DILTIA XT™
brand of DILTIAZEM HYDROCHLORIDE
EXTENDED-RELEASE CAPSULES, USP
(ONCE-A-DAY-DOSAGE)

Rx Only

Diltiazem hydrochloride 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 450.98. Its structural formula is as follows:

Diltiazem hydrochloride 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 daily dosage) contain multiple units of diltiazem HCl extended-release 60 mg, resulting in 120 mg, 180 mg, or 240 mg dosage strengths allowing for the controlled release of diltiazem hydrochloride over a 24-hour period.

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

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 HCl is 70% to 80% bound to plasma proteins. Competitive in-vitro ligand binding studies have also shown diltiazem HCl 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 hydrochloride 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 contain a degradable 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 capsule (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 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 USP (Once-a-day dosage) to maintain a controlled release of the drug and did not impact its sustained release properties over 24-hours after administration. However, simultaneous administration of diltiazem hydrochloride extended-release capsules (Once-a-day Dosage) 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 USP (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 USP (Once-a-day dosage) are indicated for the management of chronic stable angina.

Diltiazem hydrochloride 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 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 hydrochloride. 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 utilize a slowly disintegrating 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.

Diltiazem hydrochloride extended-release capsules should be taken on an empty stomach. Patients should be cautioned that the diltiazem hydrochloride extended-release capsules 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 hydrochloride 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 hydrochloride (see WARNINGS). As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem hydrochloride undergoes biotransformation by cytochrome P-450 mixed function oxidase. Co-administration of diltiazem hydrochloride 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 cyclosporin, may require adjustment when starting or stopping concomitantly administered diltiazem hydrochloride 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 hydrochloride is deemed essential, an alternate 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. It should be recognized, however, that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.

Cardiovascular: First-degree AV block, arrhythmia, postural hypotension, tachycardia, pallor, palpitations, phlebitis, ECG abnormality, ST elevation.

Nervous System: Vertigo, hypertonia, paresthesia, dizziness, somnolence.

Digestive System: Dry mouth, anorexia, tooth disorder, eructation.

Skin and Appendages: Sweating, urticaria, skin hypertrophy (nevus).

Respiratory System: Epistaxis, bronchitis, respiratory disorder.

Urogenital System: Cystitis, kidney calculus, impotence, dysmenorrhea, vaginitis, prostate disease.

Metabolic and Nutritional Disorders: Gout, edema.

Musculoskeletal System: Arthralgia, bursitis, bone pain.

Hemic and Lymphatic System: Lymphadenopathy.

Body as a Whole: Pain, unevaluable reaction, neck pain, neck rigidity, fever, chest pain, malaise.

Special Senses: Amblyopia (blurred vision), ear pain.

Cardiovascular: Palpitations, AV block, sinus bradycardia, bigeminal extrasystole, angina pectoris, hypertension, hypotension, myocardial infarct, myocardial ischemia, syncope, vasodilatation, ventricular extrasystole.

Nervous System: Abnormal thinking, neuropathy, paresthesia.

Digestive System: Diarrhea, dyspepsia, vomiting, colitis, flatulence, GI hemorrhage, stomach ulcers.

Skin and Appendages: Contact dermatitis, pruritus, sweating.

Respiratory System: Respiratory distress.

Urogenital System: Kidney failure, pyelonephritis, urinary tract infection.

Metabolic and Nutritional Disorders: Weight increase.

Musculoskeletal System: Myalgia.

Body as a Whole: Chest pain, accidental injury, infection.

Special Senses: Eye hemorrhage, ophthalmitis, otitis media, taste perversion, tinnitus.

There have been post-marketing reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of diltiazem hydrochloride.

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:

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 USP (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 USP (Once-a-day dosage) capsules should not be opened, chewed or crushed, and should be swallowed whole.

Sublingual Nitroglycerin may be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy.

Prophylactic Nitrate Therapy— Diltiazem hydrochloride may be safely co-administered with short- and long-acting nitrates.

Beta-blockers. (See WARNINGS and PRECAUTIONS.)

Antihypertensives— Diltiazem hydrochloride has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride or the concomitant antihypertensives may need to be adjusted when adding one to the other.

STORE AT CONTROLLED ROOM TEMPERATURE, 20° to 25°C (68° to 77°F) [see USP].

Keep out of the reach of children.

Manufactured by:
Watson Laboratories, Inc.
Corona, CA 92880 USA

Distributed by:
Watson Pharma, Inc.

Rev. date: 07/07
7017