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Tiazac®
(diltiazem hydrochloride)
Extended Release Capsules
USP Drug Release Test 6
DESCRIPTION
Tiazac® (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel blocker). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)-one,3-(acetyloxy)-5[2-(dimethylamino)ethyl]-2,-3-dihydro-2(4-methoxyphenyl)-, mono-hydrochloride, (+)-cis. The chemical structure is:
Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol and chloroform and has a molecular weight of 450.98. Tiazac® capsules contain diltiazem hydrochloride in extended release beads at doses of 120, 180, 240, 300, 360 and 420 mg.
Tiazac® also contains: Microcrystalline Cellulose NF, Sucrose Stearate, Eudragit, Povidone USP, Talc USP, Magnesium Stearate NF, Hypromellose USP, Titanium Dioxide USP, Polysorbate NF, Simethicone USP, Gelatin NF, FD&C Blue #1, FD&C Red #40, D&C Red #28, FD&C Green #3, Black Iron Oxide USP, and other solids.
For oral administration.
CLINICAL PHARMACOLOGY
The therapeutic effects of diltiazem hydrochloride are believed to be related to its ability to inhibit the cellular influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.
Mechanisms of Action.
Pharmacodynamics.
INDICATIONS AND USAGE
Hypertension:
Tiazac® is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.
Chronic Stable Angina:
Tiazac® is indicated for the treatment of chronic stable angina.
CONTRAINDICATIONS
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 severe hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.
WARNINGS
1. Cardiac Conduction. Diltiazem hydrochloride prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13 of 3007 patients or 0.43%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem.
2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24%± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem hydrochloride in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.
3. Hypotension. Decreases in blood pressure associated with diltiazem hydrochloride therapy may occasionally result in symptomatic hypotension.
4. Acute Hepatic Injury. Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, and SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem hydrochloride is uncertain in some cases, but probable in some (see PRECAUTIONS).
PRECAUTIONS
General. Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function 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 section) 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.
Drug Interactions. Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem hydrochloride concomitantly with other 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 Tiazac® (see WARNINGS). As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of the enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility. A 24-month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21-month study in mice at oral dosage levels of up to 30 mg/kg/day 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 a study performed in male and female rats at oral dosages 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/day or 8 mg/kg/day for a 60 kg patient) resulted in embryo and fetal lethality. These studies 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 Tiazac® is deemed essential, an alternative method of infant feeding should be instituted.
Pediatric Use. Safety and effectiveness in children have not been established.
Geriatric Use. Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Serious adverse reactions have been rare in studies with Tiazac®, as well as with other diltiazem formulations. It should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies. A total of 256 hypertensives were treated for between 4 and 8 weeks; a total of 207 patients with chronic stable angina were treated for 3 weeks with doses of Tiazac® ranging from 120-540 mg once daily. Two patients experienced first-degree AV block at the 540 mg dose. The following table presents the most common adverse reactions, whether or not drug-related, reported in placebo-controlled trials in patients receiving Tiazac® up to 360 mg and up to 540 mg with rates in placebo patients shown for comparison.
| Placebo | Tiazac® | ||
|---|---|---|---|
| Adverse Events (COSTART Term) | n=57 # pts (%) | Up to 360 mg n=149 # pts (%) | 480-540mg n=48 # pts (%) |
| edema, peripheral | 1 (2) | 8 (5) | 7 (15) |
| dizziness | 4 (7) | 6 (4) | 2 (4) |
| vasodilation | 1 (2) | 5 (3) | 1 (2) |
| dyspepsia | 0 (0) | 7 (5) | 0 (0) |
| pharyngitis | 2 (4) | 3 (2) | 3 (6) |
| rash | 0 (0) | 3 (2) | 0 (0) |
| infection | 2 (4) | 2 (1) | 3 (6) |
| diarrhea | 0 (0) | 2 (1) | 1 (2) |
| palpitations | 0 (0) | 2 (1) | 1 (2) |
| nervousness | 0 (0) | 3 (2) | 0 (0) |
| Placebo | Tiazac® | ||
|---|---|---|---|
| Adverse Events (COSTART Term) | n=50 # pts (%) | Up to 360 mg n=158 # pts (%) | 540 mg n=49 # pts (%) |
| headache | 1 (2) | 13 (8) | 4 (8) |
| edema, peripheral | 1 (2) | 3 (2) | 5 (10) |
| pain | 1 (2) | 10 (6) | 3 (6) |
| dizziness | 0 (0) | 5 (3) | 5 (10) |
| asthenia | 0 (0) | 1 (1) | 2 (4) |
| dyspepsia | 0 (0) | 2 (1) | 3 (6) |
| dyspnea | 0 (0) | 1 (1) | 3 (6) |
| bronchitis | 0 (0) | 1 (1) | 2 (4) |
| AV block | 0 (0) | 0 (0) | 2 (4) |
| infection | 0 (0) | 2 (1) | 1 (2) |
| flu syndrome | 0 (0) | 0 (0) | 1 (2) |
| cough increase | 0 (0) | 2 (1) | 1 (2) |
| extrasystoles | 0 (0) | 0 (0) | 1 (2) |
| gout | 0 (0) | 2 (1) | 1 (2) |
| myalgia | 0 (0) | 0 (0) | 1 (2) |
| impotence | 0 (0) | 0 (0) | 1 (2) |
| conjunctivitis | 0 (0) | 0 (0) | 1 (2) |
| rash | 0 (0) | 2 (1) | 1 (2) |
| abdominal enlargement | 0 (0) | 0 (0) | 1 (2) |
In addition, the following events have been reported infrequently (less than 2%) in clinical trials with other diltiazem products:
Cardiovascular. Angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasysto-les.
Nervous System. Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.
Gastrointestinal. Anorexia, constipation, diarrhea, dry mouth, dysgeusia, mild elevations of SGOT, SGPT, LDH, and alkaline phosphatase (see hepatic warnings), nausea, thirst, vomiting, weight increase.
Dermatological. Petechiae, photosensitivity, pruritus.
Other. Albuminuria, allergic reaction, amblyopia, asthenia, CPK increase, crystalluria, dyspnea, edema, epistaxis, eye irritation, headache, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, neck rigidity, nocturia, osteoarticular pain, pain, polyuria, rhinitis, sexual difficulties, gynecomastia.
In addition, the following postmarketing events have been reported infrequently in patients receiving diltiazem hydrochloride: alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, purpura, retinopathy, and thrombocytopenia. 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, characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and diltiazem hydrochloride therapy is yet to be established.
OVERDOSAGE
The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50's in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.
The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases. There have been 29 reports of diltiazem overdose in doses ranging from less than 1 gm to 10.8 gm. Sixteen of these reports involved multiple drug ingestions. Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 gm to 10.8 gm. There were seven reports with a fatal outcome; although the amount of diltiazem ingested was unknown, multiple drug ingestions were confirmed in six of the seven reports.
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 favorably 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, activated charcoal, and/or intravenous calcium. Evidence of the effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose was conflicting.
In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:
Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, 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 levarterenol bitartrate). Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride.
Due to extensive metabolism, plasma concentrations after a standard dose of diltiazem can vary over tenfold, which significantly limits their value in evaluation 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.
DOSAGE AND ADMINISTRATION
Hypertension: Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, usual starting doses are 120 to 240 mg once daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 120 to 540 mg once daily. Current clinical experience with 540 mg dose is limited; however, the dose may be increased to 540 mg once daily.
Angina: Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a dose of 120 mg to 180 mg once daily. Individual patients may respond to higher doses of up to 540 mg once daily. When necessary, titration should be carried out over 7 to 14 days.
Concomitant use with Other Cardiovascular Agents.
1. Sublingual Nitroglycerin may be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy.
2. Prophylactic Nitrate Therapy - Diltiazem hydrochloride may be safely co-administered with short- and long-acting nitrates.
3. Beta-blockers. (See WARNINGS and PRECAUTIONS.)
4. 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.
Hypertensive or anginal patients who are treated with other formulations of diltiazem can safely be switched to Tiazac® capsules at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may, however, be necessary and should be initiated as clinically indi-cated.
Sprinkling the Capsule Contents on Food
Tiazac® (diltiazem hydrochloride) Extended-release Capsules may also be administered by carefully opening the capsule and sprinkling the capsule spans on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the capsule spans. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. Any capsule spans/applesauce mixture should be used immediately and not stored for future use. Subdividing the spans of a Tiazac® (diltiazem hydrochloride) Extended-release Capsule is not recommended.
HOW SUPPLIED
Tiazac® (diltiazem hydrochloride) Extended Release Capsules
| Strength | Description | Quantity | NDC# |
|---|---|---|---|
| 120 mg | #3 lavender/lavender capsule imprinted: Tiazac 120 | 7's | 0456-2612-07 |
| 30's | 0456-2612-30 | ||
| 90's | 0456-2612-90 | ||
| 1000's | 0456-2612-00 | ||
| HUD's | 0456-2612-63 | ||
| 180 mg | #2 white/blue-green capsule imprinted: Tiazac 180 | 7's | 0456-2613-07 |
| 30's | 0456-2613-30 | ||
| 90's | 0456-2613-90 | ||
| 1000's | 0456-2613-00 | ||
| HUD's | 0456-2613-63 | ||
| 240 mg | #1 blue-green/lavender capsule imprinted: Tiazac 240 | 7's | 0456-2614-07 |
| 30's | 0456-2614-30 | ||
| 90's | 0456-2614-90 | ||
| 1000's | 0456-2614-00 | ||
| HUD's | 0456-2614-63 | ||
| 300 mg | #0 white/lavender capsule imprinted: Tiazac 300 | 7's | 0456-2615-07 |
| 30's | 0456-2615-30 | ||
| 90's | 0456-2615-90 | ||
| 1000's | 0456-2615-00 | ||
| HUD's | 0456-2615-63 | ||
| 360 mg | #0 blue-green/blue-green capsule imprinted: Tiazac 360 | 7's | 0456-2616-07 |
| 30's | 0456-2616-30 | ||
| 90's | 0456-2616-90 | ||
| 1000's | 0456-2616-00 | ||
| HUD's | 0456-2616-63 | ||
| 420 mg | #00 white/white capsule imprinted: Tiazac 420 | 7's | 0456-2617-07 |
| 30's | 0456-2617-30 | ||
| 90's | 0456-2617-90 | ||
| 1000's | 0456-2617-00 |
Storage conditions: Store at controlled room temperature
20°-25°C (68°-77°F).
Avoid excessive humidity.
Rx Only.
Manufactured by:
Biovail Corporation
Mississauga, Ontario CANADA L5N 8M5
Manufactured for:
Rev. 04/06
LB0001-09