DILTIAZEM HYDROCHLORIDE EXTENDED-RELEASE CAPSULES, USP
(Once-a-Day Dosage)
120 mg, 180 mg and 240 mg

Diltiazem is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino) ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-cis-. Its molecular formula is C₂₂H₂₆N₂O₄S HCl and its molecular weight is 450.99. Its structural formula is as follows:

Diltiazem hydrochloride, USP is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol and chloroform.

Diltiazem Hydrochloride Extended-release Capsules, USP (Once-a-Day Dosage), for oral administration, contain multiple units of diltiazem hydrochloride extended-release 60 mg, resulting in the 120 mg, 180 mg or 240 mg dosage strengths allowing for the controlled release of diltiazem hydrochloride over a 24-hour period. In addition, each capsule contains the following inactive ingredients: ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, D&C Yellow #10 aluminum lake, ethylcellulose, FD&C Red #40 aluminum lake, FD&C Blue #1 aluminum lake, FD&C Blue #2 aluminum lake, gelatin, hypromellose, magnesium stearate, maltodextrin, microcrystalline cellulose, n-butyl alcohol, oleic acid, pharmaceutical glaze, polyethylene glycol, propylene glycol, SDA-3A alcohol, sodium lauryl sulfate, synthetic black iron oxide and titanium dioxide. In addition, the 120 mg and the 180 mg strengths contain D&C Red #28 aluminum lake.

Diltiazem Hydrochloride Extended-release Capsules, USP (Once-a-Day Dosage) 120 mg, 180 mg and 240 mg meet USP Drug Release Test 8.

The therapeutic benefits of diltiazem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Like other calcium 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. In exercise tolerance studies in patients with ischemic heart disease, diltiazem reduces the double product (HR × SBP) for any given work load. 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. Increased heart failure has, however, been reported in occasional patients with pre-existing 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.

Diltiazem hydrochloride extended-release capsules produce antihypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. Diltiazem decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. No reflex tachycardia is associated with the chronic antihypertensive effects.

During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually reduced. Heart rate at maximum exercise does not change or is slightly reduced.

Diltiazem antagonizes the renal and peripheral effects of angiotensin II. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in the 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 hydrochloride in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods approximately 20%.

In two short-term, double-blind, placebo-controlled studies, 303 hypertensive patients were treated with once-daily diltiazem hydrochloride extended-release capsules in doses of up to 540 mg. There were no instances of greater than first-degree atrioventricular block, and the maximum increase in the PR interval was .08 seconds. No patients were prematurely discontinued from the medication due to symptoms related to prolongation of the PR interval.

In one short-term, double-blind, placebo-controlled study, diltiazem hydrochloride extended-release capsules (once-a-day dosage) 120, 240, 360 and 480 mg/day demonstrated a dose-related antihypertensive response among patients with mild to moderate hypertension. Statistically significant decreases in trough mean supine diastolic blood pressure were seen through four weeks of treatment: 120 mg/day (-5.1 mmHg); 240 mg/day (-6.9 mmHg); 360 mg/day (-6.9 mmHg); and 480 mg/day (-10.6 mmHg). Statistically significant decreases in trough mean supine systolic blood pressure were also seen through four weeks of treatment: 120 mg/day (-2.6 mmHg); 240 mg/day (-6.5 mmHg); 360 mg/day (-4.8 mmHg); and 480 mg/day (-10.6 mmHg). The proportion of evaluable patients exhibiting a therapeutic response (supine diastolic blood pressure < 90 mmHg or decrease > 10 mmHg) was greater as the dose increased: 31%, 42%, 48% and 69% with the 120, 240, 360 and 480 mg/day diltiazem groups, respectively. Similar findings were observed for standing systolic and diastolic blood pressures. The trough (24 hours after a dose) antihypertensive effect of diltiazem hydrochloride extended-release capsules (once-a-day dosage) retained more than one-half of the response seen at peak (3–6 hours after administration).

Significant reductions of mean supine blood pressure (at trough) in patients with mild to moderate hypertension were also seen in a short- term, double-blind, dose-escalation, placebo-controlled study after 2 weeks of once-daily diltiazem hydrochloride extended-release capsules 180 mg/day (diastolic: -6.1 mmHg; systolic: -4.7 mmHg) and again, 2 weeks after escalation to 360 mg/day (diastolic: -9.3 mmHg; systolic: -7.2 mmHg). However, a further increase in dose to 540 mg/day for 2 weeks provided only a minimal further increase in the antihypertensive effect (diastolic: -10.2 mmHg; systolic: -6.7 mmHg).

Diltiazem hydrochloride extended-release capsules (once-a-day dosage), given at 120 mg, 240 mg, and 480 mg/day, in a randomized, multicenter, double-blind, placebo controlled, parallel group, dose-ranging study, in 189 patients with chronic angina, demonstrated a dose-related increase in exercise time by Exercise Tolerance Test (ETT) and a reduction in rates of anginal attacks (based on individual patient diaries). The improvement in total exercise time (using the Bruce protocol), measured at trough exercise periods, for placebo, 120 mg, 240 mg, and 480 mg, was 20, 37, 49, and 56 seconds, respectively.

Diltiazem is well-absorbed from the gastrointestinal tract, and is subject to an extensive first-pass effect. When given as an immediate-release oral formulation, the absolute bioavailability (compared to intravenous administration) of diltiazem is approximately 40%. Diltiazem undergoes extensive hepatic metabolism in which 2% to 4% of the unchanged drug appears in the urine. Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2 to 5 hours for diltiazem. In-vitro binding studies show diltiazem is 70% to 80% bound to plasma proteins. Competitive in-vitro ligand binding studies have also shown diltiazem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life of diltiazem is approximately 3.0 to 4.5 hours. Desacetyldiltiazem, the major metabolite of diltiazem, which is also present in the plasma at concentrations of 10% to 20% of the parent drug, is approximately 25% to 50% as potent a coronary vasodilator as diltiazem. Therapeutic blood levels of diltiazem appear to be in the range of 40–200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose.

A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. Patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) contain a controlled-release tablet formulation designed to release diltiazem over a 24-hour period. Controlled absorption of diltiazem begins within 1 hour, with maximum plasma concentrations being achieved 4 to 6 hours after administration. The apparent steady-state half-life of diltiazem following once-daily administration of diltiazem hydrochloride extended-release capsules ranges from 5 to 10 hours. This prolongation of half-life is attributed to continued absorption of diltiazem rather than to alterations in its elimination.

The absolute bioavailability of diltiazem from a single dose of diltiazem hydrochloride extended-release capsules (compared to intravenous administration) is 41% (± 14). This value was shown to be similar to the 40% systemic availability reported following administration of an immediate-release diltiazem hydrochloride formulation.

As the dose of diltiazem hydrochloride extended-release capsules (once-a-day dosage) is increased from a daily dose of 120 mg to 240 mg, there is an increase in the AUC of 2.3 fold. When the dose is increased from 240 mg to 360 mg, AUC increases 1.6 fold and when increased from 240 mg to 480 mg, AUC increases 2.4 fold.

In-vivo release of diltiazem occurs throughout the gastrointestinal tract, with controlled release still occurring for up to 24 hours after administration, as determined by radio-labeled methods. As the once-daily dose of diltiazem hydrochloride extended-release capsules was increased, departures from linearity were noted. There were disproportionate increases in area under the curve for doses from 120 mg to 480 mg.

The presence of food did not affect the ability of diltiazem hydrochloride extended-release capsules to maintain a controlled release of drug and did not impact its sustained release properties over 24-hours after administration. However, simultaneous administration of diltiazem hydrochloride extended-release capsules with a high-fat breakfast resulted in increases in AUC of 13% and 19%, and in C_max by 37% and 51% respectively.

Diltiazem Hydrochloride Extended-release Capsules (Once-a-Day Dosage) are indicated for the treatment of hypertension. Diltiazem hydrochloride may be used alone or in combination with other antihypertensive medications, such as diuretics.

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) are indicated for the management of chronic stable angina.

Diltiazem is contraindicated in: (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker; (2) patients with second or third degree AV block except in the presence of a functioning ventricular pacemaker; (3) patients with hypotension (less than 90 mmHg systolic); (4) patients who have demonstrated hypersensitivity to the drug; and (5) patients with acute myocardial infarction and pulmonary congestion as documented by X-ray on admission.

Diltiazem 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 (22 of 10,119 patients, or 0.2%); 41% of these 22 patients were receiving concomitant beta-adrenoceptor antagonists versus 17% of the total group. 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 60 mg dose of diltiazem.

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 of 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 in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.

Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

Mild elevations of serum 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 alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1 to 6 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem is uncertain in some cases, but probable in some others (see PRECAUTIONS).

Diltiazem hydrochloride is extensively metabolized by the liver and is excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS) may be transient and may disappear despite continued use of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.

Although diltiazem hydrochloride extended-release capsules (once-a-day dosage) utilize a slowly erodible matrix, caution should still be used in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been no reports of obstructive symptoms in patients with known strictures in association with the ingestion of diltiazem hydrochloride extended-release capsules (once-a-day dosage).

Diltiazem hydrochloride extended-release capsules (once-a-day dosage) should be taken on an empty stomach. Patients should be cautioned that the diltiazem hydrochloride extended-release capsules (once-a-day dosage) should not be opened, chewed or crushed, and should be swallowed whole.

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with any agents known to affect cardiac contractility and/or conduction (see WARNINGS). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem (see WARNINGS). As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Co-administration of diltiazem with other agents which follow the same route of biotransformation may result in the competitive inhibition of metabolism. Especially in patients with renal and/or hepatic impairment, dosages of similarly metabolized drugs, particularly those of low therapeutic ratio such as cyclosporine, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels. Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated plasma levels of carbamazepine, resulting in toxicity in some cases.

A 24-month study in rats and an 18-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in-vitro or in-vivo in mammalian cell assays or in-vitro in bacteria. No evidence of impaired fertility was observed in male or female rats at oral doses of up to 100 mg/kg/day.

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

Safety and effectiveness in pediatric patients have not been established.

Serious adverse reactions to diltiazem hydrochloride have been rare in studies with other formulations, as well as with diltiazem hydrochloride extended-release capsules (once-a-day dosage). It should be recognized, however, that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.

The most common adverse events (frequency ≥ 1%) in placebo-controlled, clinical hypertension studies with diltiazem hydrochloride extended-release capsules (once-a-day dosage) using daily doses up to 540 mg are uled in the table below with placebo-treated patients included for comparison.

The most common adverse events (frequency ≥ 1%) in a placebo-controlled, short-term (2 week) clinical angina study with diltiazem hydrochloride extended-release capsules (once-a-day dosage) are uled in the table below with placebo-treated patients included for comparison. In this trial, following a placebo phase, patients were randomly assigned to once-daily doses of either 120, 240 or 480 mg of diltiazem hydrochloride extended-release capsules (once-a-day dosage).

The following additional events (COSTART Terms), uled by body system, were reported infrequently (less than 1%) in all subjects, hypertensive (n = 425) or angina (n = 318) patients who received diltiazem hydrochloride extended-release capsules (once-a-day dosage), or with other formulations of diltiazem.

Several literature reports have identified cases of diltiazem hydrochloride overdose, some with multiple drug ingestion, with both fatal and non-fatal outcomes. The reported events affected multiple body systems including the cardiovascular system (bradycardia, complete heart block, asystole, cardiac failure, arrhythmia, atrial fibrillation, palpitations, hypotension, ischemia, ECG changes), respiratory system (respiratory failure, hypoxia, dyspnea, pulmonary edema), central nervous system (loss of consciousness, convulsions, dizziness, confusion, agitation), gastrointestinal system (nausea, vomiting), skin and appendages (increased sweating), and other systems (hypotonia, iliac artery thrombosis, metabolic acidosis, increased blood glucose). The administration of ipecac to induce vomiting and activated charcoal to reduce drug absorption have been advocated as initial means of intervention. In addition to gastric lavage, the following measures should also be considered:

Bradycardia: Administer atropine (0.60 mg to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure: Administer inotropic agents (dopamine or dobutamine) and diuretics.

Hypotension: Vasopressors (e.g., dopamine or norepinephrine).

Actual treatment and dosage should depend on the severity of the clinical situation as well as the judgment and experience of the treating physician.

Due to extensive metabolism, plasma concentrations after a standard dose of diltiazem can vary over tenfold, which significantly limits their value in evaluating cases of overdosage.

Charcoal hemoperfusion has been used successfully as an adjunct therapy to hasten drug elimination. Overdoses with as much as 10.8 gm of oral diltiazem have been successfully treated using appropriate supportive care.

Hypertensive or anginal patients who are treated with other formulations of diltiazem can safely be switched to diltiazem hydrochloride extended-release capsules (once-a-day dosage) at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may, however, be necessary and should be initiated as clinically indicated.

Studies have shown a slight increase in the rate of absorption of diltiazem hydrochloride extended-release capsules (once-a-day dosage), when ingested with a high-fat breakfast; therefore, administration in the morning on an empty stomach is recommended.

Patients should be cautioned that the diltiazem hydrochloride extended-release capsules should not be opened, chewed or crushed and should be swallowed whole.

Diltiazem Hydrochloride Extended-release Capsules, USP (Once-a-Day Dosage) are available in 120 mg, 180 mg and 240 mg.

The 120 mg capsule is a pink opaque cap/flesh opaque body, hard-shell gelatin capsule filled with two white to off-white, round, flat-faced, beveled edge tablets with no markings. The capsule is radially printed with MYLAN over 5220 in black ink on the cap. They are available as follows:

NDC 0378-5220-01
bottles of 100 capsules
NDC 0378-5220-05
bottles of 500 capsules

The 180 mg capsule is a lavender opaque cap/flesh opaque body, hard-shell gelatin capsule filled with three white to off-white, round, flat-faced, beveled edge tablets with no markings. The capsule is radially printed with MYLAN over 5280 in black ink on the cap. They are available as follows:

NDC 0378-5280-01
bottles of 100 capsules
NDC 0378-5280-05
bottles of 500 capsules

The 240 mg capsule is a light blue opaque cap/flesh opaque body, hard-shell gelatin capsule filled with four white to off-white, round, flat-faced, beveled edge tablets with no markings. The capsule is radially printed with MYLAN over 5340 in black ink on both the cap and body. They are available as follows:

NDC 0378-5340-01
bottles of 100 capsules
NDC 0378-5340-05
bottles of 500 capsules