Atom Count 0

Covalently-Bonded Unit Count 1

4.2 Experimental Properties

4.2.1 Physical Description

4.2.2 Melting Point

In water, 75.3 mg/L at 25 deg C (est)

4.2.4 Vapor Pressure

log Kow = 3.00

4.2.8 Dissociation Constants

4.3 Spectral Properties

4.3.1 1D NMR Spectra

1D NMR Spectra: 1 of 2 (1H NMR Spectra)

1H NMR Spectra 1D NMR Spectrum 2020 - Bruker 600 MHz 1H NMR

 from Human Metabolome Database (HMDB)

1D NMR Spectra: 2 of 2 (13C NMR Spectra)

4.3.2 2D NMR Spectra

2D NMR Spectra: 1 of 1 (1H-13C NMR Spectra)

 from Human Metabolome Database (HMDB)

4.3.3 Mass Spectrometry

General MS: 1 of 11 (MS)

MS Type Chromatography identiﬁed as LC-MS

Precursor Type [M+H]+

precursor m/z 409.1525

Instrument Bruker maXis Impact

Instrument Type LC-ESI-QTOF

Ionization Mode positive

Collision Energy RAMP 23.8-35.7 eV

Retention Time 8.589 min