Diltia XT

Diltia XT is part of the drug class:

• Benzothiazepine derivatives

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• Atazanavir (Reyataz)
• Benzodiazepines such as
  • Midazolam (Versed)
  • Triazolam (Halcion)
• Beta blockers such as
  • Atenolol (Tenormin)
  • Metoprolol (Toprol XL, Lopressor)
  • Carvedilol (Coreg)
  • Bisoprolol (Zebeta)
  • Betaxolol (Kerlone)
  • Nebivolol (Bystolic)
  • Propranolol (Inderal)
  • Labetalol (Trandate)
  • Nadolol (Corgard)
• Buspirone (Buspar)
• Carbamazepine (Carbatrol, Epitol, Tegretol)
• Cimetidine (Tagamet)
• Cyclosporine (Gengraf, Neoral, Sandimmune)
• Digoxin (Lanoxin)
• Statins such as
  • Lovastatin (Altoprev, Mevacor)
  • Simvastatin (Zocor)
• Quinidine
• Rifampin 
• Clonidine (Catapres)

This is not a complete list of diltiazem drug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Diltiazem falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Oral:

Take diltiazem exactly as prescribed.

Diltiazem comes in tablet, extended release tablet, and extended release capsule forms. The tablet is usually taken 3 to 4 times a day. The extended release tablet and capsule is usually taken 1 to 2 times a day. Each diltiazem product has different instructions for whether or not it should be taken with or without food, so ask your pharmacist for more information.

Do not chew, divide, or break diltiazem extended release tablets or capsules. Swallow the tablets and capsules whole.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of diltiazem at the same time.

Injectable:

This medication is also available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

If you take too much diltiazem, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If diltiazem is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flushing.
• Headache.
• Upset stomach.
• Dizziness.
• Feeling tired or weak.
• Runny nose.
• Sore throat.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

Inactive Ingredients: Diltiazem hydrochloride extended-release capsules USP (Once-a-day dosage) also contain acetyltributyl citrate, lactose (anhydrous), hydroxypropyl cellulose, hypromellose 2208, hydroxypropyl methylcellulose phthalate, magnesium stearate, colloidal silicon dioxide, dibasic sodium phosphate, talc, gelatin, black iron oxide, D & C Yellow # 10 aluminum lake, FD & C blue # 1 aluminum lake, FD & C blue # 2 aluminum lake, FD & C red # 40 aluminum lake, and titanium dioxide. The 180 mg and 240 mg dosage forms also contain yellow iron oxide.

This product meets USP Drug Release Test 7.

For oral administration

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.

Mechanism of Action:

Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle with a 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 work loads.

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 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 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 x SBP) 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. Increased heart failure has, however, been reported in occasional 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.

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 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 0.08 seconds. No patients were prematurely discontinued from the medication due to symptoms related to prolongation of the PR interval.

Pharmacodynamics. In one short-term, double-blind, placebo-controlled study, diltiazem hydrochloride extended-release capsules 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 4 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 4 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 capsule 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 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 patients 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.

Pharmacokinetics and Metabolism.

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 Cmax by 37% and 51%, respectively.

General

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.

Information for Patients

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.

Drug Interactions

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.

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%. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).

Cimetidine: A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1,200 mg per day and diltiazem 60 mg per day. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, 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.

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 effects 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).

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy

Category C: Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg once daily. or 8 mg/kg once daily for a 60 kg patient) has resulted in embryo and fetal lethality. These studies have revealed, in one species or another, a propensity to cause abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights and pup survival, prolonged delivery, and increased incidence of stillbirths.

There are no well-controlled studies in pregnant women; therefore, use diltiazem hydrochloride in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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 (0.6 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 bitartrate).

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.