Amlodipine
Pronunciation
(am LOE di peen)
U.S. Brand Names
Norvasc®
Synonyms
Amlodipine Besylate
Generic Available
No
Canadian Brand Names
Norvasc®
Use
Treatment of hypertension and angina
Pregnancy Risk Factor
C
Pregnancy Implications
Embryotoxic effects have been demonstrated in small animals. No well-controlled studies have been conducted in pregnant women. Use in pregnancy only when clearly needed and when the benefits outweigh the potential hazard to the fetus.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to amlodipine or any component of the formulation
Warnings/Precautions
Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Use caution in severe aortic stenosis. Use caution in patients with severe hepatic impairment. Dosage titration should occur after 7-14 days on a given dose.
Adverse Reactions
>10%: Cardiovascular: Peripheral edema (2% to 15% dose related)
1% to 10%:
Cardiovascular: Flushing (1% to 3%), palpitation (1% to 4%)
Central nervous system: Headache (7%; similar to placebo 8%), dizziness (1% to 3%), fatigue (4%), somnolence (1% to 2%)
Dermatologic: Rash (1% to 2%), pruritus (1% to 2%)
Endocrine & metabolic: Male sexual dysfunction (1% to 2%)
Gastrointestinal: Nausea (3%), abdominal pain (1% to 2%), dyspepsia (1% to 2%), gingival hyperplasia
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (15% from PRAISE trial, CHF population)
<1%: Abnormal dreams, abnormal vision, allergic reactions, angioedema, anorexia, anxiety, arrhythmia, arthrosis, back pain, bradycardia, chest pain, conjunctivitis, constipation, depersonalization, depression, diaphoresis increased, diarrhea, diplopia, dysphagia, epistaxis, erythema multiforme, eye pain, female sexual dysfunction, flatulence, hot flushes, hyperglycemia, hypoesthesia, hypotension, insomnia, joint stiffness, leukopenia, malaise, micturition disorder, micturition frequency, myalgia, nervousness, nocturia, pain, pancreatitis, paresthesia, peripheral ischemia, peripheral neuropathy, postural dizziness, postural hypotension, purpura, rash erythematous, rash maculopapular, rigors, syncope, tachycardia, thirst, thrombocytopenia, tinnitus, tremor, vasculitis, vertigo, vomiting, weight gain/loss, xerostomia
<0.1%: Abnormal visual accommodation, agitation, alopecia, amnesia, apathy, appetite increased, ataxia, cardiac failure, cold and clammy skin, cough, dermatitis, dysuria, extrasystoles, gastritis, hypertonia, loose stools, migraine, muscle weakness, parosmia, polyuria, pulse irregularity, rhinitis, skin discoloration, skin dryness, taste perversion, twitching, urticaria, xerophthalmia
Postmarketing and/or case reports: Dysosmia, EPS, erythema multiforme, exfoliative dermatitis, gynecomastia, jaundice, leukocytoclastic vasculitis, nonthrombocytopenic purpura, phototoxicity, Stevens-Johnson syndrome
Overdosage/Toxicology
Primary cardiac symptoms of calcium channel blocker overdose include hypotension and bradycardia. Noncardiac symptoms include confusion, stupor, nausea, vomiting, metabolic acidosis, and hyperglycemia. Treat other signs and symptoms symptomatically.
Drug Interactions
Substrate
of CYP3A4 (major);
Inhibits
CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8/9 (weak), 2D6 (weak), 3A4 (weak)
Azole antifungals may inhibit calcium channel blocker metabolism; avoid this combination. Try an antifungal like terbinafine (if appropriate) or monitor closely for altered effect of the calcium channel blocker.
Calcium may reduce the calcium channel blocker's effects, particularly hypotension.
CYP1A2 substrates: Amlodipine may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of amlodipine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of amlodipine. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.
Grapefruit juice: May modestly increase amlodipine levels.
Rifampin increases the metabolism of calcium channel blockers; adjust the dose of calcium channel blocker to maintain efficacy.
Sildenafil, tadalafil, vardenafil: Blood pressure-lowering effects are additive; use caution.
Ethanol/Nutrition/Herb Interactions
Food: Grapefruit juice may modestly increase amlodipine levels.
Herb/Nutraceutical: St John's wort may decrease amlodipine levels. Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effects).
Stability
Store at room temperature of 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina
Pharmacodynamics/Kinetics
Onset of action: 30-50 minutes
Peak effect: 6-12 hours
Duration: 24 hours
Absorption: Oral: Well absorbed
Protein binding: 93%
Metabolism: Hepatic (>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours
Excretion: Urine
Dosage
Oral:
Children 6-17 years: Hypertension: 2.5-5 mg once daily
Adults:
Hypertension: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily. In general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily.
Angina: Usual dose: 5-10 mg
Elderly: Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: 2.5 mg once daily
Angina: 5 mg once daily
Dialysis: Hemodialysis and peritoneal dialysis does not enhance elimination. Supplemental dose is not necessary.
Dosage adjustment in hepatic impairment:
Angina: Administer 5 mg once daily.
Hypertension: Administer 2.5 mg once daily.
Administration
May be administered without regard to meals.
Dietary Considerations
May be taken without regard to meals.
Patient Education
Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; do not alter dose or discontinue without consulting prescriber. May cause headache (if unrelieved, consult prescriber); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum or sucking lozenges may help); constipation (increased dietary bulk and fluids may help); or drowsiness (use caution when driving or engaging in tasks that require alertness until response to drug is known). Report unrelieved headache; vomiting, constipation; palpitations; peripheral or facial swelling; weight gain >5 lb/week; or respiratory changes.
Pregnancy/breast-feeding precautions:
Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Anesthesia and Critical Care Concerns/Other Considerations
Amlodipine may be used safely to treat hypertension and/or angina in patients with heart failure.
Cardiovascular Considerations
Amlodipine therapy should be continued for 4-6 weeks before the dose is increased. Daily doses >10 mg are associated with an increase in side effects (eg, edema) without further reductions in blood pressure. Amlodipine may be used safely to treat hypertension and/or angina in patients with heart failure. In a study that addressed amlodipine therapy in severe heart failure, cardiovascular morbidity was decreased significantly in a subset of patients with nonischemic heart failure. This finding is being addressed in an ongoing trial (PRAISE-II).
In the treatment of unstable angina/non-ST-segment elevation MI, a nondihydropyridine calcium antagonist (diltiazem or verapamil) may be considered in patients with continuing or frequently recurring ischemia when beta-blockers are contraindicated (Class I). Oral long acting calcium antagonists may also be considered in addition to beta-blockers and nitrates (Class IIa).
Dental Health: Effects on Dental Treatment
Fewer reports of gingival hyperplasia with amlodipine than with other CCBs (usually resolves upon discontinuation); consultation with physician is suggested.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness; rarely may produce insomnia and nervousness
Mental Health: Effects on Psychiatric Treatment
None reported
Dosage Forms
Tablet, as besylate [equivalent to amlodipine base]: 2.5 mg, 5 mg, 10 mg
Extemporaneously Prepared
A 1 mg/mL suspension was stable for 91 days when refrigerated or 56 days when kept at room temperature when compounded as follows: Triturate fifty 5 mg tablets in a mortar, reduce to a fine powder. In a graduate, mix Ora-Sweet® 125 mL and Ora-Plus® 125 mL together. Add small amount of this mixture to the powder to make a paste. Add the remainder in small quantities while mixing. Shake well before using.
Nahata MC, Morosco RS, and Hipple TF, 4th ed,
Pediatric Drug Formulations
, Cincinnati, OH: Harvey Whitney Books Co, 2000.
References
Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA Guidelines for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina),"
J Am Coll Cardiol
, 2000, 36(3):970-1062.
Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,"
JAMA
, 2003, 289(19):2560-71.
Davies RF, Habibi H, Klinke WP, et al, "Effect of Amlodipine, Atenolol and Their Combination on Myocardial Ischemia During Treadmill Exercise and Ambulatory Monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators,"
J Am Coll Cardiol
, 1995, 25(3):619-25.
Grassi G, Spaziani D, Seravalle G, et al, "Effects of Amlodipine on Sympathetic Nerve Traffic and Baroreflex Control of Circulation in Heart Failure,"
Hypertension
, 1999, 33(2):671-5.
Hall WD, Reed JW, Flack JM, et al, "Comparison of the Efficacy of Dihydropyridine Calcium Channel Blockers in African American Patients With Hypertension. ISHIB Investigators Group. International Society on Hypertension in Blacks,"
Arch Intern Med
, 1998, 158(18):2029-34.
Joseffsson M, Zackrisson AL, and Ahlner J, "Effect of Grapefruit Juice on the Pharmacokinetics of Amlodipine in Healthy Volunteers,"
Eur J Clin Pharmacol
, 1996, 51(2):189-93.
Neaton JD, Grimm RH Jr, Prineas RJ, et al, "Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group,"
JAMA
, 1993, 270(6):713-24.
Packer M, O'Connor CM, Ghali JK, et al, "Effect of Amlodipine on Morbidity and Mortality in Severe Chronic Heart Failure. Prospective Randomized Amlodipine Survival Evaluation Study Group,"
N Engl J Med
, 1996, 335(15):1107-14.
Steele RM, Schuna AA, and Schreiber RT, "Calcium Antagonist-Induced Gingival Hyperplasia,"
Ann Intern Med
, 1994, 120(8):663-4.
Vincent J, Harris SI, Foulds G, et al, "Lack of Effect of Grapefruit Juice on the Pharmacokinetics and Pharmacodynamics of Amlodipine,"
Br J Clin Pharmacol
, 2000, 50(5):455-63.
International Brand Names
Agen® (CZ); Aldan® (PL); Alopres® (YU); Amdipin® (CL, CO); Amdocal® (BD); Amlobeta mesilat® (DE); Amloc® (AR, CL); Amlocard® (DE); amlo-corax® (DE); Amlodac® (IN); Amlodigamma® (DE); Amlodine® (AR); Amlodin® (JP); Amlodipin AbZ® (DE); Amlodipina Calox® (CR, PA); Amlodipina® (DO); Amlodipina Gen Med® (AR); Amlodipina Ilab® (AR); Amlodipin AL® (DE); Amlodipina ratio® (DO); Amlodipin Basics® (DE); Amlodipin Dexcel® (DE); Amlodipin dura® (DE); Amlodipin Hexal® (DE); Amlodipin Interpharm® (AT); Amlodipin IVAX® (DE); Amlodipin Kwizda® (DE); Amlodipino Genfar® (EC); Amlodipino MK® (CO, CR, DO, GT, HN, PA, SV); Amlodipin Orifarm® (DK); Amlodipin-ratiopharm® (DE); Amlodipin Sandoz® (DE); Amlodipin STADA® (DE); Amlodipinum® (PL); Amlodipin von ct® (DE); Amlodis® (TR); Amlofel® (DO); AMLO-ISIS® (DE); Amlokard® (TR); AmloLich® (DE); Amlopin® (BD, HR, PL, SI, TH, YU); Amlopine® (TH); Amlopres® (IN); Amlor® (BE, EC, FR, LU); Amlosun® (BD); Amlosyn® (CO); Amlo TAD® (DE); Amlo-Teva® (DE); Amlovas® (CR, DO, GT, HN, PA, SV, TR); Amlo Wolff® (DE); Amlozek® (PL); Amocal® (BD); Anexa® (AR); Angiofilina® (AR); Anlodipin® (EC); Antacal® (IT); Arteriosan® (AR); Astudal® (ES); Besilato de amlodipina® (BR); Cab® (BD); Calchek® (BD, IN); Calpres® (AR); Camlodin® (BD); Cardicol® (DO); Cardilopin® (HU, PL); Cardinor® (CO); Cardiorex® (AR); Cordarene® (BR); Cordipina® (BR); Coroval® (AR); Cristacor® (RO); Dilopin® (TR); Eucoran® (CO); Goritel® (EC); Ilduc® (AR); Istin® (GB, IE); Lama® (IN); Locard® (BD); Lodipar® (DO, EC); Lodipin® (BD, DO); Lodipres® (DO); Maxidipin® (DO); Mitokor® (AR); Monopina® (IT); Monovas® (TR); Nicord® (BR); Nipidol® (TR); Nor-Lodipina® (SV); Norlopin® (TR); Normodipine® (CZ, HU, PL); Norvadin® (TR); Norvadipin Paranova® (DK); Norvasc® (AT, AU, BR, CA, CH, CL, CZ, DE, DK, DO, EG, FI, FR, HR, HU, IL, IT, NL, NO, NZ, PL, PT, RO, RU, SE, SG, SI, TH, TR, YU, ZA); Norvas® (CO, ES, MX, NO); Norvas Europharma DK® (DK); Norvask® (ID, SG); Norvas Orifarm® (DK); Norvas Paranova® (DK); Orcal® (CZ); Pelmec® (AR); Pressat® (BR); Roxflan® (BR); Sinop® (AR); Stamlo® (RO); Tenox® (PL); Tensivask® (ID); Tensodin® (BR); Terloc® (AR, CL); Tervalon® (AR); Vasocal® (DO, EC); Vasocard® (TR); Vasotop® (EC); Vasten® (CO); Vazkor® (TR); Zundic® (AR)
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