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Medication Safety Issues
Sound-alike/look-alike issues:
AmLODIPine may be confused with aMILoride
Norvasc® may be confused with Navane®, Norvir®, Vascor®
Pronunciation
(am LOE di peen)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)
Pregnancy Risk Factor
C
Pregnancy Considerations
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
Concerns related to adverse effects:
• Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.
• Peripheral edema: The most common side effect is peripheral edema; occurs within 2-3 weeks of starting therapy.
• Reflex tachycardia: May occur with use.
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis.
• Hepatic impairment: Use with caution in patients with hepatic impairment; may require lower starting dose.
• Idiopathic hypertrophic subaortic stenosis (IHSS): Use with caution in patients with IHSS.
Special populations:
• Elderly: Initiate at a lower dose in the elderly.
• Pediatrics: Safety and efficacy have not been established in children <6 years of age.
Other warnings/precautions:
• Titration: 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: Cholestasis, dysosmia, EPS, erythema multiforme, exfoliative dermatitis, gynecomastia, hepatitis, jaundice, leukocytoclastic vasculitis, nonthrombocytopenic purpura, phototoxicity, Stevens-Johnson syndrome, transaminases increased
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Drug Interactions
Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Barbiturates: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Calcium Channel Blockers (Dihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy
Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy
CycloSPORINE: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Nicardipine may likewise inhibit the metabolism of cyclosporine. Cyclosporine dosage adjustments might be needed. Risk C: Monitor therapy
CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Grapefruit Juice: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification
Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Protease Inhibitors: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk D: Consider therapy modification
QuiNIDine: Calcium Channel Blockers (Dihydropyridine) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy
Quinupristin: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy
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).
Storage
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: Antihypertensive: 30-50 minutes
Duration of antihypertensive effect: 24 hours
Absorption: Oral: Well absorbed
Distribution: Vd: 21 L/kg
Protein binding: 93% to 98%
Metabolism: Hepatic (>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours; increased with hepatic dysfunction
Time to peak, plasma: 6-12 hours
Excretion: Urine (10% as parent, 60% as metabolite)
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; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect
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: Oral
May be administered without regard to meals.
Monitoring Parameters
Heart rate, blood pressure, peripheral edema
Dietary Considerations
May be taken without regard to meals.
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; do not alter dose or discontinue medication 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.
Geriatric Considerations
Elderly may experience a greater hypotensive response. Constipation may be more of a problem in elderly. Calcium channel blockers are no more effective in elderly than other therapies, however, they do not cause significant CNS effects which is an advantage over some antihypertensive agents.
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
Hypertension: 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. The ALLHAT study (ALLHAT Collaborative Group, 2002) compared CV outcomes of lisinopril, amlodipine, or chlorthalidone in hypertensive patients having at least one other risk factor for coronary heart disease. Investigators found no difference between the groups on the primary outcome of fatal coronary disease or nonfatal MI. The ASCOT-BPLA trial evaluated two regimens (calcium channel blocker/ACE inhibitor vs beta-blocker/thiazide diuretic) to test their efficacy in the primary prevention of coronary disease (nonfatal MI and fatal coronary artery disease). Patients 40-79 years of age were recruited; their blood pressures were either >160 systolic or >100 diastolic (untreated) or >140 systolic or >90 diastolic (treated). Treatment with a calcium channel blocker/ACE inhibitor was more effective at reducing cardiovascular outcomes than the beta-blocker/diuretic regimen.
Coronary Artery Disease: The Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial compared a calcium channel blocker and ACE inhibitor in normotensive patients with coronary artery disease (Nissen, 2004). The primary outcome of CV events occurred in 151 (23.1%: placebo), 110 (16.6%: amlodipine), and 136 (20.2%: enalapril) of the patients. The only significant difference being a reduction in CV events with amlodipine compared with placebo, mainly representing a reduction in coronary revascularization and hospitalizations for angina with amlodipine. In the treatment of unstable angina/non-ST-segment elevation MI, oral long-acting calcium antagonists may also be considered in addition to beta-blockers and nitrates.
Heart Failure: The ACC/AHA 2005 guidelines for management of heart failure state that calcium channel blockers are not indicated for the routine treatment of heart failure patients with current/prior symptoms of heart failure and reduced LVEF. Only amlodipine has been shown not to adversely affect survival but most experience is not in patients on concurrent beta-blockers.
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
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with prescription, OTC medications, or herbal products patient may be taking (eg, nitrates or other drugs that effect blood pressure). Assess therapeutic effectiveness (blood pressure; cardiac rhythm; frequency and intensity of angina; I & O ratio; weight; edema, according to purpose for use) and signs of adverse reactions at beginning of therapy, when changing dose, and periodically during long-term therapy. Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Amlodipine Besylate)
2.5 mg (90): $15.99
10 mg (90): $18.00
Tablets (Norvasc)
2.5 mg (30): $61.99
5 mg (30): $64.99
10 mg (30): $81.99
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
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, "Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)," JAMA, 2002, 288(23):2981-97.
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.
Hunt SA, Abraham WT, Chin MH , et al, "ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure)," available at http://www.acc.org/qualityandscience/clinical/guidelines/failure/update/index.pdf.
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.
Meredith PA and Elliott HL, "Clinical Pharmacokinetics of Amlodipine," Clin Pharmacokinet , 1992, 22(1):22-31.
National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents,” Pediatrics, 2004, 114(2 Suppl):555-76.
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.
Nissen SE, Tuzcu EM, Libby P, et al, "Effect of Antihypertensive Agents on Cardiovascular Events in Patients With Coronary Disease and Normal Blood Pressure: The CAMELOT Study: A Randomized Controlled Trial," JAMA, 2004, 292(18):2217-25.
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.
Sever PS, Dahlof B, Poulter NR, et al, "Rationale, Design, Methods and Baseline Demography of Participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT Investigators," J Hypertens, 2001, 19(6):1139-47.
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
Lexi-Comp.com
Last full review/revision September 2008
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