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Amlodipine (Systemic)


VA CLASSIFICATION
Primary: CV200
Secondary: CV250; CV409

Commonly used brand name(s): Norvasc.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antianginal—

antihypertensive—

Indications

Accepted

Angina, chronic stable (treatment)—Amlodipine is indicated for the treatment of chronic stable angina; it may be used alone or in combination with other antianginal agents. {01}{33.}

Angina, vasospastic (treatment)1—Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. It may be used alone or in combination with other antianginal agents. {01}

Hypertension (treatment)—Amlodipine is indicated for the treatment of hypertension; it may be used alone or in combination with other antihypertensive agents. {01}{33.}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    567.05 {02}

Mechanism of action/Effect:

Amlodipine is a dihydropyridine calcium channel blocking agent. {01} {03} {04} Like the other dihydropyridine agents, amlodipine selectively inhibits calcium influx across cell membranes in cardiac and vascular smooth muscle, with a greater effect on vascular smooth muscle. {01} Amlodipine is a peripheral arteriolar vasodilator; thus it reduces afterload. {04} {05}


Other actions/effects:

Amlodipine exhibits negative inotropic effects in vivo , {01} but appears to have no significant effect on the sinoatrial (SA) or atrioventricular (AV) node in humans. {04}

Absorption:

Slowly and almost completely absorbed from the gastrointestinal tract; {03} {04} {06} absorption not affected by food. {01} {12} Bioavailability is approximately 60 to 65%. {03} {04} {06} {07} {08} {09}

Distribution:

Vol D—21 L per kg. {03} {04} {06} {08}

Protein binding:

Very high (95 to 98%). {04} {06} {08} {09}

Biotransformation:

Undergoes minimal presystemic metabolism. {04} {06} Amlodipine undergoes slow but extensive hepatic metabolism, producing metabolites lacking significant pharmacological activity. {04} {06} {08}

Half-life:

Elimination—Mean, 35 hours in healthy volunteers; {04} {06} {07} {08} {09} {10} {11} may be prolonged to a mean of 48 hours in hypertensive patients, {04} {06} 65 hours in the elderly, {04} {06} {14} and 60 hours in patients with hepatic function impairment. {04} {06} {13} Not affected by renal function impairment. {01} {15}

Time to peak concentration:

Single-dose—6 to 9 hours. {06} {07} {08}

Duration of action:

24 hours. {06}

Elimination:
    Renal—59 to 62% (about 5% as unchanged amlodipine). {04} {06} {08} {10}
    Biliary/fecal—20 to 25%. {04} {06} {10}
    In dialysis—Amlodipine is not removed by hemodialysis. {01}


Precautions to Consider

Carcinogenicity

No evidence of carcinogenicity was revealed in studies with rats and mice given amlodipine at dosages of 0.5, 1.25, and 2.5 mg per kg of body weight (mg/kg) per day for 2 years. {01}

Mutagenicity

No evidence of mutagenicity was observed at the gene or chromosome level. {01}

Pregnancy/Reproduction
Fertility—
No impairment of fertility was observed in rats given amlodipine at doses 8 times the maximum recommended human dose prior to mating. {01}

Pregnancy—
Studies have not been done in humans.

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. {01} However, the number of intrauterine deaths increased about five-fold, and rat litter size was significantly decreased (by 50%). {01}

FDA Pregnancy Category C. {01}

Labor—

Amlodipine has been shown to prolong the duration of labor in rats. {01}

Breast-feeding

It is not known whether amlodipine is distributed into breast milk. {01}

Pediatrics

No information is available on the relationship of age to the effects of amlodipine in pediatric patients. Safety and efficacy have not been established.


Geriatrics


The half-life of amlodipine may be increased in the elderly. {01} {14} These patients may be more sensitive to the hypotensive effects of amlodipine and may require a lower initial dose. {01}


Dental

Gingival hyperplasia is a rare side effect that has been reported with amlodipine. {20} It also has been reported with other calcium channel blocking agents, such as diltiazem, felodipine, verapamil, and, most commonly, nifedipine. {17} It usually starts as gingivitis or gum inflammation in the first 1 to 9 months of treatment. Resolution of the hyperplasia and improvement of the clinical symptoms usually occur one to four weeks after discontinuation of therapy. {17} A strictly enforced program of professional teeth cleaning combined with plaque control by the patient will minimize growth rate and severity of gingival enlargement. Periodontal surgery may be indicated in some cases, and should be followed by careful plaque control to inhibit recurrence of gum enlargement.

Surgical

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery may be undesirable. However, the anesthesiologist must be aware of such therapy. {16}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, hydrocarbon inhalation {21} {22} {31}    (concurrent use with amlodipine may produce additive hypotension; although calcium channel blocking agents may be useful to prevent supraventricular tachycardias, hypertension, or coronary spasm during surgery, caution is recommended during use)


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin {18} {19}    (NSAIDs may reduce the antihypertensive effects of amlodipine by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention)


Beta-adrenergic blocking agents    (although reports of adverse effects resulting from concurrent use of amlodipine with the beta-adrenergic blocking agents are lacking, caution is recommended given the similarity of amlodipine to nifedipine; concurrent use of nifedipine with the beta-adrenergic blocking agents, although usually well-tolerated, may produce excessive hypotension and, in rare cases, may increase the possibility of congestive heart failure {23} {24} {25})


Estrogens    (estrogen-induced fluid retention may tend to increase blood pressure; the patient should be carefully monitored to confirm that the desired effect is being obtained {26})


Highly protein-bound medications, such as:
Anticoagulants, coumarin- and indandione-derivativeAnticonvulsants, hydantoin
Anti-inflammatory drugs, nonsteroidal
Quinine
Salicylates
Sulfinpyrazone    (caution is advised when these medications are used concurrently with amlodipine since amlodipine is highly protein bound; changes in serum concentrations of the free, unbound medications may occur)


Hypotension-producing medications, other (see Appendix II )    (antihypertensive effects may be potentiated when amlodipine is used concurrently with hypotension-producing medications; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, when any of these medications are used concurrently, dosage adjustments may be necessary)


Lithium {31}    (concurrent use with amlodipine potentially may result in neurotoxicity in the form of nausea, vomiting, diarrhea, ataxia, tremors, and/or tinnitus; caution is recommended)


Sympathomimetics    (concurrent use may reduce antihypertensive effects of amlodipine; the patient should be carefully monitored to confirm that the desired effect is being obtained)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Hepatic enzyme values{01}{33.}    (increases consistent with hepatitis or cholestasis have been reported; in some cases, the elevations have been severe enough to require hospitalization{01}{33.})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypotension, severe{33.}    (amlodipine may aggravate this condition)


Risk-benefit should be considered when the following medical problems exist
Aortic stenosis {01}    (increased risk of heart failure because of fixed impedance to flow across aortic valve)


Congestive heart failure {01}    (amlodipine should be used with caution in patients with congestive heart failure because of the slight risk for negative inotropic effect)


Hepatic function impairment {01}    (clearance of amlodipine may be reduced since it undergoes extensive hepatic metabolism; elimination half-life may be prolonged to 60 hours)


Sensitivity to amlodipine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure determinations and
» ECG readings and
» Heart rate determinations and
Reduced frequency or severity of anginal attacks and
Decreased nitrate consumption and
Improved exercise tolerance without angina    (recommended primarily during dosage titration or when dosage is increased from established maintenance dosage level; also recommended when other medications are added that affect cardiac conduction or blood pressure)

    (blood pressure determinations are recommended at periodic intervals to monitor efficacy and safety of amlodipine therapy; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Edema, peripheral {01}{27}{28}{29}{30}{33.}(swelling of ankles and feet)— dose-related incidence of 1.8–10.8% between 2.5–10 mg daily; higher prevalence in women than men{01}

Incidence less frequent
    
Dizziness {01}{27}{30}— dose-related incidence of 1.1–3.4% between 2.5–10 mg daily{01}
    
palpitations (pounding heartbeat ){01}{27}{29}{30}{33.}— dose-related incidence of 0.7–4.5% between 2.5–10 mg daily; higher prevalence in women than men

Incidence rare
    
Angina {01}(chest pain)
    
bradycardia {01}(slow heartbeat)
    
hypotension (dizziness)
    
jaundice {01}{33.}(dark yellow urine; yellow eyes or skin)
    
orthostatic hypotension (dizziness or light-headedness when getting up from a lying or sitting position){01}{33.}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain {01}{33.}
    
flushing {01}{27}{30}{33.}— dose-related incidence of 0.7–2.6% between 2.5–10 mg daily; higher prevalence in women than men{01}
    
headache {01} {27} {28} {29} {30}{33.}
    
somnolence {01}{33.}(sleepiness or unusual drowsiness)—higher prevalence in women than men{01}

Incidence less frequent
    
Fatigue (unusual tiredness or weakness){01}{30}{33.}
    
nausea {01} {27} {29} {30}{33.}





Overdose
For specific information on the agents used in the management of amlodipine or calcium channel blocking agent toxicity or overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Calcium Chloride or Calcium Gluconate in Calcium Supplements (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Dopamine, Dobutamine, Isoproterenol, Metaraminol, or Norepinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph;
   • Lidocaine (Systemic) monograph; and/or
   • Procainamide (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Hypotension, symptomatic {01}
    
reflex tachycardia {01}
    
bradycardia


Treatment of overdose


To decrease absorption:
Ipecac is not recommended since emesis may produce vagal stimulation and (theoretically) worsen an overdose with calcium antagonists. {34}{35} Furthermore, ipecac has not been demonstrated to improve patient outcome{38}

Consider prehospital administration of activated charcoal as an aqueous slurry in patients who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion.{34}{35}



To enhance elimination :
High protein binding of all calcium channel blocking agents would suggest hemodialysis or hemoperfusion would have limited usefulness.{01}



Specific treatment:
Recommended treatment consists of the following:

   • Hypotension, symptomatic—Intravenous fluids, intravenous dopamine or dobutamine, calcium gluconate, isoproterenol, metaraminol, or norepinephrine should be used as appropriate.{31}
   • Tachycardia, rapid ventricular rate in patients with antegrade conduction in atrial flutter fibrillation, and accessory pathway with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome—Direct-current cardioversion, intravenous lidocaine, or intravenous procainamide. Intravenous fluids given by slow-drip.{31}
   • Bradycardia, rarely second or third degree atrioventricular (AV) block, with a few patients progressing to asystole—Intravenous atropine, isoproterenol, norepinephrine, or calcium chloride, or use of electronic cardiac pacemaker, as appropriate.{31}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Monitoring:
Patients with suspected calcium channel blocker overdose should be placed on a cardiac monitor. Monitor hemodynamic status closely including heart rate blood pressure, EKG, and urinary output.{01}

Monitor electrolytes, renal function tests and glucose.{01} Swan Ganz monitoring may help guide fluid and hemodynamic management.

Monitor respiratory function and oxygenation; pulmonary edema may occur.{01}{37}

Calcium antagonist dosage forms are generally radiolucent. Sustained-release forms may be an exception.{36}

Qualitative and/or quantitative serum levels for calcium antagonists are not readily available, predictive of toxicity, nor helpful in directing therapy.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Amlodipine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to amlodipine





Use in the elderly—Half-life increased; increased sensitivity to hypotensive effects





Dental—Risk of gingival hyperplasia
Other medical problems, especially severe hypotension

Proper use of this medication
» Compliance with therapy; importance of not taking more medication than amount prescribed

» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

» Proper storage

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; serious consequences of untreated hypertension

Precautions while using this medication
Regular visits to physician to check progress during therapy

Checking with physician before discontinuing medication; gradual dosage reduction may be necessary

» Discussing exercise or physical exertion limits with physician; reduced occurrence of chest pain may tempt patient to be overactive

Possible headache; checking with physician if continuing or severe

» Maintaining good dental hygiene and seeing dentist frequently for teeth cleaning to prevent tenderness, bleeding, and gum enlargement

For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician


Side/adverse effects
Signs of potential side effects, especially peripheral edema, dizziness, palpitations, angina, bradycardia, hypotension, jaundice, or orthostatic hypotension


General Dosing Information
Concurrent administration of sublingual nitroglycerin, long-acting nitrates, beta-blockers, or other antianginal agents with amlodipine may produce additive antihypertensive{39} and antianginal effects. Sublingual nitroglycerin may be used as needed to abort acute angina attacks during amlodipine therapy. Nitrate medication may be used during amlodipine therapy for angina prophylaxis. Amlodipine will not protect against the consequences of abrupt beta-blocker withdrawal; gradual beta-blocker dose reduction is recommended I.{01}

Although no “rebound effect” has been reported upon discontinuation of amlodipine, a gradual decrease of dosage with physician supervision is recommended.


Oral Dosage Forms

AMLODIPINE BESYLATE TABLETS

Usual adult dose
Angina, chronic stable or
Angina, vasospastic1 or
Hypertension
Oral, 5 to 10 mg once a day.{01}{33.}

Note: An initial antihypertensive dose of 2.5 mg is recommended for small, fragile, or elderly patients, patients with hepatic function impairment, or when adding amlodipine to other antihypertensive therapy.{01} Because of amlodipine's prolonged elimination half-life, dosage increases should be accomplished slowly at five- to seven-day intervals.{37} Rapid titration without complete assessment of the patient's response at each dosage level may result in hypotension.{37}
An initial antianginal dose of 5 mg is recommended for the elderly and for patients with hepatic function impairment.{01}



Usual pediatric dose
Safety and efficacy have not been established.{01}

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Norvasc{01}]


5 mg (Rx) [Norvasc{01}]


10 mg (Rx) [Norvasc{01}]

Canada—


5 mg (Rx) [Norvasc{33.}]


10 mg (Rx) [Norvasc{33.}]

Packaging and storage:
Store at controlled room temperature between 15 and 30° C (59 and 86° F), in a tight, light-resistant container .{01}

Auxiliary labeling:
   • Do not take other medicines without physician's advice.



Revised: 05/12/2000



References
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