Professional Information

Calcium Channel Blocking Agents (Systemic)

This monograph includes information on the following:

1) Amlodipine
2) Bepridil ^†
3) Diltiazem
4) Felodipine
5) Flunarizine ^*
6) Isradipine ^†
7) Nicardipine ^†
8) Nifedipine
9) Nimodipine
10) Verapamil

VA CLASSIFICATION
Amlodipine
Primary: CV200
Secondary: CV250; CV409

^{234}Bepridil
Primary: CV200
Secondary: CV250

Diltiazem
Primary: CV200
Secondary: CV250; CV300; CV409

Felodipine
Primary: CV200
Secondary: CV409

Flunarizine
Primary: CV200
Secondary: CN105

Isradipine
Primary: CV200
Secondary: CV409

Nicardipine
Primary: CV200
Secondary: CV250; CV409

Nifedipine
Primary: CV200
Secondary: CV250; CV409

Nimodipine
Primary: CV200

Verapamil
Primary: CV200
Secondary: CN105; CV250; CV300 ; CV409; CV900

Commonly used brand name(s): Adalat⁸; Adalat CC⁸; Adalat PA⁸; Adalat XL⁸; Apo-Diltiaz³; Apo-Nifed⁸; Apo-Verap¹⁰; Calan¹⁰; Calan SR¹⁰; Cardene⁷; Cardizem³; Cardizem CD³; Cardizem SR³; Dilacor-XR³; DynaCirc⁶; Isoptin¹⁰; Isoptin SR¹⁰; Nimotop⁹; Norvasc¹; Novo-Diltazem³; Novo-Nifedin⁸; Novo-Veramil¹⁰; Nu-Diltiaz³; Nu-Nifed⁸; Nu-Verap¹⁰; Plendil⁴; Procardia⁸; Procardia XL⁸; Renedil⁴; Sibelium⁵; Syn-Diltiazem³; Vascor²; Verelan¹⁰.

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

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Antianginal—Amlodipine; Bepridil; Diltiazem ; Felodipine ; Isradipine; Nicardipine; Nifedipine; Verapamil;

Antiarrhythmic—Diltiazem; Verapamil;

Antihypertensive—Amlodipine; Diltiazem; Felodipine; Isradipine; Nicardipine; Nifedipine; Verapamil;

Hypertrophic cardiomyopathy therapy adjunct—Verapamil;

Subarachnoid hemorrhage therapy— Flunarizine; Nicardipine; Nimodipine;

Vascular headache prophylactic— Flunarizine; Verapamil;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Angina pectoris, chronic (treatment)—Amlodipine, ^{234}^{235}bepridil ^{110} ^{204}, diltiazem ^{160}, [felodipine ] ^{135}, [isradipine] ^{129} ^{130} ^{131} ^{134}, nicardipine^{190}, nifedipine, and verapamil are indicated in the management of classic angina (chronic stable angina or effort-associated angina) with no evidence of vasospasm. Nicardipine , amlodipine ^{234}^{235} [and other calcium channel blocking agents] may be used alone or in combination, with caution, with beta-adrenergic blocking agents ^{64} ^{190}.
—Amlodipine, ^{234}^{235}diltiazem ^{160}, [felodipine] ^{135}, [ isradipine] ^{129} ^{130} ^{131} ^{134}, [nicardipine] ^{70}, nifedipine, and verapamil are also indicated in the management of vasospastic angina (Prinzmetal's variant, or at-rest angina) or unstable angina in patients who are unable to tolerate or whose symptoms are not relieved by adequate doses of beta-adrenergic blocking agents or organic nitrates. They are generally indicated when vasospastic angina is confirmed by: (a) the classical pattern accompanied by elevation of ST segment; (b) ergonovine-induced angina or coronary artery spasm; or (c) coronary artery spasm demonstrated by angiography, although they may also be used when a vasospastic component is indicated but not confirmed (e.g., where pain has a variable threshold on exertion or in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm) ^{196}.

Tachycardia, supraventricular (treatment and prophylaxis)—Verapamil and parenteral diltiazem are indicated in the treatment of supraventricular tachyarrhythmias. Diltiazem ^{161} and verapamil produce rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (including those associated with accessory bypass tracts, such as Wolff-Parkinson-White [W-P-W] or Lown-Ganong-Levine [L-G-L] syndrome) in patients who do not respond to vagal maneuvers ^{161} when the atrioventricular (AV) node is required for reentry to sustain tachycardia ^{125}. Parenteral diltiazem ^{161} and verapamil also produce temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation. Oral verapamil is indicated, alone or in association with digitalis, ^{169} for control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (not otherwise controllable with digitalis^{195}), and for prophylaxis of repetitive paroxysmal supraventricular tachycardia. Diltiazem and verapamil do not produce class I, II, or III antiarrhythmic effects.

Hypertension (treatment)—Amlodipine, ^{234}^{235} diltiazem, felodipine ^{01}, isradipine ^{206}, nicardipine ^{190}, nifedipine, and verapamil are indicated, alone or in combination with other agents ^{159} ^{190} ^{191} ^{196} ^{206}, for treatment of hypertension .
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

[Cardiomyopathy, hypertrophic (treatment adjunct) ]—Verapamil is used in the treatment of hypertrophic cardiomyopathy ^{195} to relieve ventricular outflow obstruction. However, extreme caution is recommended when hypertrophic cardiomyopathy is complicated by left ventricular obstruction, high pulmonary wedge pressure, paroxysmal nocturnal dyspnea or orthopnea, sinoatrial (SA) nodal function impairment, or severe heart block.

Raynaud's phenomenon (treatment)—[ Felodipine] ^{135}, [isradipine ] ^{129} ^{134}, [ nicardipine] , and [nifedipine]¹ are used for symptomatic treatment of Raynaud's phenomenon ^{71}.

Subarachnoid hemorrhage–associated neurologic deficits (treatment) —Nimodipine is indicated for improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured congenital intracranial aneurysms who are in good neurological condition post-ictus (e.g., Hunt and Hess Grades I–III) ^{140} ^{141} ^{142} ^{144} ^{146} ^{153} ^{154} ^{157}. [Flunarizine] ^{129} ^{134} and [nicardipine] ^{129} ^{134} are also used for this indication.

Headache, vascular (prophylaxis)—Flunarizine ^{205} and [verapamil] ^{129} ^{132} ^{133} ^{134} are indicated for reducing frequency and severity of vascular headaches, but are not recommended for treatment of acute attacks.

Acceptance not established
A preliminary study and case report suggest diltiazem may be used in pediatric patients for the treatment of pulmonary hypertension.^{{ 230}}^{231}^{232} However, data are insufficient to establish safety and efficacy of diltiazem for this indication.^{{ 230}}^{231}^{232}

Unaccepted
Sublingual use of nifedipine capsules for hypertensive crisis is not recommended because it has been associated with severe hypotension, acute myocardial infarction, stroke, and death ^{219}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Amlodipine besylate: 567.1 ^{234}
    Bepridil hydrochloride: 421.02
    Diltiazem hydrochloride: 450.98
    Felodipine: 384.26
    Flunarizine hydrochloride: 477.42
    Isradipine: 371.39
    Nicardipine hydrochloride: 515.99
    Nifedipine: 346.34
    Nimodipine: 418.45
    Verapamil hydrochloride: 491.07

Mechanism of action/Effect:

These agents are calcium-ion influx inhibitors (slow-channel blocking agents). Although their mechanism is not completely understood, they are thought to inhibit calcium ion entry through select voltage-sensitive areas termed “slow channels” across cell membranes. By reducing intracellular calcium concentration in cardiac and vascular smooth muscle cells, they dilate coronary arteries and peripheral arteries and arterioles, and may reduce heart rate, decrease myocardial contractility (negative inotropic effect), and slow atrioventricular (AV) nodal conduction. Serum calcium concentrations are unchanged, although there is some evidence that elevated serum calcium concentrations may alter the therapeutic effect of verapamil ^{169}.

Calcium channel blocking agents may be classified into subgroups according to structure:

Bepridil.

Benzothiazepine (diltiazem) ^{109} ^{115} ^{117} ^{118}.

Diphenylpiperazine (flunarizine) ^{117} ^{118}.

Dihydropyridine ( amlodipine, ^{234}felodipine, isradipine, nicardipine, nifedipine, nimodipine) ^{01} ^{109} ^{110} ^{111} ^{113} ^{115} ^{117} ^{118} ^{206}.

Diphenylalkylamine (verapamil) ^{117}.

Effects within each subgroup are generally the same:

Bepridil is a nonselective calcium channel blocking agent that affects both cardiac and smooth muscle ^{113} ^{114} ^{204}. It also inhibits the fast sodium inward current in myocardial and vascular smooth muscle ^{204}.

Piperazine derivatives act on vascular smooth muscle, with few or no direct myocardial effects ^{113} ^{114}.

Dihydropyridines are selective for vascular smooth muscle compared with myocardium and therefore act primarily as vasodilators ^{111} ^{113} ^{114} ^{115}. Hypotensive effects are accompanied by reflex tachycardia ^{111}. However, amlodipine appears to have no significant effect on the sinoatrial (SA) or atrioventricular (AV) node in humans. ^{234}

Diltiazem (a benzothiazepine) and verapamil (a diphenylalkylamine) are less selective vasodilators that also have direct effects on the myocardium, including depression of sinoatrial (SA) and atrioventricular (AV) nodal conduction ^{111} ^{114} ^{115}.

Table 1. Pharmacology/Pharmacokinetics

Hemodynamic effect	Legend ^: I = Bepridil II = Diltiazem III* = Felodipine IV = Flunarizine V = Isradipine					VI = Nicardipine VII = Nifedipine VIII = Nimodipine IX = Verapamil X = Amlodipine
Hemodynamic effect	I	II	III	IV	V	VI	VII	VIII	IX	X
Peripheral vasodilation	+	+	++	+	++	++	++	++	+	++
Heart rate	D	D	I ^†	N	I ^†	I ^†	I ^†	I ^†	D	N
Depression of sinoatrial (SA) or atrioventricular (AV) nodal conduction	+	+	-	-	-	-	-	-	+	-
Negative inotropic effect ^{127} ^{128}	+ ^‡	+/-	+/- ^‡	-	+/- ^‡	+/- ^‡	+/- ^‡	+/- ^‡	+ ^‡	-
Antihypertensive effect	-	+	+	-	+	+	+	+	+	+
Cerebrovascular selectivity				+		+		+

^* Legend: I = Increase; D = Decrease; N = No effect; + = Some effect; ++ = Significant effect; - = No effect.
^† Reflex increase occurs in response to vasodilating action. Isradipine causes only a slight increase or no change^{121}.
^‡ Bepridil's negative inotropic effect is small and tends to occur at high doses^{110}^{204}.
For felodipine, isradipine, nicardipine, nifedipine, and nimodipine, the effect is masked by the reflex increase in heart rate.
The effect of verapamil is countered by a reduction in afterload.

Antianginal:

Dilation of the peripheral vasculature reduces systemic pressure or cardiac afterload, which results in lessened myocardial wall tension^{126} and reduced oxygen requirements of the myocardial tissues^{204}. In vasospastic angina, a relaxation of coronary arteries and arterioles and inhibition of coronary artery spasm^{169}^{187} improves blood flow and oxygen supply to myocardial tissues^{64}^{72}. May also be related to enhanced left ventricular diastolic relaxation and decreased wall stiffness^{29} (improved diastolic compliance).^{126}In vasospastic angina, amlodipine blocks constriction and restores blood flow in coronary arteries and arterioles in response to calcium, potassium, epinephrine, serotonin, and thromboxane A₂ analog in human coronary vessels in vitro^{234}.

Antiarrhythmic:

The inhibited influx of calcium ions in cardiac tissues prolongs the effective refractory period and results in slowed AV nodal conduction^{169}. Normal sinus rhythm is usually not affected, except in some elderly patients^{101} or patients with sick sinus syndrome^{204}, in whom calcium channel blockade may interfere with sinus-node impulse generation and may induce sinus or sinoatrial block^{169}. Normal atrial action potential or intraventricular conduction are not altered, but in depressed atrial fibers amplitude, velocity of depolarization, and conduction velocity are decreased^{169}. The antegrade effective refractory period of the accessory bypass tract may be shortened^{169}.

Antihypertensive:

Reduction of total peripheral vascular resistance as a result of vasodilation.

Hypertrophic cardiomyopathy therapy adjunct:

Improvement of left ventricular outflow. May also be related to enhanced left ventricular diastolic relaxation and decreased wall stiffness^{29}.

Subarachnoid hemorrhage therapy:

Theoretically, nimodipine may prevent cerebral arterial spasm following subarachnoid hemorrhage, but that has not been confirmed by arteriography^{140}^{142}^{144}^{153}. Its exact mechanism of action in treatment of neurologic deficits caused by subarachnoid hemorrhage is not known^{140}^{144}^{153}.

Vascular headache prophylactic:

By inhibiting the vasoconstriction that occurs in the prodromal phase, calcium channel blockade may relieve or prevent reactive vasodilation^{121}.

Other actions/effects:

Inhibition of platelet aggregation^{66}^{67} ^{69} ^{146}^{196}. Decrease in esophageal contraction amplitude^{61}^{62}^{146}. Diltiazem and verapamil may inhibit cytochrome P450^{03}^{14}^{26} ^{160} metabolism, thereby inhibiting the metabolism of other medications or compounds. Flunarizine has antihistaminic effects^{205}. Isradipine has diuretic effects^{206}. Verapamil decreases gastrointestinal transit time^{171}.

Absorption:

Amlodipine—bioavailability 64 to 90% absorption, not affected by food.^{234}

Bepridil—Rapid and complete^{110}^{204}; bioavailability 60 to 70% because of first-pass metabolism^{110}; rate, but not extent of absorption, is reduced in the presence of food ^{110}^{204}.

Diltiazem—Well absorbed ^{192}^{193}; bioavailability approximately 40% because of first-pass metabolism^{160}; bioavailability may increase with chronic use and increasing dose (i.e., bioavailability is nonlinear)^{159}^{191}.

Felodipine—Almost completely absorbed^{01}; bioavailability approximately 20% because of first-pass metabolism^{01}. Bioavailability is not affected in the presence of food; however, bioavailability more than doubled when felodipine was taken with doubly concentrated grapefruit juice as compared to when it was taken with water or orange juice (a similar, but lesser, effect is also seen with other dihydropyridines)^{01}.

Flunarizine—Well absorbed^{205}.

Isradipine—Absorption is 90 to 95%^{206}; bioavailability approximately 15 to 24% because of first-pass metabolism ^{206}; rate, but not extent, of absorption is reduced in the presence of food ^{206}.

Nicardipine—Completely absorbed ^{190}; bioavailability approximately 35% because of first-pass metabolism ^{190}.

Nifedipine—Rapidly and completely absorbed ^{164} ^{166}; bioavailability approximately 60 to 75% because of first-pass metabolism ^{164} ^{166}. Bioavailability of extended-release formulations may be 10 to 15% lower than that of immediate-release formulations, but plasma concentrations are more stable, with smaller fluctuations over the dosing interval ^{220} ^{222} ^{223}. Bioavailability of both formulations is increased with hepatic function impairment ^{165}. Rate, but not extent, of absorption of Procardia XL may be reduced in the presence of food ^{196}.

Nimodipine—Rapidly absorbed ^{140}. Because of extensive first-pass metabolism, biovailability is only about 13% (significantly increased [up to double the peak serum concentration] in patients with hepatic function impairment) ^{140}. The effect of food on absorption is unknown ^{140}.

Verapamil—More than 90% of an oral dose is absorbed ^{170} ^{180}; bioavailability approximately 20 to 35% because of first-pass metabolism ^{170} ^{180}; bioavailability of oral verapamil may increase with chronic use and increasing dose (i.e., bioavailability is nonlinear) ^{169}.

Distribution:

Bepridil—In breast milk: Concentration is approximately one-third serum concentration ^{204}.

Protein binding:

Amlodipine—Very high (93%) ^{234}.

Bepridil—Very high (more than 99%) ^{110} ^{204}.

Diltiazem—High (70 to 80% ^{158}, 35 to 40% to albumin).

Felodipine—Very high (more than 99%) ^{01}.

Flunarizine—Very high (99%) ^{205}.

Isradipine—Very high (95%) ^{206}.

Nicardipine—Very high (more than 95%) ^{190}.

Nifedipine—Very high (92 to 98%) ^{165}.

Nimodipine—Very high (over 95%); independent of concentration ^{140} ^{145}.

Verapamil—Very high (approximately 90%) ^{175}.

Biotransformation:

Hepatic ^{140} ^{145} ^{160} ^{161}; extensive and rapid, with a prominent first-pass effect ^{110}.

Amlodipine—Extensive hepatic metabolism; 90% converted to inactive metabolites ^{234}.

Bepridil—At least 17 metabolites, 1 or more of which may have cardiovascular activity ^{120}.

Diltiazem—By cytochrome P450 mixed function oxidase ^{160}. A major metabolite, detected following oral and continuous intravenous administration but not rapid intravenous administration ^{161}, is desacetyl diltiazem, which has one quarter to one half the coronary dilatation activity of the parent compound ^{160}.

Felodipine—Six metabolites, accounting for 23% of an oral dose, have been identified; none has significant vasodilating activity ^{01}.

Isradipine—Completely metabolized; six metabolites identified ^{206}.

Nifedipine—No known active metabolites.

Verapamil—Principal metabolite is norverapamil, which has approximately 20% of the hypotensive cardiovascular activity of verapamil ^{29} ^{102} ^{169}; 11 other metabolites occur only in trace amounts ^{169}.

Half-life:

Amlodipine (biphasic) ^{234}:

Elimination:

Terminal: 30 to 50 hours ^{234}

Bepridil (biphasic) ^{204}:

Distribution—

Approximately 2 hours ^{204}.

Elimination—

Terminal: Average, 42 hours (range, 26 to 64 hours) ^{204}.

Dosing interval: Less than 24 hours ^{204}.

Diltiazem:

Oral (biphasic)—

Extended-release capsules—

Cardizem CD: Apparent—5 to 8 hours ^{193}.

Cardizem SR: Apparent—5 to 7 hours ^{191}.

Tablets—

Early: 20 to 30 minutes.

Terminal: Approximately 3.5 hours ^{159} (5 to 8 hours with high and repetitive dosage ^{29}).

Intravenous—

Approximately 3.4 hours ^{161}.

Felodipine (polyphasic) ^{01}:

Terminal—

11 to 16 hours ^{01}.

Flunarizine:

19 days ^{205}.

Isradipine (biphasic) ^{206}:

Early: 1.5 to 2 hours ^{206}.

Terminal: About 8 hours ^{206}.

Nicardipine (biphasic):

Early: 2 to 4 hours ^{190}.

Terminal: 8.6 hours ^{190}.

Nifedipine:

Approximately 2 hours ^{165} ^{197}.

Extended-release tablets—

Adalat CC: Terminal—Approximately 7 hours ^{229}

Adalat PA: Terminal—6 to 12 hours ^{228}

Adalat XL, Procardia XL: Not available. The gastrointestinal therapeutic system (GITS) is designed to deliver nifedipine by zero-order systemic absorption over a period of approximately 18 hours ^{{ 230}}.

Nimodipine:

Terminal: 8 to 9 hours. Earlier, more rapid elimination rates (equivalent to a half-life of 1 to 2 hours) necessitate frequent dosing. ^{140}

Verapamil:

Oral—

Single dose—Range, 2.8 to 7.4 hours.

Repetitive dosage—Range, 4.5 to 12 hours (half-life is increased because of saturation of hepatic enzyme systems as plasma verapamil concentrations increase).

Intravenous (biphasic)—

Early—About 4 minutes.

Terminal—2 to 5 hours.

Onset of action:

Diltiazem:

Oral—

Extended-release capsules—2 to 3 hours ^{87}.

Tablets—30 to 60 minutes.

Parenteral—

Rapid intravenous injection—

Reduction in heart rate or conversion of paroxysmal supraventricular tachycardia to sinus rhythm: Within 3 minutes ^{161}.

Felodipine:

Within 2 to 5 hours ^{01}.

Isradipine:

2 to 3 hours ^{206}.

Nifedipine:

Oral—

Capsules—20 minutes.

Verapamil:

Oral—

1 to 2 hours.

Intravenous—

Antiarrhythmic—Within 1 to 5 minutes and usually less than 2 minutes.

Hemodynamic—Within 3 to 5 minutes.

Time to peak concentration:

Amlodipine:

6 to 12 hours ^{234}.

Bepridil:

2 to 3 hours ^{110} ^{204}.

Diltiazem:

Oral (wide individual variation in concentrations achieved ^{159})—

Extended-release capsules—

Cardizem CD: 10 to 14 hours ^{193}.

Cardizem SR: 6 to 11 hours ^{191}.

Tablets—

2 to 3 hours ^{160}.

Felodipine:

2.5 to 5 hours ^{01}. Peak plasma concentrations at steady state are about 20% higher than after a single dose ^{01}.

Flunarizine:

2 to 4 hours ^{205}.

Isradipine:

About 1.5 hours ^{206}.

Nicardipine:

30 minutes to 2 hours (mean, 1 hour) ^{190}.

Nifedipine:

Capsules—

About 30 to 60 minutes ^{88}.

Extended-release tablets—

Adalat CC—2.5 to 5 hours ^{220}

Adalat PA—4 hours ^{88}.

Adalat XL ^{222}, Procardia XL—Approximately 6 hours ^{196}.

Nimodipine:

Within 1 hour ^{140} ^{145}.

Verapamil:

Oral—

Extended-release capsules—7 to 9 hours ^{202}.

Tablets—1 to 2 hours (wide individual variation in concentrations achieved).

Extended-release tablets—5 to 7 hours.

Time to peak effect:

Amlodipine:

Time to steady-state plasma concentration: 7 to 8 days ^{234}.

Bepridil:

Time to steady-state plasma concentration: 8 days ^{204}.

Diltiazem:

Antihypertensive: Multiple doses—Within 2 weeks ^{191}.

Antiarrhythmic: Rapid intravenous injection—Hypotension or reduction in heart rate: Within 2 to 7 minutes ^{161}.

Flunarizine:

Multiple doses: Several weeks ^{205}.

Isradipine:

Antihypertensive: Multiple doses—2 to 4 weeks ^{206}.

Nicardipine:

Single dose: 1 to 2 hours ^{190}.

Verapamil:

Oral: About 30 to 90 minutes. The maximum effects from oral dosage are usually evident sometime during the first 24 to 48 hours of therapy (for some patients the time may be slightly extended because the half-life of verapamil tends to increase during this period).

Intravenous: Within 3 to 5 minutes after completion of injection.

Elimination:

Amlodipine—
        Renal: 60% as metabolites and 10% as unchanged amlodipine.^{234}

Bepridil—
        Renal: 70% (none unchanged) ^{204}.
        Biliary/fecal: 22% (none unchanged) ^{204}.
        In dialysis: Not removable by hemodialysis ^{120}.

Diltiazem—
        Biliary and renal (2 to 4% unchanged) ^{159} ^{191}.
        In dialysis: Does not appear to be removable by hemodialysis or peritoneal dialysis ^{160}.

Felodipine—
        Renal: 70% (less than 0.5% unchanged) ^{01}.
        Biliary/fecal: 10% (less than 0.5% unchanged) ^{01}.

Flunarizine—
        Drug and metabolites: Very slow and prolonged ^{205}.
        Biliary/fecal: Less than 6% in the first 48 hours ^{205}.
        Renal: Less than 0.2% in the first 48 hours ^{205}.

Isradipine—
        Renal: 60 to 65% (none unchanged) ^{206}.
        Biliary/fecal: 25 to 30% (none unchanged) ^{206}.
        In dialysis: No information, but not likely to be removable by hemodialysis because of plasma protein binding ^{206}.

Nicardipine—
        Renal: 60% (less than 1% unchanged) ^{190}.
        Biliary/fecal: 35% ^{190}.

Nifedipine—
        Renal: 80% (as metabolites), only traces unchanged ^{196}.
        Biliary/fecal: 20% (as metabolites) ^{196}.
        In dialysis: Does not appear to be removed by hemodialysis or chronic ambulatory peritoneal dialysis ^{196}; however, plasmapheresis may be beneficial ^{165}.

Nimodipine—
        Renal (less than 1% unchanged) ^{140} ^{143}.
        Biliary/fecal ^{140} ^{142}.
        In dialysis: Because of extensive protein binding, unlikely to be significantly removed by hemodialysis or peritoneal dialysis ^{140}.

Verapamil—

Renal—
        As conjugated metabolites—70% as metabolites and 3 to 4% unchanged within 5 days ^{169}.
        Unmetabolized—3%.

Biliary/fecal—
        9 to 16%.

In dialysis—
        Not removable by hemodialysis ^{29} ^{183}.

Precautions to Consider

Carcinogenicity/Mutagenicity

For amlodipine

No evidence of carcinogenicity was found in rats or mice given dosages of 0.5, 1.25, and 2.5 mg per kg of body weight (mg/kg) per day for 2 years.^{234}

No mutagenicity was found in studies at either the gene or chromosome level.^{234}

For bepridil

A lifetime study in mice at doses up to 60 times the maximum recommended human dose (MRHD) (based on a 60-kg subject) found no evidence of carcinogenicity. A lifetime study in rats at doses 20 times the usual recommended human dose found unilateral follicular adenomas of the thyroid ^{204}.

Mutagenicity studies (micronucleus test for chromosomal effects, liver microsome activated bacterial assay for mutagenicity, Chinese hamster ovary cell assay for mutagenicity, sister chromatid exchange assay) were negative ^{204}.

For diltiazem

A 24-month study with diltiazem in rats and a 21-month study in mice found no evidence of carcinogenicity.

There was no mutagenic response in in vitro bacterial tests. ^{160}

For felodipine

A 2-year study in rats at doses of 7.7, 23.1, or 69.3 mg per kg of body weight (mg/kg) per day (up to 28 times the MRHD [based on a 50-kg subject]) found an increased incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) in males, probably secondary to a reduction in testicular testosterone and corresponding increase in serum luteinizing hormone (which have not been observed in humans). In addition, a dose-related increase in the incidence of focal squamous cell hyperplasia in the esophageal groove of both males and females at all doses (humans have no anatomical structure comparable to the esophageal groove). Felodipine was not carcinogenic and did not increase the incidence of Leydig cell tumors in mice at doses up to 138.6 mg/kg per day (28 times the MRHD [based on a 50-kg subject]) for periods up to 80 and 99 weeks in males and females, respectively; no effect on the esophageal groove occurred. ^{01}

Mutagenicity studies (Ames test, mouse lymphoma forward mutation assay, mouse micronucleus test, human lymphocyte chromosome aberration assay) were negative ^{01}.

For flunarizine

A 24-month study in 4 groups of 50 male and 50 female Wistar rats at doses of 0, 5, 20, or 40 mg/kg per day (the 40-mg/kg group received 80 mg/kg for the first 2 months) did not produce an effect on tumor rate or type; however, the validity of the study is questionable because of an extremely high mortality rate (more than 90% in the males and 80% in the females) ^{205}.

Mutagenicity studies (Ames test, sister chromatid exchange test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster , micronucleus test in male rats, dominant lethal test in male and female mice) were negative ^{205}.

For isradipine

A 2-year study in male rats at doses of 2.5, 12.5, or 62.5 mg/kg per day (approximately 6, 31, and 156 times the MRHD, respectively, based on a 50-kg subject) found a dose-dependent increase in the incidence of benign Leydig cell tumors and testicular hyperplasia relative to untreated control animals; these findings were replicated in a subsequent study. A 2-year study in mice at doses of 6, 38, and 200 times the MRHD found no evidence of oncogenicity ^{206}.

Mutagenicity studies were negative ^{206}.

For nicardipine

A 2-year study in rats with nicardipine at dosage levels of 5, 15, or 45 mg/kg per day found a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month studies in the rat suggest that the mechanism for this effect is a nicardipine-induced reduction in plasma thyroxine (T ₄) concentrations with a resulting increase in thyroid-stimulating hormone (TSH) concentrations, which is known to cause hyperstimulation of the thyroid; in rats on an iodine-deficient diet, one month of nicardipine administration produced thyroid hyperplasia that was prevented by T ₄ supplementation. Studies in mice for up to 18 months at doses up to 100 mg/kg per day and in dogs for 1 year at doses up 25 mg/kg per day found no evidence of neoplasia of any tissue and no evidence of thyroid changes. No effects of nicardipine on thyroid function (plasma T ₄ and TSH) have been reported in humans. ^{190}

No evidence of mutagenicity was found in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters ^{190}.

For nifedipine

Nifedipine was not shown to be carcinogenic when administered orally to rats for 2 years.

In vivomutagenic tests were negative. ^{196}

For nimodipine

A 2-year study in rats found an increased incidence of adenocarcinoma of the uterus and Leydig-cell adenoma of the testes, but the increases were not significant. A 91-week study in mice found no evidence of carcinogenicity, although the life expectancy was shortened. ^{140}

Mutagenicity studies, including the Ames, micronucleus, and dominant lethal tests, have been negative ^{140}.

For verapamil

A 2-year study in rats with verapamil at doses up to 12 times the MRHD found no evidence of carcinogenicity ^{29}.

There was no mutagenic response in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation.

Pregnancy/Reproduction
Fertility—

Amlodipine

No effects were seen on the fertility of rats treated with amlodipine at doses up to 10 mg per kg per day, which represents 8 times the maximum recommended human dose.^{234}

For felodipine

No significant effect on reproductive performance was found in male or female rats given doses of 3.8, 9.6, or 26.9 mg/kg per day ^{01}.

For flunarizine

In studies in male and female Wistar rats at doses of 0 and approximately 10, 40, and 160 mg/kg given for 60 days pre-mating in the males or 14 days pre-mating and 21 days of gestation in the females, treated animals were mated with non-treated animals. In treated females at the highest dose, there were no pregnancies and a large number of deaths; at the 40-mg/kg dose, there was decreased weight gain during pregnancy, decreased rate of pregnancy, increase in the number of resorbed fetuses, decreased litter size, and decreased weight of pups at birth. In non-treated females mated with treated males, a slight increase in resorption was seen only at the highest dose. ^{205}

For nifedipine

Reduced fertility occurred in rats given 30 times the maximum recommended human dose (MRHD) prior to mating.

Pregnancy—

For amlodipine

Adequate and well-controlled studies have not been done in humans. ^{234}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. ^{234} However, in rats the number of intrauterine deaths increased about five-fold, and litter size was significantly decreased by 50%. ^{234}

FDA Pregnancy Category C. ^{234}

For bepridil

Adequate and well-controlled studies in humans have not been done.

Studies in rats at maternal doses of 37 times the MRHD found reduced litter size at birth and decreased pup survival during lactation. No teratogenicity was observed in rats or rabbits at the same dose. ^{204}

FDA Pregnancy Category C.

For diltiazem

Well-controlled studies in humans have not been done.

Studies in mice, rats, and rabbits, using doses of diltiazem 5 to 10 times greater than the recommended daily dose on a mg/kg basis, resulted in embryo and fetal deaths, reduced neonatal survival rates, and skeletal abnormalities. In addition, there was an increased incidence of stillbirths at doses of 20 or more times the recommended human dose. ^{160}

FDA Pregnancy Category C.

For felodipine

Adequate and well-controlled studies in humans have not been done ^{01}.

Studies in rabbits at doses of 0.46, 1.2, 2.3, and 4.6 mg/kg per day (from 0.4 to 4 times the MRHD [based on a 50-kg subject] on a mg per square meter of body surface area basis) found digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. Frequency and severity of the changes were dose-related and occurred even at the lowest dose. These changes are similar to those occurring with other dihydropyridines and may be the result of compromised uterine blood flow. The anomalies did not occur in rats; abnormal position of the distal phalanges (but not reduction in size of the terminal phalanges) occurred in about 40% of cynomolgus monkey fetuses. ^{01}

Studies in rats at doses of 9.6 mg/kg per day (4 times the MRHD [based on a 50-kg subject] on a mg per square meter of body surface area basis) produced a prolongation of parturition with a difficult labor and an increased frequency of fetal and early postnatal deaths ^{01}.

Studies in rabbits at doses greater than or equal to 1.2 mg/kg per day (equal to the MRHD on a mg per square meter of body surface area basis) found significant enlargement (in excess of normal) of the mammary glands during pregnancy, which regressed during lactation. These effects were not observed in rats or monkeys. ^{01}

FDA Pregnancy Category C.

For flunarizine

Studies in humans have not been done.

There was a slight increase in resorptions and decrease in number of live fetuses in female Wistar rats given 40 mg/kg, with no effects seen at doses of 0, 10, or 20 mg/kg; there was no evidence of teratogenicity ^{205}. There was a dose-related increase in the number of resorptions in New Zealand rabbits given doses of 0, 2.5, or 10 mg/kg from day 6 to day 18 of pregnancy, with a corresponding decrease in number of live births; there was no evidence of teratogenicity ^{205}.

For isradipine

Studies in humans have not been done.

Studies in rats at doses of 6, 20, or 60 mg/kg per day produced a significant reduction in maternal weight gain at the highest dose (150 times the MRHD), but with no lasting effects on the mother or offspring. Studies in rabbits at doses of 1, 3, or 10 mg/kg per day (2.5, 7.5, and 25 times the MRHD, respectively) found decreased maternal weight gain and increased fetal resorptions at the two highest doses. There was no evidence of embryotoxicity at doses that were not maternotoxic and no evidence of teratogenicity at any dose. With peri- and postnatal administration of doses of 20 and 60 mg/kg per day, reduced maternal weight gain during late pregnancy was associated with reduced birth weights and decreased peri- and postnatal pup survival. ^{206}

FDA Pregnancy Category C.

For nicardipine

Adequate and well-controlled studies in humans have not been done.

Studies in Japanese White rabbits at doses of 150 mg/kg per day during organogenesis (but not at doses of 50 mg/kg per day [25 times the MRHD]) found nicardipine to be embryocidal and to cause marked body weight gain suppression in the treated doe. Studies in rats with nicardipine at doses 50 times the MRHD found no evidence of embryolethality or teratogenicity, but dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain occurred ^{190}.

FDA Pregnancy Category C.

For nifedipine

Adequate and well-controlled studies in humans have not been done.

Nifedipine has been shown to be teratogenic in rodents and embryotoxic (increased fetal resorptions, reduced fetal weight, increase in stunted forms, increased fetal deaths, and decreased fetal survival) in rodents and rabbits at doses 30 times and 3 to 10 times the MRHD, respectively. In pregnant monkeys, small placentas and underdeveloped chorionic villi occurred at two thirds and two times the MRHD. In rats, three times or more the MRHD caused prolongation of pregnancy.

FDA Pregnancy Category C.

For nimodipine

Adequate and well-controlled studies in humans have not been done.

Two studies in Himalayan rabbits found an increased incidence of teratogenic malformations in the fetuses at doses of 1 and 10 (but not 3) mg/kg per day given on days 6 through 18 of pregnancy; in these same studies, stunted fetuses were found at doses of 1 and 10 (but not 3) mg/kg per day in one study, and only at 1 mg/kg per day in the other. Studies in Long Evans rats at doses of 100 mg/kg per day given on days 6 through 15 found embryotoxicity, including fetal resorption and stunted fetal growth. In other rat studies, doses of 30 mg/kg per day from days 16 to 20 or 21 produced an increased incidence of skeletal variation, stunted fetuses, and stillbirths, but no malformations. ^{140}

FDA Pregnancy Category C.

For verapamil

Adequate and well-controlled studies in humans have not been done.

Verapamil crosses the placenta and can be detected in umbilical vein blood at delivery ^{169}. Occasionally, rapid intravenous injection of verapamil in humans may cause maternal hypotension resulting in fetal distress.

Studies in rats, using doses of verapamil up to 6 times the recommended daily dose for humans, resulted in embryo deaths and slowed growth.

FDA Pregnancy Category C.

Breast-feeding

For all calcium channel blocking agents:

Although problems in humans have not been documented, bepridil ^{204}, diltiazem ^{28} ^{159} ^{191}, nifedipine ^{65} ^{165}, and verapamil ^{30} ^{169} ^{180}, and possibly other calcium channel blocking agents, are distributed into breast milk.

For felodipine and amlodipine only:

It is not known whether felodipine or amlodipineis distributed into breast milk in humans ^{01} ^{234}.

For flunarizine only:

It is not known whether flunarizine is distributed into breast milk in humans; however, it is distributed into the milk of dogs, at concentrations much higher than in plasma ^{205}.

For nimodipine only:

It is not known whether nimodipine is distributed into breast milk in humans; however, nimodipine and/or its metabolites have been found in the milk of treated rats, at concentrations much higher than maternal plasma concentrations ^{140}.

Pediatrics

Although appropriate studies on the relationship of age to the effects of calcium channel blocking agents have not been performed in the pediatric population, pediatrics-specific problems that would limit the usefulness of calcium channel blocking agents in children are not expected. However, in rare instances, severe adverse hemodynamic effects have occurred after intravenous administration of verapamil in neonates and infants ^{30}.

Geriatrics

For diltiazem ^{60},nimodipine ^{146}^{147}^{149},verapamil^{59}^{169}^{180},and possibly other calcium channel blocking agents:

Half-life of calcium channel blocking agents may be increased in the elderly as a result of decreased clearance.

For amlodipine only:

Due to a decreased clearance of amlodipine with a resulting increase in AUC of 40 to 60%, a lower initial dose may be required.^{234}

For felodipine only:

Plasma concentrations increase with age ^{01}. Mean clearance at mean age of 76 was found to be only 45% of that at mean age of 26 ^{01}.

For isradipine only:

Bioavailability may be increased in patients over 65 years of age ^{206}.

For nicardipine only:

Studies in patients 65 years of age and older found no difference in half-life or protein binding from that in young normal volunteers ^{190}.

For nimodipine only:

Risk of hypotension may be increased ^{146} ^{147} ^{149}.

For all calcium channel blocking agents:

Elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving calcium channel blocking agents ^{86}.

Pharmacogenetics

Pharmacogenetic differences with amlodipine

In clinical trials there was a greater incidence of edema, flushing and palpitations seen in women than in men^{234}

Dental

Gingival enlargement is a rare side effect that has been reported with amlodipine, diltiazem, felodipine, nifedipine, and verapamil. It usually starts as gingivitis or gum inflammation in the first 1 to 9 months of treatment. A strictly enforced program of teeth cleaning by a professional 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. ^{01} ^{05} ^{06} ^{07} ^{08} ^{09} ^{234} ^{10} ^{11} ^{30} ^{95} ^{205}

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: Information concerning interactions between calcium channel blocking agents and other medications is still limited. Therefore, some of the following potential interactions are stated for cautionary reference until additional information is available.
Combinations containing any of the following medications, depending on the amount present, may also interact with these medications.

Anesthetics, hydrocarbon inhalation    (concurrent use with calcium channel blocking agents 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 ^{35} ^{36} ^{37} ^{38} ^{39} ^{160} ^{180} ^{206})

Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin     (indomethacin, and possibly other NSAIDs, may antagonize the antihypertensive effect of calcium channel blocking agents by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained ^{122}.Amlodipine was not affected by coadministration with NSAIDs.^{234} )

» Beta-adrenergic blocking agents, systemic or ophthalmic     (concurrent use of oral dosage forms with oral bepridil ^{204}, diltiazem ^{160}, or verapamil ^{180} or intravenous verapamil usually results in no serious negative inotropic, chronotropic, or dromotropic effects. However, caution and careful monitoring are necessary since the additive effect may prolong sinoatrial [SA] and atrioventricular [AV] conduction [which may lead to severe hypotension, bradycardia, and cardiac failure], especially in patients with impaired ventricular function or abnormal cardiac conduction or sinus node depression ^{29}. When verapamil and beta-adrenergic blocking agents are to be given intravenously, they should be administered at least a few hours apart since they may have additive depressant effects on myocardial contractility or SA or AV conduction, and asystole has been reported with concurrent use)

    (In clinical trials amlodipine has been safely administered with beta-adrenergic blocking agents.^{234})

    (in a single small study, diltiazem was reported to significantly increase the bioavailability of propranolol ^{159}; in other studies, verapamil was found to decrease clearance of both metoprolol and propranolol, with a variable effect on atenolol ^{171})

    (concurrent use with dihydropyridines, although usually well tolerated, may produce excessive hypotension, and in rare cases may increase the possibility of congestive heart failure ^{01}. Occasionally, angina has occurred upon initiation of nicardipine ^{190} or nifedipine therapy, especially after recent abrupt discontinuation of beta-adrenergic blocking agent therapy. If possible, it is recommended that beta-adrenergic blocking agent dosage be discontinued gradually, but especially before nicardipine or nifedipine therapy is begun. However, if concurrent use is necessary, nicardipine or nifedipine may be preferred over other calcium channel blocking agents in some patients because both have less effect on heart rate and conduction )

    (if significant systemic absorption of an ophthalmic beta-adrenergic blocking agent ^{174} ^{180} occurs, concurrent use of calcium channel blocking agents may result in atrioventricular conduction disturbances, left ventricular failure, and hypotension; in some patients, if a calcium antagonist is necessary, nicardipine or nifedipine may be preferred because both have less effect on heart rate and conduction, although they may also cause greater hypotension; concurrent use of calcium channel blocking agents and ophthalmic beta-adrenergic blocking agents should be avoided in patients with impaired cardiac function)

Calcium supplements    (concurrent use in quantities sufficient to elevate serum calcium concentrations above normal ^{30} may reduce the response to verapamil and probably other calcium channel blocking agents ^{12} ^{17} ^{31})

» Carbamazepine ^{23} ^{24} ^{25} ^{26} ^{54} ^{55} ^{169} ^{180} or
» Cyclosporine ^{13} ^{20} ^{21} ^{22} ^{41} ^{42} ^{169} ^{180} ^{190} or
» Quinidine ^{13} ^{27} or
Theophylline ^{13} ^{171} or
Valproate ^{13}    (diltiazem or verapamil may inhibit cytochrome P450 ^{03} ^{14} ^{26} ^{160} metabolism, resulting in increased concentrations and toxicity of these medications)

    (an idiosyncratic reaction has been reported in which concurrent use of nifedipine and quinidine resulted in significantly reduced serum quinidine concentrations; caution is recommended when nifedipine therapy is initiated or discontinued in a patient stabilized on quinidine ^{49} ^{50} ^{51} ^{52} ^{165})

Cimetidine    (concurrent use may result in accumulation of the calcium channel blocking agent as a result of inhibition of first-pass metabolism; caution and careful titration of the calcium channel blocking agent dose is recommended on initiation of therapy in patients receiving cimetidine ^{01} ^{146} ^{151} ^{190} ^{191}; ranitidine and famotidine do not appear to significantly affect calcium channel blocking agent metabolism ^{73}Amlodipine was not affected by coadministration with cimetidine^{234}.)

» Digitalis glycosides    (concurrent use of digoxin with some calcium channel blocking agents [especially verapamil and, to a lesser extent, bepridil ^{120}, diltiazem, and nifedipine ^{165}] has been reported to increase the serum concentration of digoxin ^{159} ^{180}; the effect of verapamil on digoxin kinetics is enhanced in patients with hepatic function impairment ^{169} ^{180}; felodipine significantly increased peak plasma concentrations of digoxin, although there was no significant change in the area under the plasma concentration–time curve [AUC] ^{01}; amlodipine^{234}, isradipine ^{206} and nicardipine ^{190} do not appear to have a significant effect. Digoxin serum concentrations should be monitored and dosage may need to be altered when concurrent dosage of the calcium channel blocking agent is initiated, changed, or discontinued. Concurrent use of oral digitalis preparations with oral diltiazem or verapamil or intravenous verapamil has resulted in no serious adverse effects when patients were closely monitored; however, both groups of medications slow AV conduction. Patients receiving them concurrently should be monitored for AV block or excessive bradycardia, especially during the first week of concurrent dosage. To avoid toxicity, dosage reduction of digitalis glycoside may be necessary)

» Disopyramide or
Flecainide ^{177} ^{180}    (disopyramide should not be administered within 48 hours before or 24 hours following verapamil administration since both medications possess negative inotropic properties; deaths have been reported; caution is also recommended when disopyramide is used concurrently with diltiazem, nicardipine ^{190}, or nifedipine ^{30}; caution is also recommended when flecainide ^{171} ^{177} ^{180} is used concurrently with a calcium channel blocking agent)

Estrogens    (estrogen-induced fluid retention tends to increase blood pressure; the patient should be carefully monitored to confirm that the desired effect is being obtained ^{122})

» Grapefruit juice    (concurrent administration with 200 mL of grapefruit juice has been shown to increase felodipine plasma concentration more than twofold by inhibiting first-pass metabolism in the gastrointestinal wall and/or the liver; a lesser effect also has been seen with two other dihydropyridines, nifedipine and nisoldipine.^{226} There are no effects seen with the concurrent use of amlodipine.^{234})

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

» Hypokalemia-producing medications, such as:
Amphotericin B, parenteral
Carbonic anhydrase inhibitors
Corticosteroids, glucocorticoid, especially those with significant mineralocorticoid activity
Corticosteroids, mineralocorticoid
Corticotropin (ACTH)
Diuretics, potassium-depleting (such as bumetanide, ethacrynic acid, furosemide, indapamide, mannitol, or thiazides)
Sodium phosphates    (risk of bepridil-induced arrhythmias may be increased ^{204})

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

Lithium    (concurrent use with calcium channel blocking agents ^{180} may result in neurotoxicity in the form of nausea, vomiting, diarrhea, ataxia, tremors, and/or tinnitus; caution is recommended ^{82} ^{83} ^{84} ^{85} ^{92})

Neuromuscular blocking agents    (verapamil may potentiate the activity of curare-like and depolarizing neuromuscular blocking agents; dosage reduction of either or both medications may be necessary during concurrent use ^{180})

Phenobarbital    (may increase clearance of verapamil ^{180})

Prazosin, and possibly other alpha-adrenergic blocking agents     (concurrent use with calcium channel blocking agents may produce an increased hypotensive effect, possibly related to impairment of compensatory responses by alpha-blockade ^{18} ^{34} ^{169} ^{180} and/or inhibition of prazosin metabolism by calcium channel blocking agents ^{13} ^{18} ^{19}; caution is recommended)

» Procainamide ^{204} or
» Quinidine ^{204} or
» Other medications causing Q-T interval prolongation ^{204}    (risk of increased Q-T interval prolongation ^{204})

    (caution is recommended when procainamide ^{74} or quinidine ^{74} ^{110} is used with a calcium channel blocking agent since both groups of medications possess negative inotropic properties )

» Rifampin, and possibly other hepatic enzyme inducers    (rifampin may reduce the bioavailability of oral verapamil by induction of first-pass metabolism ^{180}; other calcium channel blocking agents may also be affected, depending on the extent of first-pass metabolism ^{56} ^{57} ^{58} ^{169})

Sympathomimetics    (concurrent use may reduce antihypertensive effects of calcium channel blocking agents; the patient should be carefully monitored to confirm that the desired effect is being obtained ^{122})

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):

With physiology/laboratory test values
Antinuclear antibody (ANA) titers and
Direct Coombs test, with or without hemolytic anemia    (positive results have been reported during nifedipine therapy ^{163})

Arterial blood pressure    (may be reduced by calcium channel blocking agents [except bepridil and flunarizine] ^{140} ^{153})

Electrocardiograph (ECG) effects
P-R interval    (may be increased by diltiazem and verapamil)

Note: Increase tends to be proportional to serum concentration.

Q-T interval    (may be increased by bepridil ^{110} ^{204})

T-wave morphology    (may be altered by bepridil ^{110} ^{204})

Hepatic enzymes
    (may rarely be increased after several days of therapy; concentrations return to normal upon withdrawal of therapy)

Prolactin
    (serum concentrations may be slightly increased by flunarizine ^{205})

Note: Total serum calcium concentrations are not affected by the calcium channel blocking agents.

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).

Table 2. 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).	Legend: I = Bepridil II = Diltiazem III = Felodipine IV = Flunarizine V = Isradipine					VI = Nicardipine VII = Nifedipine VIII = Nimodipine IX = Verapamil X=Amlodipine
	I	II	III	IV	V	VI	VII	VIII	IX	X
*Except under special circumstances, this medication should not be used when the following medical problems exist:*
» Arrhythmias, ventricular, serious, history of ^{204} or
» Q-T interval prolongation, history of ^{204} (increased risk of bepridil-induced arrhythmias) ^{204}
»block—2nd- or 3rd- degree atrioventricular (AV) block, except in patients with a functioning artificial ventricular pacemaker ^{169} ^{204} ^{110} (use of calcium channel blocking agent may lead to excessive bradycardia)
» Hypotension, severe ^{204}
»Sinoatrial (SA) nodal function impairment (sick sinus syndrome) except in patients with functioning artificial ventricular pacemaker ^{204} (use of calcium channel blocking agent may lead to severe hypotension, bradycardia, and asystole)
» Wolff-Parkinson-White or Lown-Ganong-Levine syndrome accompanied by atrial flutter or fibrillation, except in patients with a functioning artificial ventricular pacemaker ^{161} ^{169} ^{180} (use of a calcium channel blocking agent for treatment of atrial fibrillation or flutter may precipitate severe ventricular arrhythmias)
*Risk-benefit should be considered when the following medical problems exist:* Aortic stenosis, severe (increased risk of heart failure when a calcium channel blocking agent is initiated, because of fixed impedance to flow across aortic valve)
» Bradycardia, extreme, or
»Heart failure (reduced sinus node and AV node activity may be worsened)
Note: When not severe or rate-related, heart failure should be controlled with digitalization and diuretics before administration of a calcium channel blocking agent. Heart failure, severe or moderately severe (pulmonary wedge pressure above 20 mm of mercury, ejection fraction less than 30% ^{169}), may be acutely worsened by administration of a calcium channel blocking agent.
Bradycardia, extreme, or Heart failure (because these agents have a slight negative inotropic effect, caution is recommended) ^{110} ^{164} ^{167} ^{190} ^{204} ^{206}
» Cardiogenic shock
Cerebral infarction or hemorrhage, acute ^{190}
Hepatic function impairment (clearance and duration of effect may be prolonged ^{01} ^{165} ^{204} ^{205} ^{206}; clearance of felodipine is reduced to about 60% ^{01}; half-life of nicardipine may be increased to 19 hours in patients with severe hepatic function impairment ^{190}; half-life of verapamil may be increased to 14 to 16 hours and plasma clearance reduced to about 30% of normal ^{169}; dosage reduction may be necessary)
» Hypokalemia (risk of bepridil-induced arrhythmias may be increased) ^{204}
Hypotension, mild to moderate (tendency to hypotension is augmented by the peripheral vasodilating effect of the calcium channel blocking agent)
Mental depression, history of (flunarizine may precipitate mental depression) ^{205}
»Myocardial infarction, acute, with pulmonary congestion documented by x-ray on admission (associated heart failure may be acutely worsened by administration of a calcium channel blocking agent) ^{93} ^{94} ^{160} ^{204}
Myocardial infarction, acute, with pulmonary congestion documented by x-ray on admission (because these agents have a slight negative inotropic effect, there is a possibility that associated heart failure may be acutely worsened)
Narrowing of the gastrointestinal tract, pathologic or iatrogenic, severe (passage of the nondeformable extended-release nifedipine system [ Procardia XL] may be impaired; obstructive symptoms may occur) ^{197}
Neuromuscular transmission deficiency (verapamil has been reported to decrease neuromuscular transmission in patients with Duchenne's muscular dystrophy, and to prolong recovery from the neuromuscular blocking agent vecuronium; dosage reduction may be required) ^{180}
Parkinsonian syndrome ^{205} or Extrapyramidal disorders, other ^{205} (flunarizine may produce parkinsonian extrapyramidal symptoms not responsive to antiparkinsonian medications) ^{205}
Renal function impairment (possible reduced clearance of the calcium channel blocking agent or metabolites, although half-life is only slightly increased; dosage adjustment may be necessary) ^{205} ^{206}
(plasma concentrations of felodipine are unchanged ^{01}; although reduced excretion results in increased concentrations of metabolites, they are inactive ^{01})
»Sensitivity to the calcium channel blocking agent prescribed ^{01} ^{159} ^{167} ^{169} ^{180} ^{190}
Ventricular tachycardia, wide-complex (risk of ventricular fibrillation if intravenous diltiazem or verapamil administered ^{161} ^{173})

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 ^{123}    (recommended primarily during dosage titration or when dosage is increased from established maintenance dosage level, or during addition of medications affecting cardiac conduction or blood pressure; also recommended during intravenous verapamil administration)

    (blood pressure determinations are recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)

Hepatic function determinations or
Renal function determinations    (may be required at periodic intervals during long-term therapy)

For bepridil
Potassium concentrations, serum    (recommended at periodic intervals during therapy to watch for hypokalemia ^{204})

For nimodipine
Neurological examinations    (recommended at periodic intervals during treatment ^{142} ^{144} ^{153})

Side/Adverse Effects

Table 3. Side/Adverse Effects

Note: Side/adverse effects tend to be dose-related and occur most frequently during periods of dosage titration.
Although not reported to occur in humans, lenticular changes and cataracts have developed during chronic dosage with verapamil in beagles. These effects resulted from daily dosage of 30 mg and more per kg of body weight and are considered likely to be species-specific.
A possible hyperglycemic effect has been reported with nicardipine (at a daily dose of 40 mg) ^{63} ^{190} and nifedipine therapy (when the daily dosage exceeds 60 mg). No significant effect on fasting serum glucose has been seen with felodipine ^{01}.
Depression of atrioventricular (AV) and sinoatrial (SA) nodal conduction by bepridil, diltiazem, and verapamil may result in asymptomatic first-degree block and transient sinus bradycardia, sometimes accompanied by nodal escape rhythms ^{159} ^{169}.
Use of verapamil for hypertrophic cardiomyopathy, especially in patients with pre-existing risk factors, has resulted in serious side effects (including pulmonary edema, sinus bradycardia, severe hypotension, second-degree AV block, and sudden death).

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: ^*	Legend: I = Bepridil II = Diltiazem III = Felodipine IV = Flunarizine V = Isradipine	VI = Nicardipine VII = Nifedipine VIII = Nimodipine IX = Verapamil X= Amlodipine
	I	II	III	IV	V	VI	VII	VIII	IX	X
Medical attention needed *Agranulocytosis—*not symptomatic ^{204}	R	U


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