Hypertension: Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension: thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.
Angina: Diltiazem HCl has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal workloads.
Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasms are inhibited by diltiazem.
In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of the coronary vascular smooth muscle and dilation of both large and small coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.
Hemodynamic and Electrophysiologic Effects
Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.
In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem.
Tiazac produces antihypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.
Diltiazem hydrochloride decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem hydrochloride produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem hydrochloride reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio. In man, transient natriuresis and kaliuresis have been reported, but only in high intravenous doses of 0.5 mg/kg of body weight.
Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases). Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%.
In two short-term, double-blind, placebo-controlled studies in 256 hypertensive patients with doses up to 540 mg/day, Tiazac showed a clinically unimportant but statistically significant, dose-related increase in PR interval (0.008 seconds). There were no instances of greater than first-degree AV block in any of the clinical trials (see WARNINGS).
Hypertension: In short-term, double-blind, placebo-controlled clinical trials Tiazac demonstrated a dose-related antihypertensive response among patients with mild to moderate hypertension. In one parallel-group study of 198 patients Tiazac was given for four weeks. The changes in diastolic blood pressure measured at trough (24 hours after the dose) for placebo, 90 mg, 180 mg, 360 mg and 540 mg were -5.4, -6.3, -6.2, -8.2, and -11.8 mm Hg, respectively. Supine diastolic blood pressure as well as standing diastolic and systolic blood pressures also showed statistically significant linear dose response effects.
In another clinical trial that followed a dose-escalation design, Tiazac also reduced blood pressure in a linear dose-related manner. Supine diastolic blood pressure measured following two-week intervals of treatment was reduced by -3.7 mm Hg with 120 mg/day versus -2.0 mm Hg with placebo, by -7.6 mm Hg after escalation to 240 mg/day versus -2.3 mm Hg with placebo, by -8.1 mm Hg after escalation to 360 mg/day versus -0.9 mm Hg with placebo, and by -10.8 mm Hg after escalation to 480/540 mg/day versus -2.2 mm Hg with placebo.
Angina: In a double-blind, parallel-group, placebo-controlled trial (approximately 50 patients/group, in patients with chronic stable angina), Tiazac at doses of 120 to 540 mg/day increased exercise tolerance time. At trough, 24 hours after dosing, exercise tolerance times using a Bruce exercise protocol, increased by 14, 26, 41, 33 and 32 seconds over baseline for placebo and the 120 mg, 240 mg, 360 mg, and 540 mg treated patient groups, respectively. At peak, 8 hours after dosing, exercise tolerance times relative to baseline were statistically significantly increased by 13, 38, 64, 55 and 42 seconds for placebo and 120 mg, 240 mg, 360 mg, and 540 mg Tiazac treated patients, respectively. Compared to baseline, Tiazac treated patients experienced statistically significant reductions in anginal attacks and decreased nitroglycerin requirements when compared to placebo treated patients.
Tiazac Capsules: When compared to a regimen of immediate-release tablets at steady-state, approximately 93% of drug is absorbed from the Tiazac formulation. When Tiazac was coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected; Tmax, however, occurred slightly earlier. The apparent elimination half-life after single or multiple dosing is 4 to 9.5 hours (mean 6.5 hours).
Tiazac demonstrates non-linear pharmacokinetics. As the daily dose of Tiazac capsules was increased from 120 to 540 mg, there was a more than proportional increase in diltiazem plasma concentrations as evidenced by an increase of AUC, Cmax and Cmin of 6.8, 6 and 8.6 times, respectively, for a 4.5 times increase in dose.
1. Cardiac Conduction: Diltiazem hydrochloride prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13 of 3007 patients or 0.43%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem.
2. Congestive Heart Failure: Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dP/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dP/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem hydrochloride in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.
3. Hypotension: Decreases in blood pressure associated with diltiazem hydrochloride therapy may occasionally result in symptomatic hypotension.
4. Acute Hepatic Injury: Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, and SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem hydrochloride is uncertain in some cases but probable in some (see PRECAUTIONS).
Anesthetics: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium channel blockers should be titrated carefully.
Benzodiazepines: Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.
Beta-blockers: Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem hydrochloride and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Administration of diltiazem hydrochloride concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).
Buspirone: In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T½ and Tmax of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.
Carbamazepine: Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40% to 72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.
Cimetidine: A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week course of cimetidine 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.
Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine.
Cyclosporine: A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15% to 48% was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.
The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.
Digitalis: Administration of diltiazem hydrochloride with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing diltiazem hydrochloride therapy to avoid possible over- or under-digitalization (see WARNINGS).
Ivabradine: Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem.
Quinidine: Diltiazem significantly increases the AUC(0→∞) of quinidine by 51%, T½ by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.
Rifampin: Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.
Statins: Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 is increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin with diltiazem. Otherwise, reduce the dose for both diltiazem and the statin and monitor for signs and symptoms of muscle toxicity.
In a healthy volunteer cross-over study (N=10), coadministration of a single 20 mg dose of simvastatin at the end of a 14-day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater increase in simvastatin exposure. If coadministration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.
In a ten-subject randomized, open-label, 4-way cross-over study, coadministration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.
Hypertension: Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, usual starting doses are 120 to 240 mg once daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 120 to 540 mg once daily. Current clinical experience with 540 mg dose is limited; however, the dose may be increased to 540 mg once daily.
Angina: Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a dose of 120 mg to 180 mg once daily. Individual patients may respond to higher doses of up to 540 mg once daily. When necessary, titration should be carried out over 7 to 14 days.
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
By:
Valeant Pharmaceuticals International, Inc.
Steinbach, Manitoba R5G 1Z7 Canada
Tiazac is a trademark of Valeant Pharmaceuticals
International, Inc. or its affiliates.
©Valeant Pharmaceuticals North America LLC
9405002
20001790
Rev. 11/2016
