sustained-release verapamil formulations for treating hypertension

J Clin Pharmacol 1992;32:455-462 455

Sustained-Release Verapamil Formulationsfor Treating Hypertension

William H. Frishman, MD, and Eliot J. Lazar, MD

Verapamil, the first calcium-channel blocker to be introduced for clinical use, is a majordrug used for the treatment of systemic hypertension. During the past 10 years, the use of

verapamil for hypertension has produced a considerable clinical database to support theefficacy and safety of the agent in many patients. Because of its short half-life, verapamilwas originally administered 3 to 4 times daily. During the past decade, a sustained-re-lease formulation of verapamil has been marketed in the US. This product allows foronce-daily dosing up to 240 mg/d; however, when higher doses are needed, this sus-tained-release formulation should be administered twice daily. In addition, the medicineshould be taken with food to avoid the high peak blood levels of verapamil, whichappears to be related to the delivery system. A new pellet-filled capsule formulation ofverapamil (Verelan, Lederle, Wayne, NJ and Wyeth-Ayerst, Philadelphia, PA) is available

and provides controlled absorption, 24-hour blood pressure control, improved peak-to-trough plasma levels, and once-daily dosing regardless of dosage size. Prolonged-releaseverapamil can be taken without food.

A lthough the goal of antihypertensive therapy isto reduce blood pressure, one also hopes to

prevent major cardiovascular complications fromsystemic hypertension. In addition, the physicianstrives to accomplish these ends with the least possi-ble adverse effect on the patient or the quality of life.

Verapamil, a papaverine derivative, was the firstcalcium-entry blocker used clinically. Verapamilhas been used many years in the treatment of pa-tients with various cardiovascular disorders. Thisarticle reviews the clinical experiences with tradi-tional and new prolonged-release verapamil formu-lations for antihypertensive therapy.

MECHANISM OF ACTION

Like other calcium-channel blockers, verapamil in-hibits the slow inward flux of calcium ions acrosscell membranes of cardiac and vascular smoothmuscle cells. This inhibition results in vasodilationof coronary and peripheral arteries. In addition,conduction in the atrioventricular and sinoatrial

From the Department of Medicine, Albert Einstein College of Medicine,Hospital of The Albert Einstein College of Medicine/Montefiore Medi-cal Center, Bronx, New York. Address for reprints: William Frishman,MD, Department of Medicine, Hospital of the Albert Einstein College ofMedicine/Montefiore Medical Center, 1825 Eastchester Road, Bronx,

NY 10461.

nodes is slowed, and a slight negative inotropic ac-tion has been observed.1 These pharmacologic ac-tions are the foundation for the efficacy of calcium-channel blockers in the treatment of patients withhypertension, angina pectoris, and supraventriculararrhythmias (Table I),2

HEMODYNAMIC EFFECTS

Verapamil is an effective peripheral vasodilator andhas a direct negative chronotropic and inotropic ef-fect on the heart. The sum of these actions meansthat little change is seen in heart rate, cardiac out-put, or ejection fraction after verapamil administra-tion.3

Oral verapamil administration has no effect onblood pressure in normal volunteers but consis-tently lowers systolic and diastolic blood pressuresin hypertensive patients.2-4 The antihypertensive ef-fect of verapamil in patients seems to be greater withhigher pretreatment blood pressures. The age of thepatient and the pretreatment renin status also influ-ence the antihypertensive response to verapamil;blood pressure reductions are directly correlatedwith age and inversely correlated with reninstatus.4’5

PHARMACOKINETICS

More than 90% of an oral dose of verapamil is ab-

sorbed, and peak plasma levels are reached within I

FRISHMAN AND LAZAR

456 #{149}J Clln Pharmacol 1992;32:455-462

TABLE I

Pharmacologic Effects of AvailableCalcium-Channel Blockers

Effect Dlltlazem Verapamll Nifedlpine Nicardipine

Heart rate4 4Myocardial

contractility 4 44 4-Atrio-ventricular

(AV) nodalconduction 4 44 -

Peripheralvasodilation 4 4 44

t-

4-

-

l4

The indicates decrease; f increases; and - no change.

to 2 hours after a single dose. Since the drug is sub-ject to extensive first-pass hepatic extraction, thebioavailability of a single dose is approximately 10 to20% of the oral dose. Verapamil is approximately90% bound to plasma proteins.

The plasma concentration, bioavailability, andhalf-life of oral verapamil increase when the drug isgiven long term. Maximum plasma verapamil con-centration may be up to 70% higher after repeateddosing than after a single dose. This effect may bedue to a reduction in first-pass hepatic metabolismsecondary to changes in hepatic blood flow, satura-tion of metabolic pathways, inhibition of the metab-olism of verapamil induced by the drug itself, or theexistence of a deep tissue compartment of drug dis-tribution that is not apparent after administration ofsingle doses.3

The elimination of verapamil varies from one pa-tient to another-variations of up to 85% in oralclearance have been reported in patients receivinglong-term verapamil therapy.2 Verapamil clearancemay decrease significantly during chronic adminis-tration and when the drug is given to elderly pa-tients and to patients with hepatic dysfunction. Incontrast, dosage reductions do not appear necessaryin patients with chronic renal failure.3

CLINICAL EXPERIENCE

Calcium-channel blockers are one of the drugclasses considered appropriate for initial antihyper-tensive therapies.6 In addition to their usefulness asmonotherapy, these drugs may be used in combina-tion therapy since they act by mechanisms differentfrom those of other antihypertensive drugs.7

Verapamil has a short half-life, and immediate-release formulations must be given in a thrice-dailyregimen. For antihypertensive therapy, doses of 240

to 480 mg/d are prescribed. In elderly or small pa-

tients, a starting dose of 120 mg/d (40 mg thricedaily) may be appropriate.

The relationship of plasma verapamil levels to

antihypertensive efficacy remains problematic; nosatisfactory plasma concentration guidelines havebeen defined.8 This is undoubtedly a function of themarked intersubject variability of verapamil plasma

levels after oral dosing. Therefore, monitoring of theefficacy of verapamil therapy is best done by clinicalobservation.9

Placebo-Controlled Studies. Conventional verapamilformulations (160 to 480 mg/d) have consistentlyreduced systolic and diastolic blood pressures in hy-pertensive patients. In elderly patients (mean age: 75yr), smaller verapamil doses (80 to 240 mg/d) appearto produce greater reductions in blood pressure.2

Long-term Efficacy of Verapamil. Documentation ofthe long-term efficacy of an antihypertensive agent(i.e., lack of development of tolerance) is essential,since therapy for hypertension must continuethroughout the life of the patient. A number of stud-ies in which verapamil was used have shown thatthe ability of verapamil to lower blood pressure inhypertensive patients is not impaired by long-term use.1#{176}

Comparisons With Other Agents. Immediate-releaseverapamil formulations have been compared withnifedipine, nicardipine, and diltiazem in hyperten-sive patients. Verapamil produced blood pressurereductions comparable with those seen with theother calcium-channel blockers.2

The antihypertensive effects of verapamil arecomparable with those of beta blockers, includingpropranolol, atenolol, pindolol, metoprolol, and la-betolol.1#{176}However, beta blockers may be less effec-tive in black patients, whereas no such differenceshave been observed with verapamil and other cal-cium-channel blockers.10

The limited number of studies that compared di-uretics and verapamil have shown similar reduc-tions in systolic and diastolic blood pressures with

both types of drugs. Both verapamil and diureticsappear to be more effective than other agents inolder patients and individuals with low plasmarenin activity. Some investigators believe that vera-pamil may be an appropriate alternative to diureticsin these patients.2

Only a few studies have been done that compareverapamil with ACE inhibitors. Blood pressure re-ductions observed in these studies were similar withboth drugs.14

SUSTAINED-RELEASE VERAPAMIL FOR HYPERTENSION

HYPERTENSION 457

Combination Therapy. When hypertension in a pa-

tient is resistant to the range of drugs suitable for useas monotherapy, a combination of agents can oftenbe successful. Verapamil has been used successfullyin combination with diuretics, ACE inhibitors, pra-zosin, and methyldopa.2-4 The combination of vera-pamil and propranolol has been studied,2-5-7 but thiscombination should be approached with cautionsince these two classes of drugs have additive effectson myocardial contractility, heart rate, and atrio-ventricular conduction. In some patients, these ef-fects could lead to dangerous adverse cardiac ef-fects. 27

SAFETY

Target Organs and Co-existing Diseases. Antihyper-

tensive doses of verapamil have no significant effectson renal plasma flow, glomerular filtration rate, so-dium or water excretion, plasma renin activity, cir-culating concentrations of the renin-angiotensin-al-dosterone system, glucose tolerance in diabetic ornondiabetic patients, or plasma lipid profiles in nor-molipidemic patients.15 Unlike beta blockers, vera-pamil administration is not contraindicated in asth-matic patients. Verapamil administration may slowthe progression of atherosclerosis, although more

clinical studies are needed on this topic.2-7 Regres-sion of left ventricular hypertrophy has been ob-served with verapamil therapy in elderly patients.16Verapamil has mild inhibitory effects on platelet ag-gregation, and it appears to preferentially inhibitepinephrine-induced aggregation.2-7

Drug Interactions. Since verapamil is metabolized bythe hepatic cytochrome P-450 enzyme system, in-teractions might be expected with drugs that alsouse this metabolic pathway. The potential hazards ofcombined verapamil/beta-blocker therapy havebeen described earlier. Verapamil administration in-creases the bioavailability of oral prazosin by about69%, whereas prazosin administration blocks thecompensatory reactions to vasodilatation producedby verapamil administration, When verapamil is

given with antiarrhythmic drugs such as disopyra-

mide or procainamide, additional cardiodepressionand conduction defects may be provoked. Combinedtreatment with verapamil and digoxin leads to in-creased plasma glycoside concentrations, possiblydue to decreased glycoside clearance. Concomitantverapamil administration will result in increasedplasma concentrations of theophylline, carbamaze-pine, doxorubicin, and cyclosporin. A clinicallysignificant interaction between verapamil and ri-fampin has also been documented, wherein oral ye-

rapamil bioavailability was decreased by simulta-neous dosing with rifampin. This was probably dueto induction of hepatic drug metabolism by ri-fampin.2’3

Adverse Experience Profile. The overall incidence ofadverse effects noted with verapamil administrationwas approximately 9% in one analysis of more than8000 patients; 1% of patients withdrew from treat-ment because of adverse reactions.2 Many of the ad-verse experiences reported with verapamil adminis-tration are extensions of the vasodilatory action andnegative inotropic properties of the drug; these ef-fects are less common after oral administration than

after IV dosing. These effects include flushing, head-ache, peripheral edema, dizziness, and palpitations.The most common side effect of verapamil adminis-

tration is constipation, which is a consequence ofdose-related relaxation of gastrointestinal smoothmuscle.2-3

SUSTAINED-RELEASE VERAPAMILFORMULATIONS

Rationale

Verapamil has a relatively short half-life (3-7 hr)and must therefore be given in divided dosesthroughout the day for effective control of bloodpressure over a 24-hour period. Even with thisschedule of administration, there will be constantfluctuations between peak and trough plasma levelsafter each dose. Under these conditions of adminis-tration, there is the possibility of alternately exceed-

ing or falling below the plasma drug level needed fora therapeutic effect in a given patient. Another dif-ficulty is patient compliance with a dosing regimen

that requires taking a tablet several times a day. Pa-tient compliance is generally inversely related to thenumber of daily doses required. If a thrice-daily regi-men can be replaced by a once-daily dose, patientcompliance should be improved.

One way around these problems is to develop adrug formulation that releases a therapeuticallyequivalent amount of active agent slowly and con-tinuously over a sustained period. Such a formula-tion should reduce the high peak concentrations as-sociated with the immediate-release preparations,thereby avoiding “dumping.” Drug absorption willbe more uniform over time, and the peak-to-troughconcentration disparities will decrease. Ideally, thiswould result in maintenance of drug levels within

the therapeutic concentration range for a prolongedperiod.


458 #{149}J ClIn Pharmacol 1992;32:455-462

By inference, the therapeutic effect of the drugshould also be prolonged with sustained-releasepreparations. A by-product of the flattened peak-to-trough configuration should be a decreased chanceof toxic effects and a reduced incidence of intervalswhere plasma drug levels are subtherapeutic. Ide-ally, drug absorption from a sustained-release for-mulation should not be affected by gastric motility,pH, or the presence of food in the stomach.17

PREVIOUSLY AVAILABLE SUSTAINED-RELEASE VERAPAMIL PREPARATIONS

Until recently, a sustained-release formulation of

verapamil was marketed as two products in theUnited States: Calan SR (Searle, Chicago, IL) andIsoptin SR (Knoll, Whippany, NJ). A number of otherpreparations are available internationally.

These products have been evaluated in hyperten-

sive patients using a variety of techniques, includingmanual blood pressure monitoring218 and 24-hourmonitoring by invasive19 and noninvasive2021methods. Although complete 24-hour blood pres-

sure control with traditional sustained-release vera-pamil products has been debated,2-’79 the 240-mgdose has been effective as a monotherapy in manyhypertensive patients.

Clinical studies comparing sustained-release for-mulations with conventional verapamil formula-tions in hypertensive patients have, in general,shown therapeutic equivalence between treatmentregimens incorporating identical total daily dosagesof verapamil (i.e., 80 mg immediate-release vera-pamil thrice daily or one 240-mg sustained-releaseverapamil dose).2’2224 However, some controlledstudies that used 24-hour monitoring showed thatblood pressure control waned before the end of the24-hour dosing interval with sustained-release prep-arations.2

The two traditional sustained-release verapamilproducts marketed in the United States have thesame release, absorption, and clinical efficacy pro-files. Although these products are marketed as sus-tained-release formulations for once-daily dosing,pharmacokinetic data show that the bulk of activedrug is actually released in less than 8 hours.17 As aconsequence of the comparatively rapid release of

drug from these sustained-release products, maxi-mum plasma verapamil concentrations are higherthan those that might be obtained if drug absorptionwere more prolonged; drug is dumped fairly rapidlyinto systemic circulation.

Verapamil absorption from both conventional andcurrently available sustained-release products is sig-nificantly affected by the presence of food in the

stomach.2526 Patients are instructed to take the sus-tained-release products with food. The prescribinginformation for both products notes that if the drugis taken in a state of fasting, plasma verapamil levels

may be more than 100% higher than when the drugis taken with food. Although the specific mechanismof action for this rise is unknown, immediate-releaseverapamil is not affected by food27; therefore, theincreased blood levels of verapamil may be relatedto the sustained-release technology. If a patient doesnot comply with directions to take the sustained-re-lease preparation with meals, plasma levels of vera-

pamil will be adversely affected, which might po-tentially reduce the efficacy and safety of the treat-ment regimen.

NEW CONTROLLED-ABSORPTION VERAPAMILFORMULATION

Verelan (verapamil HCI, Lederle, Wayne, NJ, andWyeth-Ayerst, Philadelphia, PA) was recently in-

troduced in the US for the treatment of hyperten-

sion. The controlled-absorption system of Verelan-

spheroidal oral drug absorption system (SODAS)-was formulated to overcome the food effect foundwith the two previous sustained-release verapamilproducts (Calan SR, Searle, Chicago IL, Isoptin SR

Knoll, Whippany, NJ) and provide a true once-dailyformulation while retaining the efficacy and safety

advantages of the drug in the treatment of hyper-

tension.

Pharmacokinetics

Compared with traditional sustained-release vera-pamil, the controlled-absorption verapamil deliverysystem of SODAS shows a significantly extendeddissolution profile in vitro.28-29 Pharmacokinetic pa-rameters for the two products with food and underfasting conditions are shown in Table II. Controlled-

absorption verapamil administration produces a fa-

vorable peak-to-trough ratio.

Pharmacokinetic Studies

Single Doses. Data obtained after oral administrationof single doses of an immediate-release verapamilproduct (Isoptin 80-mg) or controlled-absorption ye-rapamil capsules, 120 mg, 240 mg, or 360 mgshowedthe bioavailability and sustained-release character-istics of controlled-absorption verapamil, as well asthe dose-proportionality relationships among the

three controlled-absorption verapamil doses (Fig-ure 1).

18-N rra,OpO,all 00 tO))

A- C nailed b,O,pl0r urrrapunai 20 rag.-... c0000ilad-ab,o,p’rofl oe,OpOfln.l 210 nag

.... corlaolied-abaorplion veroplanil 360 nrg

Tm, Otter admnstraI,on(hour,)


HYPERTENSION 459

TABLE Il

Mean Pharmacokinetic Parameters After Single Doses of Controlled-Absorption Verapamlland Sustained-Release Verapamil

Drug Dose Fed/FastAUC

(ng hr/mi)C

(ng/mL)T(hr)

SODAS controlled-absorption verapamil*SODAS controlled-absorption verapamil’SODAS controlled-absorption verapamil*SODAS controlled-absorption verapamil4SODAS controlled-absorption verapamil*Sustained-release verapamiltSustained-release verapamilt

120240360240240240240

FastFastFastFedFastFedFast

5651660272913871541

8411478

38108174

777779

164

8.27.97.29.09.87.75.2

Verelan, adapted from reference 28; t Calan SR. adap ted from reference 29.

Mean plasma verapamil concentration increasedin a nonlinear fashion with a linear increase in ad-ministered controlled-absorption verapamil dose.Both the time-to-peak plasma verapamil concentra-

tion and the plasma-elimination half-life were inde-pendent of dose. All controlled-absorption vera-pamil preparations exhibited an excellent sus-tained-release profile; absorption of drug wasslower, peak plasma concentrations were lower, andthe peak-to-trough fluctuations in plasma levelswere significantly less than with the immediate-re-

lease preparation.

Mean steady-state plasma verapamil concentra-tion data, obtained after oral dosing for several dayswith the immediate-release preparation (80 mg

thrice daily) or the controlled-absorption verapamilof SODAS, 120 mg, 240 mg, or 360 mgonce daily, aresummarized in Figure 2.

Figure 1. Mean plasma concentrations of verapamil after singledoses of a reference immediate-release verapamil product (80 mgiand controlled-absorption verapamil (120 mg. 240 mg. and 360

mg).3’

Results with controlled-absorption verapamil arequalitatively similar to the single-dose data; the im-

mediate-release preparation shows the expected“sawtooth” configuration for plasma verapamillevels. The areas under the concentration-time

curves (AUCs) for the immediate-release prepara-tion (240 mg daily in divided doses) and the 240-mg

controlled-absorption verapamil formulation were

comparable, indicating similar total absorption for

these two products.

Effect of Food on Controlled-Absorption Verapamil

Absorption. A single 240-mg oral dose of controlled-absorption verapamil was given to volunteers inboth fasting and fed conditions to determine the ex-

tent of verapamil absorption. There were no statisti-cally significant differences in pharmacokinetic pa-rameters between the fasting and fed states, indicat-

Figure 2. Mean steady-state plasma veroparnil concentrationsafter multiple doses of a reference imme(Iiate-release verapamilproduct (80 mgi and controlled-obsorption Vera pamil (120 mg. 240mg. or 360 nig once daily).”

10

! :I-5

I 7AM NOOn 6pM MIdnight PAM

lime ot day

FRISHMAN AND LAZAR

460 #{149}J Clin Pharmacol 1992;32:455-462

ing that food had no effect on the rate and extent of

absorption of verapamil from controlled-absorptionverapamil.

Comparison of Controlled-absorption Vera pamil anda Reference Sustained-release Verapamil Product.

The pharmacokinetics and dissolution rates of con-trolled-absorption 240-mg verapamil dose and a240-mg reference sustained-release verapamil prod-uct (Isoptin SR) were compared in volunteers. Thereference product showed 50% release 4 hours after

dosing; with controlled-absorption verapamil, 50%of the drug was released 8 hours after dosing. After 8hours, 90% of the drug had been released from thereference formulation, whereas the controlled-ab-sorption verapamil formulation had released only70% of its drug 11 hours after dosing. The meanplasma verapamil concentrations achieved over a36-hour period by each of the formulations is shownin Figure 3. Intersubject variability was greater withthe reference product than with controlled-absorp-tion verapamil.

Clinical Experience

The safety and antihypertensive efficacy of con-trolled-absorption verapamil (120, 240, 480 mg) oncedaily in patients with mild-to-moderate essentialhypertension was studied in a randomized, double-

blind, placebo-controlled study.3#{176} After a single-blind placebo qualifying period, eligible patientswere randomized to one of four parallel treatmentgroups. The dosage level could be adjusted duringthe double-blind period. Visits were at weekly in-

tervals throughout the study.

Blood pressure was measured manually for all pa-tients throughout the study. In a subset of patients,24-hour ambulatory blood pressure recordings wereobtained once during the placebo qualifying periodand once during the double-blind period.

Data from 107 patients with mild-to-moderate es-sential hypertension who were randomized to dou-ble-blind treatment were analyzed for efficacy. Theprimary measure of efficacy was the change in su-pine diastolic blood pressure at the last treatmentvisit. A satisfactory clinical response was defined as

a supine diastolic blood pressure below 90 mm Hg or

a �10 mm Hg reduction from baseline in supine dia-stolic blood pressure after 4 weeks of continuoustreatment.

All treatment groups were statistically compara-ble at baseline. Patient compliance with treatmentregimens, as documented by capsule counts, re-mained excellent throughout the study.

The mean changes from baseline values in supineblood pressures at the last treatment visit are sum-marized in Table III for each of the treatment groups.

There were no statistically significant changes frombaseline values in heart rate in any of the treatmentgroups.

A comparison of the changes in blood pressurefrom baseline to the last treatment visit for the var-ious treatment groups showed that the placebo re-sponse was smaller than the response in any of thegroups receiving controlled-absorption verapamil.The group receiving 120-mg doses of controlled-ab-sorption verapamil showed a lesser response thaneither of the higher-dosage groups, but the changefrom baseline was not statistically significantly dif-

TABLE Ill

Figure 3. Mean change from baseline in mean diastolic bloodpressure as recorded by 24-hour ambulatory blood pressure moni-toring in patients receiving j-lacebo or controlled-absorption vera-pamil.31

Supine Blood Pressure Changes (From Baseline) In107 Mild-to-Moderate Hypertensive Patients3#{176}

Treatment SystolIc/DIastolIc

Placebo (n = 26)

SODAS controlled-absorptionverapamil (120 mg)(n = 28)



-3.6/3.7(18.80)/(12.28)

-2.0/5.4(11.55)/(9.24)*

-12.3/10.9(15.54)/(10.68)*

- 10.4/11.2(15.75)/(9.73)*

0Standard deviations are in parentheses.

TABLE V

Adverse Experience Incidence (%)

* Verelan, adapted from reference 31; f Adapted from reference 32.

TABLE IV


HYPERTENSION 461

ferent from that seen in subjects receiving placebo.

The race of the patient had no effect on the efficacyof controlled-absorption verapamil. The drug had agreater antihypertensive effect in elderly patients.

One-fourth to one-half of the patients in eachtreatment group participated in ambulatory 24-hourblood pressure monitoring during the study. Thesedata showed that the blood pressure response tocontrolled-absorption verapamil was maintainedthroughout the 24-hour post-dosing period. Duringmost of the 24-hour period, the antihypertensive ef-fect of the 240-mg controlled-absorption verapamildose was sufficient, and the effects of the 480-mgcontrolled-absorption verapamil dose were evenmore profound (Figure 3).

Safety

Table IV shows the adverse experiences reported ineach treatment group during this controlled-absorp-tion verapamil study of 107 patients. Serious adversereactions were uncommon, and few patients discon-tinued treatment due to adverse effects.

No clinically significant changes were observed inthe hematologic or urinalysis data. Serum chemistryresults showed seven instances of elevated liverfunction tests results compared with baseline valuesduring the double-blind period; two occurred in theplacebo group, one in the controlled-absorption ye-rapamil 120-mg group, and four in the controlled-absorption verapamil 240-mg group. A significantmean weight gain of 1 kg was reported for both the240-mg and 480-mg controlled-absorption verapamilgroups. Data from this clinical trial show that con-trolled-absorption verapamil was safe and well tol-erated in this group of patients with mild-to-moder-ate essential hypertension.

Number of Side Effec ts Reported During Study3#{176}

SIde Effect Placebo 120 mg 240 mg 480 mg

Headache 3 1 1 1Edema 1 1 - 1Palpitation - 1 - -

Atrial flutter - 1 - -

Dizziness - - 1 -

Constipation 2 3 3 5Myalgia - - 1 -

Rash - - - 1Nocturia - - 1 -

Polyuria 1 - - -

7 7 7 8

SODAS Controlled-AbsorptIonVerapamll18(n = 285)

Placebot(n 26)

Constipation 7.4 11.5Headache 5.3 11.5Dizziness 4.2 3.8Lethargy 3.2 0Dyspepsia 2.5 0Rash 1.4 0Ankle edema 1.4 3.8Sleep disturbance 1.4 0Myalgia 1.1 0

In a group of 285 hypertensive patients treatedwith controlled-absorption verapamil, the mostcommon adverse effects reported were constipationand headache. Adverse effects of controlled-absorp-tion verapamil are presented in Table V.

DISCUSSION

During the past decade, verapamil administrationhas shown excellent efficacy and safety in the treat-ment of essential hypertension. In recent years, twosustained-release formulations of verapamil, whichallowed for once-daily verapamil dosing up to 240mg/d, have been widely prescribed. Whether tradi-tional sustained-release formulations provide bloodpressure control during the last hours of the 24-hour

dosing period is questionable. Recently, a new con-trolled-absorption verapamil capsule formulationbecame available that provides comparable com-plete 24-hour efficacy and safety to previous sus-tained-release verapamil preparations and can betaken once daily regardless of dosage strength anddoes not have to be taken with food. In addition to240-mg capsules, SODAS controlled-absorption ye-rapamil is the only sustained-release verapamil alsoavailable in a low 120-mg strength, which may con-trol hypertension in some patients, that allows foreasy dosing titration or may be applicable as an add-on agent to other classes of antihypertensive drugs.

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29. Calan SR package insert, 1990.

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sustained-release verapamil formulations for treating hypertension

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