Tiadylt Er Drug Information

• Hypertension: Tiadylt ® ER capsules are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.
• Chronic Stable Angina: Tiadylt ® ER capsules are indicated for the treatment of chronic stable angina.

• 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 (NTG): May be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy. 2.
• Prophylactic Nitrate Therapy: Diltiazem hydrochloride may be safely coadministered 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 Tiadylt ® ER 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 indicated.
• Sprinkling the Capsule Contents on Food: Tiadylt ® ER (diltiazem hydrochloride extended-release) Capsules may also be administered by carefully opening the capsule and sprinkling the capsule contents 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 contents. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. Any capsule contents/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a Tiadylt ® ER (diltiazem hydrochloride extended-release) Capsules is not recommended.

Serious adverse reactions have been rare in studies with Tiadylt, 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 Tiadylt ranging from 120 to 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 Tiadylt up to 360 mg and up to 540 mg with rates in placebo patients shown for comparison. MOST COMMON ADVERSE EVENTS IN DOUBLE-BLIND PLACEBO-CONTROLLED HYPERTENSION TRIALS Adverse events occurring in treated patients at 2% or more than placebo-treated patients.

Placebo Tiadylt Adverse Events (COSTART Term) n=57 # pts (%) Up to 360 mg n=149 # pts (%) 480 to 540 mg n=48 # pts (%) edema, peripheral 1 8 7 dizziness 4 6 2 vasodilation 1 5 1 dyspepsia 0 7 0 pharyngitis 2 3 3 rash 0 3 0 infection 2 2 3 diarrhea 0 2 1 palpitations 0 2 1 nervousness 0 3 0 headache 1 13 4 edema, peripheral 1 3 5 pain 1 10 3 dizziness 0 5 5 asthenia 0 1 2 dyspepsia 0 2 3 dyspnea 0 1 3 bronchitis 0 1 2 AV block 0 0 2 infection 0 2 1 flu syndrome 0 0 1 cough increase 0 2 1 extrasystoles 0 0 1 gout 0 2 1 myalgia 0 0 1 impotence 0 0 1 conjunctivitis 0 0 1 rash 0 2 1 abdominal enlargement 0 0 1 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 extrasystoles. 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 WARNINGS, Acute Hepatic Injury ), 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: acute generalized exanthematous pustulosis, alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), 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.

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Tiadylt (see WARNINGS ). Diltiazem is both a substrate and an inhibitor of the Pg-p and cytochrome P450 3A4 enzyme system which may affect exposure to diltiazem and concomitant drugs metabolized by those pathways. Patients with renal and/or hepatic impairment may be particularly at risk of exposure changes. 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: Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and the C max by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5-to 2.5-fold) during coadministration with diltiazem.

These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects ( e.g., prolonged sedation) of both midazolam and triazolam. 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%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem.

If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS ). Buspirone: In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and C max 4.1-fold compared to placebo. The T ½ and T max of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem.

Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment. 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 six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week course of cimetidine 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P450, 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. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem.

Monitor heart rate in patients receiving concomitant diltiazem and clonidine. 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: 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 effect 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 ). Ivabradine: Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem. Quinidine: Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T ½ by 36%, and decreases its CL oral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.

Rifampin: Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered. Statins: Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins.

The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 is increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin with diltiazem. Otherwise, reduce the dose for both diltiazem and the statin and monitor for signs and symptoms of muscle toxicity.

In a healthy volunteer cross-over study (N=10), coadministration of a single 20 mg dose of simvastatin at the end of a 14-day regimen with 120 mg BID diltiazem sustained-release resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater increase in simvastatin exposure. If coadministration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.

In a ten-subject randomized, open label, 4-way cross-over study, coadministration of diltiazem (120 mg BID diltiazem sustained-release for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and C max versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and C max during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Pregnancy 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.

Pediatric Use Safety and effectiveness in children have not been established.

Diltiazem is contraindicated in: Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker Patients with severe hypotension (less than 90 mm Hg systolic) Patients who have demonstrated hypersensitivity to the drug Patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

The oral LD 50 s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD 50 s in these species were 60 and 38 mg/kg, respectively. The oral LD 50 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 g to 10.8 g.

Sixteen of these reports involved multiple drug ingestions. Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 g to 10.8 g. 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 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 norepinephrine). 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 g of oral diltiazem have been successfully treated using appropriate supportive care.