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299 AHFS cardiac agent

Administration and Dosage
Swallow extended-release tablets and sustained-release capsule forms whole; do not bite,
open, chew, crush, or divide.
AMLODIPINE: May be taken without regard to meals.
Hypertension - Usual dose is 5 mg once daily. Maximum dose is 10 mg once daily.
Small, fragile, or elderly patients or patients with hepatic function impairment may
be started on 2.5 mg once daily; or when adding amlodipine to other
antihypertensive therapy. In general, titrate over 7 to 14 days; proceed more
rapidly if clinically warranted.
Angina (chronic stable or vasospastic) - 5 to 10 mg, using the lower dose for
elderly patients and patients with hepatic function impairment. Most patients
require 10 mg.
Actions
Pharmacology: The calcium channel blockers share the ability to inhibit movement
of calcium ions across the cell membrane. The effects on the cardiovascular system
include depression of mechanical contraction of myocardial and smooth muscle
and depression of both impulse formation (automaticity) and conduction velocity.
Calcium channel blockers are classified by structure as follows:
Diphenylalkylamines - verapamil; benzothiazepines - diltiazem; dihydropyridines -
amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine.



Contraindications
Hypersensitivity to the drug; hypersensitivity to dihydropyridine calcium channel blockers
(nisoldipine); sick sinus syndrome or second- or third-degree AV block except with a
functioning pacemaker, hypotension less than 90 mm Hg systolic (diltiazem and
verapamil).
Diltiazem: Acute MI and pulmonary congestion.
Injectable -
o Sick sinus syndrome except in the presence of a functioning ventricular
pacemaker.
o Second- or third-degree AV block except in the presence of a functioning
ventricular pacemaker.
o Severe hypotension or cardiogenic shock.
o Hypersensitivity to the drug.
o Do not be administer IV diltiazem and IV beta-blockers together or in close
proximity (within a few hours).
o Atrial fibrillation or atrial flutter associated with an accessory bypass tract
such as in Wolff-Parkinson-White syndrome or short PR syndrome.
o Initial use of injectable forms of diltiazem should be, if possible, in a
setting where monitoring and resuscitation capabilities, including DC
cardioversion/defibrillation, are present. Once familiarity of the patient's
response is established, use in an office setting may be acceptable.
o Ventricular tachycardia.
o In newborns, because of the presence of benzyl alcohol (Cardizem Lyo-Ject
Syringe only).
Verapamil: Severe left ventricular dysfunction; cardiogenic shock and severe congestive
heart failure (CHF), unless secondary to a supraventricular tachycardia amenable to
verapamil therapy and in patients with atrial flutter or atrial fibrillation and an accessory
bypass tract.
Verapamil IV - Do not administer concomitantly with IV -adrenergic blocking
agents (within a few hours), because both may depress myocardial contractility and
AV conduction; ventricular tachycardia (VT), because use in patients with
widecomplex VT (QRS 0.12 seconds or more) can result in marked hemodynamic
deterioration and ventricular fibrillation; atrial fibrillation or atrial flutter
associated with an accessory bypass tract.
Nicardipine: Advanced aortic stenosis.
Warnings/Precautions
Hypotension: Hypotension, usually modest and well tolerated, may occasionally occur
during initial therapy or with dosage increases, and may be more likely in patients taking
concomitant -blockers.
CHF: CHF has developed rarely, usually in patients receiving a -blocker, after beginning
nifedipine.
Oral verapamil may precipitate heart failure. Control patients with milder
ventricular dysfunction with digitalis or diuretics before verapamil, if possible.
Use diltiazem, nicardipine, isradipine, felodipine, and amlodipine with caution in
CHF patients.
Cardiac conduction: IV verapamil slows AV nodal conduction and SA nodes; it rarely
produces second- or third-degree AV block, bradycardia, and in extreme cases, asystole.
This is more likely to occur in patients with sick sinus syndrome.
Oral verapamil - Oral verapamil may lead to first-degree AV block and transient
bradycardia, sometimes accompanied by nodal escape rhythms.
IV diltiazem - If second- or third-degree AV block occurs in sinus rhythm,
discontinue and institute appropriate supportive measures.
Premature ventricular contractions (PVCs): During conversion or marked reduction in
ventricular rate, benign complexes of unusual appearance (sometimes resembling PVCs)
may occur after IV verapamil.
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Hypertrophic cardiomyopathy: Serious adverse effects were seen in 120 patients with
hypertrophic cardiomyopathy (especially with pulmonary artery wedge pressure more than
20 mm Hg and left ventricular outflow obstruction) who received oral verapamil at doses
up to 720 mg/day. Sinus bradycardia occurred in 11%, second-degree AV block in 4%,
and sinus arrest in 2%.
Withdrawal syndrome: Abrupt withdrawal of calcium channel blockers may be associated
with an exacerbation of angina. Gradually taper the dose.
-blocker withdrawal: Patients recently withdrawn from -blockers may develop a
withdrawal syndrome with increased angina, probably related to increased sensitivity to
catecholamines. Initiation of nifedipine will not prevent this occurrence and might
exacerbate it by provoking reflex catecholamine release. Taper -blockers rather than
stopping them abruptly before beginning nifedipine.
Gradually reduce beta-blocker dose over 8 to 10 days with nicardipine
administration.
Hepatic function impairment: The pharmacokinetics, bioavailability, and patient response
to verapamil and nifedipine may be significantly affected by hepatic cirrhosis.
Because amlodipine, diltiazem, nicardipine, felodipine, and nimodipine are
extensively metabolized by the liver, use with caution in patients with hepatic
function impairment or reduced hepatic blood flow.
Renal function impairment: The pharmacokinetics of diltiazem and verapamil in patients
with renal function impairment are similar to the pharmacokinetic profile of patients with
normal renal function. However, caution is still advised. Nifedipine's plasma concentration
is slightly increased in patients with renal function impairment. Nicardipine's mean plasma
concentrations, AUC, and maximum concentration were about 2-fold higher in patients
with mild renal function impairment.
Increased angina: Occasional patients have increased frequency, duration, or severity of
angina on starting nifedipine or nicardipine, or at the time of dosage increases.
Duchenne muscular dystrophy: Verapamil may decrease neuromuscular transmission in
patients with Duchenne muscular dystrophy and prolong recovery from the neuromuscular
blocking agent vecuronium. Decrease in verapamil dosage may be necessary.
Acute hepatic injury: In rare instances, symptoms consistent with acute hepatic injury, as
well as significant elevations in enzymes such as alkaline phosphatase, CPK, LDH, AST,
and ALT, have occurred with diltiazem and nifedipine.
Elevations of transaminases with and without concomitant elevations in alkaline
phosphatase and bilirubin have occurred with verapamil.
Isolated cases of elevated LDH, alkaline phosphatase, and ALT levels have
occurred rarely with nimodipine.
Clinically significant transaminase elevations have occurred in approximately 1%
of patients receiving these agents; however, no patient became clinically
symptomatic or jaundiced, and values returned to normal when the drug was
stopped.
Edema: Edema, mild to moderate, typically associated with arterial vasodilation and not
due to left ventricular dysfunction, occurs in 10% to 30% of patients receiving nifedipine.
It occurs primarily in the lower extremities and usually responds to diuretics. In patients
with CHF, differentiate this peripheral edema from the effects of decreasing left
ventricular function.
Peripheral edema, generally mild and not associated with generalized fluid
retention, may occur with felodipine within 2 to 3 weeks of therapy initiation. The
incidence is both age- and dose-dependent, with frequency ranging from 10% in
patients less than 50 years of age taking 5 mg/day to 30% in patients more than 60
years of age taking 20 mg/day.
Pregnancy: Category C.
Lactation: Discontinue breast-feeding while taking amlodipine, diltiazem, nicardipine,
verapamil, or nimodipine. If using felodipine, isradipine, nifedipine, or nisoldipine,
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decide whether to discontinue breast-feeding or discontinue the drug, taking into account
the importance of the drug to the mother.
Children: Safety and efficacy of oral verapamil, diltiazem, felodipine, amlodipine,
nicardipine, nifedipine, nisoldipine, and isradipine have not been established. Use of
Procardia in the pediatric population is not recommended.
Controlled studies of IV verapamil have not been conducted in children, but
uncontrolled experience indicates that results of treatment are similar to those in
adults. Patients younger than 6 months of age may not respond to IV verapamil;
this resistance may be related to a developmental difference of AV node
responsiveness.
Elderly: Verapamil, nifedipine, and felodipine may cause a greater hypotensive effect than
that seen in younger patients, probably due to age-related changes in drug disposition.
Drug Interactions
Drugs that may affect calcium blockers include amiodarone, antineoplastics, azole
antifungals, barbiturates, beta blockers, calcium salts, carbamazepine, , cisapride,
cyclosporine, erythromycin, H2 antagonists, hydantoins, melatonin, nafcillin,
oxcarbazepine, quinupristine/dalfopristin, moricizine, quinidine, rifampin, ritonavir,
sparfloxacin, St. John's wort, valproic acid.
Drugs that may be affected by calcium blockers include anesthetics, antiarrhythmic agents,
antineoplastics, benzodiazepines, buspirone, carbamazepine, digoxin, dofetilide, ethanol,
HMG-CoA reductase inhibitors, imipramine, lithium, lovastatin, methylprednisolone,
moricizine, nondepolarizing muscle relaxants, prazosin, quinidine, sirolimus, tacrolimus,
theophyllines, and vincristine.
Diltiazem and verapamil inhibit other CYP3A4 substrates, whereas the dihydropyridines
do not.
Drug/Food interactions: Nifedipine, amlodipine, and verapamil may be administered
without regard to meals.
Bioavailability of felodipine is not affected by food, but increased more than 2-fold
when taken with doubly concentrated grapefruit juice versus water or orange juice.
Avoid high-fat meals and grapefruit juice with nisoldipine.
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Adverse Reactions
Generally not serious; rarely requires discontinuation or dosage adjustment.