Cardizem SR (Diltiazem HCl)

CARDIZEM® CARDIZEM® SR CARDIZEM® CD

Hoechst Marion Roussel

Diltiazem HCl

Antianginal

Antihypertensive – Antianginal

Action And Clinical Pharmacology: Diltiazem is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist).

The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Diltiazem blocks transmembrane influx of calcium through the slow channel without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues. Diltiazem does not alter total serum calcium.

Angina: The precise mechanism by which diltiazem relieves angina has not been fully determined, but it is believed to be brought about largely by its vasodilator action.

In angina due to coronary spasm, diltiazem increases myocardial oxygen delivery by dilating both large and small coronary arteries and by inhibiting coronary spasm at drug levels which cause little negative inotropic effect. The resultant increases in coronary blood flow are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.

In angina of effort it appears that the action of diltiazem is related to the reduction of myocardial oxygen demand. This is probably caused by a decrease in blood pressure brought about by the reduction of peripheral resistance and of heart rate.

Hypertension: The antihypertensive effect of diltiazem is believed to be brought about largely by its vasodilatory action on peripheral blood vessels with resultant decrease in peripheral vascular resistance.

Hemodynamic and Electrophysiologic Effects: Diltiazem produces antihypertensive effects both in the supine and standing positions. Resting heart rate is usually slightly reduced. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually unaffected. Heart rate at maximum exercise is reduced.

Studies to date, primarily in patients with normal ventricular function, have shown that cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected.

Chronic therapy with diltiazem produces no change, or an increase, in circulating plasma catecholamines. However, no increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem inhibits the renal and peripheral effects of angiotensin II.

In man i.v. diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. Chronic oral administration of diltiazem in doses up to 540 mg/day has resulted in small increases in PR interval. Second degree and third degree AV block have been observed (see Warnings). In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Pharmacokinetics: Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect giving absolute bioavailability (compared to i.v. dosing) of about 40%. Therapeutic blood levels appear to be in the 50 to 200 ng/mL range and the plasma elimination half-life (beta-phase) following single or multiple drug administration is approximately 3.5 to 6.0 hours. In vitro human serum binding studies revealed that 70 to 80% of diltiazem is bound to plasma proteins.

Cardizem undergoes extensive hepatic metabolism in which only 2 to 4% of the drug appears unchanged in the urine and 6 to 7% appears as metabolites. The metabolic pathways of Cardizem include N- and O-demethylation (via cytochrome P450), deacetylation (via plasma and tissue esterases), in addition to conjugation (via sulfation and glucuronidation). In vitro studies have demonstrated that CYP 3A4 is the principal CYP isoenzyme involved in N-demethylation. The major metabolite, desacetyl diltiazem, is present in the plasma at levels 10 to 20% of the parent drug and is 25 to 50% as potent as diltiazem in terms of coronary vasodilation.

Cardizem Tablets: Single oral doses of 30 to 120 mg of Cardizem tablets result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. There is a departure from linearity of accumulation of diltiazem when Cardizem tablets are administered to steady-state in normal subjects. A 240 mg daily dose (60 mg q.i.d.) gave plasma levels 2.3 times higher than a 120 mg daily dose (30 mg q.i.d.) and a 360 mg daily dose (90 mg q.i.d.) had levels 1.7 times higher than the 240 mg daily dose.

Cardizem SR: Diltiazem is absorbed from the sustained release (SR) capsule formulation to about 93% of the tablet form at steady-state. A single 120 mg dose of the capsule resulted in detectable plasma levels within 2 to 3 hours and peak plasma levels at 7 to 11 hours. The apparent elimination half-life after single or multiple dosing is 5 to 7 hours. A departure from linearity similar to that observed with the Cardizem tablet is observed. As the dose of Cardizem SR capsules is increased from a daily dose of 120 mg (60 mg b.i.d.) to 240 mg (120 mg b.i.d.) daily, there is an increase in bioavailability of 2.6 times. When the dose is increased from 240 to 360 mg daily there is an increase in bioavailability of 1.8 times. The average plasma levels of the capsule dosed twice daily at steady-state are equivalent to the tablet dosed 4 times daily when the same total daily dose is administered.

Cardizem CD: When compared to a regimen of Cardizem tablets at steady-state, more than 95% of drug is absorbed from the Cardizem CD formulation. A single 360 mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours. When Cardizem CD was taken with a high fat content breakfast, the extent of diltiazem absorption was not affected but was delayed. Dose-dumping does not occur. The apparent elimination half-life after single or multiple dosing is 5 to 8 hours. A departure from linearity similar to that seen with Cardizem tablets and Cardizem SR capsules is observed. As the dose of Cardizem CD capsules is increased from a daily dose of 120 to 240 mg, there is an increase in the area under the curve (AUC) of 2.7 times. When the dose is increased from 240 to 360 mg there is an increase in AUC of 1.6 times.

A study which compared patients with normal hepatic function to liver cirrhosis patients noted an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single dose study in patients with severely impaired renal function showed no difference in the half-life of diltiazem as compared to patients with normal renal function (see Precautions and Dosage).

Indications And Clinical Uses: Cardizem: Angina: In the management of angina resulting from coronary artery spasm.

For the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents.

Cardizem tablets may be useful in unstable angina when spasm of the coronary vessels is definitely a contributing factor (e.g., ST segment elevation). In the absence of objective evidence of a spastic component, nitrates or nitrates plus a beta-blocker are, at present, the treatment of choice. If, in the view of a cardiologist, the addition of Cardizem to this regimen is considered necessary and safe, then the use of Cardizem tablets might be considered. Generally, the patient should be hospitalized and treatment initiated under the supervision of a cardiologist.

Cardizem tablets may be tried in combination with beta-blockers in chronic stable angina in patients with normal ventricular function. When such concomitant therapy is introduced, patients must be monitored closely (see Warnings).

Cardizem SR: Angina: For maintenance therapy in the management of chronic stable angina. Treatment should be initiated and individual titration of dosage carried out using the regular tablets. The sustained release formulation may be substituted as maintenance, provided the dosage requirement is suitable (see also Pharmacology). When patients who have been stabilized on tablets are switched to SR capsules for maintenance, close medical supervision is recommended since in some patients the dosage of the SR formulation may require adjustment.

Since the safety and efficacy of SR capsules in the management of unstable or vasospastic angina has not been substantiated, use of this formulation for these indications is not recommended.

Hypertension: In the treatment of mild to moderate essential hypertension. Cardizem SR should normally be used in those patients in whom treatment with diuretics or beta-blockers has been associated with unacceptable adverse effects.

Cardizem SR can be tried as initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

Combination of Cardizem SR with a diuretic has been found to be compatible and showed additive antihypertensive effect. In a single clinical study, the concomitant use of Cardizem SR with captopril was also found to be compatible.

Safety of concurrent use of Cardizem SR with other antihypertensive agents has not been established.

Cardizem CD: Angina: For the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents.

Cardizem CD may be tried in combination with beta-blockers in chronic stable angina patients with normal ventricular function. When such concomitant therapy is introduced, patients must be monitored closely (see Warnings).

Since the safety and efficacy of CD capsules in the management of unstable or vasospastic angina have not been substantiated, use of this formulation for these indications is not recommended.

Hypertension: For the treatment of mild to moderate essential hypertension. Cardizem CD should normally be used in those patients in whom treatment with diuretics or beta-blockers has been ineffective, or has been associated with unacceptable adverse effects.

Cardizem CD can be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated, or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

Safety of concurrent use of Cardizem CD with other antihypertensive agents has not been established.

Contra-Indications: In patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker; in patients with second or third degree AV block; in patients with known hypersensitivity to diltiazem; and in patients with severe hypotension (less than 90 mmHg systolic); in myocardial infarction patients who have left ventricular failure manifested by pulmonary congestion.

Pregnancy: In pregnancy and in women of childbearing potential. Fetal malformations and adverse effects on pregnancy have been reported in animals. In repeated dose studies a high incidence of vertebral column malformations were present in the offspring of mice receiving more than 50 mg/kg of diltiazem orally.

In the offspring of mice receiving a single oral dose of 50 or 100 mg/kg on day 12 of gestation, the incidence of cleft palate and malformed extremities was significantly higher. Vertebral malformations were most prevalent when they received the drug on day 9. In rats, a significantly higher fetal death rate was present when 200 and 400 mg/kg were given orally on days 9 to 14 of gestation. Single oral dose studies in rats resulted in a significant incidence of skeletal malformations in the offspring of the group receiving 400 mg/kg on day 11. In rabbits, all pregnant dams receiving 70 mg/kg orally from day 6 to 18 of gestation aborted; at 35 mg/kg, a significant increase in skeletal malformations was recorded in the offspring.

Manufacturers’ Warnings In Clinical States: Cardiac Conduction: 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 (6 of 1 208 patients or 0.5%).

First degree AV block was observed in 5.8% of patients receiving Cardizem CD (see Adverse Effects).

Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction.

Congestive Heart Failure: Because diltiazem has a negative inotropic effect in vitro and it affects cardiac conduction, the drug should only be used with caution and under careful medical supervision in patients with congestive cardiac failure (see also Contraindications).

Use with Beta-blockers: The combination of diltiazem and beta-blockers warrants caution since in some patients additive effects on heart rate, AV conduction, blood pressure or left ventricular function have been observed. Close medical supervision is recommended.

Generally, diltiazem should not be given to patients with impaired left ventricular function while they receive beta-blockers. However, in exceptional cases when, in the opinion of the physician, concomitant use is considered essential, such use should be instituted gradually in a hospital setting.

Diltiazem gives no protection against the dangers of abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-blocker.

Hypotension: Since diltiazem lowers peripheral vascular resistance, decreases in blood pressure may occasionally result in symptomatic hypotension. In patients with angina or arrhythmias using antihypertensive drugs, the additional hypotensive effect of diltiazem should be taken into consideration.

Patients with Myocardial Infarction: Use of immediate release diltiazem at 240 mg/day started 3 to 15 days after a myocardial infarction was associated with an increase in cardiac events in patients with pulmonary congestion, and no overall effect on mortality. Although there has not been a study of Cardizem SR or Cardizem CD in acute myocardial infarction reported, their use may have effects similar to those of immediate release diltiazem in acute myocardial infarction.

Acute Hepatic Injury: In rare instances, significant elevations in alkaline phosphatase, CPK, LDH, AST, ALT and symptoms consistent with acute hepatic injury have been observed. These reactions have been reversible upon discontinuation of drug therapy. Although a causal relationship to diltiazem has not been established in all cases a drug induced hypersensitivity reaction is suspected (see Adverse Effects). As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.

Precautions: Impaired Hepatic or Renal Function: Because diltiazem is extensively metabolized by the liver and excreted by the kidney and in bile, monitoring of laboratory parameters and cautious dosage titration are recommended in patients with impaired hepatic or renal function (see Adverse Effects).

Children: The safety of diltiazem in children has not yet been established.

Lactation: Diltiazem has been reported to be excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. Since diltiazem safety in newborns has not been established, it should not be given to nursing mothers.

Geriatrics: Administration of diltiazem to elderly patients (over or equal to 65 years of age) requires caution. The incidence of adverse reactions is approximately 13% higher in this group. Those adverse reactions which occur more frequently include: peripheral edema, bradycardia, palpitation, dizziness, rash and polyuria. Therefore, particular care in titration is advisable (see Dosage).

Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of diltiazem with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, terfenadine, theophylline.

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: Diltiazem significantly increases peak plasma levels and the elimination half-life of triazolam and midazolam.

Beta-blockers: The concomitant administration of diltiazem with beta adrenergic blocking drugs warrants caution and careful monitoring. Such an association may have an additive effect on heart rate, on AV conduction or on blood pressure (see Warnings). Appropriate dosage adjustments may be necessary. A study in 5 normal subjects showed that diltiazem increased propranolol bioavailability by approximately 50%.

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 6 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/day and a single dose of oral diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. 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.

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: Diltiazem and digitalis glycosides may have an additive effect in prolonging AV conduction. In clinical trials, concurrent administration of diltiazem and digoxin have resulted in increases in serum digoxin levels with prolongation of AV conduction. This increase may result from a decrease in renal clearance of digoxin. Patients on concomitant therapy, especially those with renal impairment, should be carefully monitored. The dose of digoxin may need downward adjustment.

Rifampin: Administration of diltiazem with rifampin markedly reduced plasma diltiazem concentrations and the therapeutic effect of diltiazem.

Short and Long-Acting Nitrates: Diltiazem may be safely coadministered with nitrates, but there have been few controlled studies to evaluate the antianginal effectiveness of this combination.

Other Calcium Antagonists: Limited clinical experience suggests that in certain severe conditions not responding adequately to verapamil or to nifedipine, using diltiazem in conjunction with either of these drugs may be beneficial.

Adverse Reactions: See also Overall Cardizem Safety Profile.

Cardizem: A safety evaluation was carried out in controlled clinical trials with 1 208 North American angina patients, some of whom were severely ill and were receiving multiple concomitant therapy. Adverse effects were reported in 19.6% of patients and required discontinuation of treatment in 7.2%.

The most common occurrences and their frequency are: nausea (2.7%), swelling/edema (2.4%), arrhythmia (2.0%) (AV block, bradycardia, tachycardia and sinus arrest), headache (2.0%), rash (1.8%) and asthenia (1.1%).

In addition, the following events were reported in less than 1% of cases: Cardiovascular: angina, bradycardia, congestive heart failure, flushing, hypotension, palpitations, syncope. A patient with Prinzmetal’s angina, experiencing episodes of vasospastic angina, developed periods of transient asymptomatic asystole approximately 5 hours after receiving a single 60 mg dose of diltiazem.

CNS: amnesia, confusion, depression, dizziness, drowsiness, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, tremor, weakness.

Gastrointestinal: anorexia, constipation, diarrhea, dyspepsia, vomiting.

Dermatologic: petechiae, pruritus, urticaria.

Other: amblyopia, decreased sexual performance, dysgeusia, dyspnea, epistaxis, eye irritation, hyperglycemia, nocturia, osteo-articular pain, paresthesia, photosensitivity, polyuria, thirst, tinnitus, weight increase.

Rarely, reports of extremely elevated liver enzymes, cholestasis, hyperbilirubinemia, jaundice, epigastric pain, anorexia, nausea, vomiting, stool discoloration, dark urine and weight loss have been reported. The symptoms and laboratory test abnormalities have been reversible on drug discontinuation (see Warnings).

Two incidents of marked hyperglycemia, hyperkalemia, bradycardia, asthenia, hypotension and gastrointestinal disturbances have been reported in diabetic patients receiving diltiazem, glyburide and a beta-blocker along with several other medications. Drugs were discontinued and supportive measures were administered which resulted in the patients fully recovering within a few days.

Laboratory Tests: In rare instances, mild to moderate transient elevations of alkaline phosphatase, AST, ALT, LDH and CPK, have been noted during diltiazem therapy.

Cardizem SR: A safety evaluation was carried out in controlled and open label studies in 611 hypertensive patients treated with Cardizem SR either alone or in combination with other antihypertensive agents. Adverse effects were reported in 34.2% of patients and required discontinuation of therapy in 7.2%.

The most common adverse effects were: peripheral edema (8.3%), headache (4.9%), dizziness (4.7%), asthenia (3.9%), vasodilation (flushing) (2.3%) and bradycardia (2.1%).

The following percentage of adverse effects, divided by system, was reported: Cardiovascular: edema peripheral (8.3%), vasodilation (flushing) (2.3%), bradycardia (2.1%), AV block (first degree) (1.6%), palpitations (1.3%), arrhythmia (1.0%), heart failure right (0.5%).

CNS: headache (4.9%), dizziness (4.7%), asthenia (3.9%), somnolence (1.0%), nervousness (anxiety) (0.8%), paresthesia (0.7%), insomnia (0.5%), depression (0.5%), dream abnormality (0.5%), tinnitus (0.5%).

Gastrointestinal: dyspepsia (1.1%), nausea (1.1%), constipation (0.7%).

Dermatologic: rash (1.6%).

Laboratory Tests: increased alkaline phosphatase (0.7%).

Other: impotence (1.6%), musculoskeletal pain (1.5%), nocturia (1.1%), polyuria (1.0%), rhinitis (0.5%).

The following additional adverse effects have occurred with an incidence of less than 0.5% in clinical trials: syncope, AV block, postural hypotension, chest pain, dyspnea, tremor, gait abnormality, vertigo, taste alteration, anorexia, increased appetite, dry mouth, vomiting, diarrhea, increased saliva, acute hepatic injury, pruritus, urticaria, conjunctivitis, amblyopia, ejaculation abnormality, malaise, fever.

The following abnormal laboratory findings have been rarely reported: increased AST/ALT, bilirubinemia, hyperproteinemia, hypercholesteremia, hyperlipidemia, hyperglycemia, hypokalemia, urine abnormality (see Precautions).

Cardizem CD: Angina: The safety of Cardizem CD, administered at doses up to 360 mg a day, was evaluated in 365 patients with chronic stable angina treated in controlled and open-label clinical trials. Adverse events were reported in 21.1% of patients, and required discontinuation in 2.2% of patients.

The most common adverse effects reported were: first degree AV block (5.8%), dizziness (3.0%), headache (3.0%), asthenia (2.7%), bradycardia (2.5%), and angina pectoris (1.6%).

The following percentage of adverse effects, divided by system, was reported: Cardiovascular: first degree AV block (5.8%), bradycardia (2.5%), angina pectoris (1.6%), peripheral edema (1.4%), palpitations (1.1%), and ventricular extrasystoles (0.8%).

CNS: dizziness (3.0%), headache (3.0%), asthenia (2.7%), insomnia (1.1%), nervousness (0.8%).

Gastrointestinal: nausea (1.4%), diarrhea (0.5%).

Dermatological: rash (0.8%).

Other: amblyopia (0.5%).

The following additional adverse effects have occurred with an incidence of less than 0.5% in clinical trials: bundle branch block, ventricular tachycardia, ECG abnormality, supraventricular extrasystoles, chest pain, syncope, postural hypotension, paresthesia, tremor, depression, mental confusion, impotence, abdominal pain, constipation, gastrointestinal disorder, epistaxis, nuchal rigidity, myalgia.

Hypertension: A safety evaluation was carried out in controlled studies in 378 hypertensive patients treated with Cardizem CD at doses up to 360 mg a day. Adverse effects were reported in 30.7% of patients and required discontinuation of therapy in 2.1%.

The most common adverse effects were: headache (8.7%), edema (4.0%), bradycardia (3.7%), dizziness (3.4%), ECG abnormality (2.9%), asthenia (2.6%) and first degree AV block (2.1%).

The following percentage of adverse effects, divided by system, was reported: Cardiovascular: edema peripheral (4.0%), bradycardia (3.7%), ECG abnormalities (2.9%), first degree AV block (2.1%), arrhythmia (1.6%), vasodilation (flushing) (1.6%), bundle branch block (0.8%), cardiomegaly (0.5%), hypotension (0.5%).

CNS: headache (8.7%), dizziness (3.4%), asthenia (2.6%), somnolence (1.3%), nervousness (1.1%).

Gastrointestinal: constipation (1.3%), dyspepsia (1.3%), diarrhea (0.6%).

Laboratory Tests: ALT increase (0.8%).

Other: leukopenia (1.1%), nocturia (0.5%).

The following additional adverse effects have occurred with an incidence of less than 0.5% in clinical trials: systolic murmur, supraventricular extrasystoles, migraine, tachycardia, increased appetite, increase in weight, albuminuria, bilirubinemia, hyperuricemia, thirst, insomnia, vertigo, nausea, pruritus, rash, increased perspiration, polyuria, amblyopia, tinnitus, and elevations in creatine kinase, alkaline phosphatase, and AST.

Overall Cardizem Safety Profile: In clinical trials of Cardizem tablets, Cardizem SR capsules and Cardizem CD capsules involving over 3 300 patients, the most common adverse reactions were headache (4.6%), edema (4.6%), dizziness (3.5%), asthenia (2.7%), first degree AV block (2.4%), bradycardia (1.7%), flushing (1.5%), nausea (1.4%), rash (1.2%), and dyspepsia (1.0%).

In addition, the following events were reported with a frequency of less than 1.0%.

Cardiovascular: angina, arrhythmia, bundle branch block, tachycardia, ventricular extrasystoles, congestive heart failure, syncope, palpitations, AV block (second or third degree), hypotension, ECG abnormalities.

Nervous System: amnesia, depression, gait abnormality, nervousness, somnolence, hallucinations, paresthesia, personality change, tinnitus, tremor, abnormal dreams, insomnia.

Gastrointestinal: anorexia, diarrhea, dysgeusia, mild elevations of AST, ALT, LDH, and alkaline phosphatase (see Warnings), vomiting, weight increase, thirst, constipation.

Dermatological: petechiae, pruritus, photosensitivity, urticaria.

Other: amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, sexual difficulties, nasal congestion, nocturia, osteo-articular pain, impotence, dry mouth, polyuria, hyperuricemia.

The following postmarketing events have been reported infrequently in patients receiving Cardizem: allergic reactions, alopecia, asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, detached retina, increased bleeding time, leukopenia, purpura, retinopathy, and thrombocytopenia. Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty. In addition, events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease in these patients. A number of well-documented cases of generalized rash, some characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and Cardizem therapy is yet to be established.

Symptoms And Treatment Of Overdose: Events observed following diltiazem overdose included bradycardia, hypotension, heart block and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favourably to atropine as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and i.v. calcium.

The effectiveness of i.v. calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received i.v. calcium. In some cases i.v. calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes, and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administrated as a continuous infusion at a rate of 2 g/hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

In the event of overdosage or exaggerated response, appropriate supportive measures should be employed in addition to gastric lavage. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination. The following measures may be considered: Bradycardia: Administer atropine. 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 (isoproterenol, 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.

Dosage And Administration: Cardizem: Angina: Chronic Stable Angina or Vasospastic Angina: Dosage must be adjusted to each patient’s needs. Starting with 30 mg 4 times daily, before meals and at bedtime, dosage may be increased gradually to 240 mg a day (given in 3 to 4 equally divided doses) at 1 to 2 day intervals, until optimum response is obtained. Limited clinical experience in rare resistant cases suggests that dosage of up to 360 mg a day in 3 to 4 equally divided doses may be tried under careful supervision.

In patients with vasospastic angina, the last dose of the day may be given at bedtime to help minimize angina pain which, in such patients, frequently occurs in early morning.

Unstable Angina Pectoris: Dosage of Cardizem tablets should be carefully titrated in the Intensive Care Unit, up to 360 mg/day given in 3 to 4 equally divided doses. The titration should be done as rapidly as possible with consideration of concomitant therapy (see Precautions, Drug Interactions).

Geriatrics: Pharmacokinetics of diltiazem in elderly patients has not been fully elucidated. Preliminary results in elderly patients (over 65 years old) suggest that a lower dosage might be required in this age group (see Precautions).

There are few available data concerning dosage requirements in patients with impaired renal or hepatic function. If diltiazem must be used in these patients, the dosage should be carefully and gradually adjusted depending on patient tolerance and response (see Precautions).

Cardizem SR: Angina: Cardizem SR is intended for maintenance therapy in chronic stable angina patients requiring doses within the range of 120 to 360 mg/day. Initiation of treatment and individual titration of dosage should be carried out using the conventional tablets. Cardizem SR may be preferred for maintenance because of the convenience of twice daily dosage. Patients stabilized on a maintenance regimen between 120 and 360 mg of regular tablets may be changed to the same daily dose of Cardizem SR capsules divided into 2 equal doses and taken every 12 hours. When patients are switched to SR capsules, close medical supervision is recommended since in some patients the dosage of the SR formulation may require adjustment.

Hypertension: Dosage should be individualized depending on patient’s tolerance and responsiveness to Cardizem SR capsules and to concurrent antihypertensive medications (see Indications and Precautions).

The adult dose range is 120 to 360 mg/day administered in 2 equally divided doses. Although individual patients may respond to any dosage level, the average optimum dosage range in clinical trials is between 240 and 360 mg/day. Maximum antihypertensive effect is usually observed by the second to fourth week of chronic therapy, therefore dosage adjustments should be scheduled accordingly.

A maximum daily dose of 360 mg should not be exceeded.

There is evidence that the effective dose in the elderly (over 65 years of age) is somewhat lower than in younger patients (average dose: 255 mg vs 288 mg respectively); therefore, Cardizem SR should be administered cautiously to elderly patients and the dosage should be carefully and gradually adjusted depending on patient tolerance and response (see Precautions).

Cardizem SR has an additive antihypertensive effect when used concomitantly with other antihypertensive agents. Therefore, it may be necessary to decrease the dose of Cardizem SR and/or the dose of the concomitant antihypertensive drug when adding one to the other (see Indications and Warnings).

Cardizem SR should not be used in severe hepatic or renal dysfunction.

Cardizem CD: 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 360 mg once daily. When necessary, titration should be carried out over a 7 to 14 day period.

Patients controlled on diltiazem alone or in combination with other medications may be safely switched to Cardizem CD capsules at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited experience with doses above 360 mg, however, the incidence of adverse reactions increases as the dose increases with first degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose. Therefore, doses greater than 360 mg are not recommended.

Hypertension: Dosage should be individualized depending on patient’s tolerance and responsiveness to Cardizem CD capsules. When used as monotherapy, usual starting doses are 180 to 240 mg once daily, although some patients may respond to 120 mg once daily. Maximum antihypertensive effect is usually observed after approximately 2 to 4 weeks of therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 240 to 360 mg once daily.

A maximum daily dose of 360 mg once daily should not be exceeded.

The dosage of Cardizem CD or concomitant antihypertensive agents may need to be adjusted when adding one to the other (see Warnings and Precautions regarding use with beta-blockers).

Hypertensive patients controlled on Cardizem SR alone or in combination with other antihypertensive agents may be safely switched to Cardizem CD at the same total daily dose. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted.

The tablets and capsules should not be chewed or crushed.

Availability And Storage: Cardizem: 30 mg: Each green, unscored tablet, engraved with HMR on one side and 30 on the other, contains: diltiazem HCl 30 mg. Nonmedicinal ingredients: Blue FD&C No. 1, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydrogenated vegetable, oil, lactose, magnesium stearate, polyethylene glycol, povidone, sodium methylparaben, talc and Yellow D&C No. 10. Bisulfites-, gluten- and tartrazine-free. Bottles of 100 and 500. Blister packs of 100.

60 mg: Each yellow, scored tablet, engraved with HMR on one side and 60 on the other, contains: diltiazem HCl 60 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydrogenated vegetable oil, lactose, magnesium stearate, polyethylene glycol, povidone, sodium methylparaben, talc, Yellow D&C No. 10 and Yellow FD&C No. 6. Bisulfites-, gluten- and tartrazine-free. Bottles of 100 and 500. Blister packs of 100.

Cardizem SR: 60 mg: Each ivory/brown, sustained-release capsule, imprinted with the CARDIZEM logo on one end and CARDIZEM SR 60 mg on the opposite end, contains: diltiazem HCl 60 mg. Nonmedicinal ingredients: Blue FD&C No. 1, cornstarch, fumaric acid, gelatin, povidone, Red FD&C No. 40, shellac, sucrose, talc, titanium dioxide, Yellow D&C No. 10 and Yellow FD&C No. 6. Bisulfites-, gluten- and tartrazine-free. Bottles of 100. Blister packs of 100.

90 mg: Each gold/brown, sustained-release capsule, imprinted with the CARDIZEM logo on one end and CARDIZEM SR 90 mg on the opposite end, contains: diltiazem HCl 90 mg. Nonmedicinal ingredients: Blue FD&C No. 1, cornstarch, fumaric acid, gelatin, povidone, Red FD&C No. 40, shellac, sucrose, talc, titanium dioxide, Yellow D&C No. 10 and Yellow FD&C No. 6. Bisulfites-, gluten- and tartrazine-free. Bottles of 100 and 300. Blister packs of 100.

120 mg: Each caramel/brown, sustained-release capsule, imprinted with the CARDIZEM logo on one end and CARDIZEM SR 120 mg on the opposite end, contains: diltiazem HCl 120 mg. Nonmedicinal ingredients: Blue FD&C No. 1, cornstarch, fumaric acid, gelatin, povidone, Red FD&C No. 40, shellac, sucrose, talc, titanium dioxide, Yellow D&C No. 10 and Yellow FD&C No. 6. Bisulfites-, gluten- and tartrazine-free. Bottles of 100 and 300. Blister packs of 100.

Cardizem CD: 120 mg: Each light turquoise blue, controlled delivery capsule, imprinted with CARDIZEM CD 120 mg, contains: diltiazem HCl 120 mg. Nonmedicinal ingredients: acetyltributyl citrate, beeswax, Blue FD&C No. 1, castor oil, cornstarch, ethylcellulose, fumaric acid, gelatin, polymethyl methacrylate, silica, simethicone, sucrose, stearic acid, talc and titanium dioxide. Bisulfites-, gluten- and tartrazine-free. Bottles of 100. Blister packs 100.

180 mg: Each light blue/light turquoise blue, controlled delivery capsule, imprinted with CARDIZEM CD 180 mg, contains: diltiazem HCl 180 mg. Nonmedicinal ingredients: acetyltributyl citrate, beeswax, Blue FD&C No. 1, castor oil, cornstarch, ethylcellulose, fumaric acid, gelatin, polymethyl methacrylate, silica, simethicone, sucrose, stearic acid, talc and titanium dioxide. Bisulfites-, gluten- and tartrazine-free. Bottles of 100. Blister packs of 100.

240 mg: Each light blue/light blue, controlled delivery capsule, imprinted with CARDIZEM CD 240 mg, contains: diltiazem HCl 240 mg. Nonmedicinal ingredients: acetyltributyl citrate, beeswax, Blue FD&C No. 1, castor oil, cornstarch, ethylcellulose, fumaric acid, gelatin, polymethyl methacrylate, silica, simethicone, sucrose, stearic acid, talc and titanium dioxide. Bisulfites-, gluten- and tartrazine-free. Bottles of 100. Blister packs of 100.

300 mg: Each light blue/light gray, controlled delivery capsule, imprinted with CARDIZEM CD 300 mg, contains: diltiazem HCl 300 mg. Nonmedicinal ingredients: acetyltributyl citrate, beeswax, Blue FD&C No. 1, castor oil, cornstarch, ethylcellulose, fumaric acid, gelatin, iron oxide, polymethyl methacrylate, silica, simethicone, stearic acid, sucrose, talc and titanium dioxide. Bisulfites-, gluten- and tartrazine-free. Bottles of 100. Blister packs of 100.

Keep between 15 and 30°C. (Shown in Product Recognition Section)

CARDIZEM® CARDIZEM® SR CARDIZEM® CD Hoechst Marion Roussel Diltiazem HCl AntianginalAntihypertensive – Antianginal Antihypertensive – Antianginal

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