diltiazem HCl 180 MG 24HR Extended Release Oral Capsule
WARNINGS
Cardiac Conduction 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 of 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 in combination with beta-blockers in patients with impaired ventricular function is limited.
Caution should be exercised when using this combination.
Hypotension Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.
Acute Hepatic Injury Mild elevations of serum 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 alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted.
These reactions tended to occur early after therapy initiation (1 to 6 weeks) and have been reversible upon discontinuation of drug therapy.
The relationship to diltiazem is uncertain in some cases, but probable in some others (see PRECAUTIONS ).
DRUG INTERACTIONS
Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem 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 (see WARNINGS ).
As with all drugs, care should be exercised when treating patients with multiple medications.
Diltiazem undergoes biotransformation by cytochrome P-450 mixed function oxidase.
Coadministration of diltiazem 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 cyclosporine, may require adjustment when starting or stopping concomitantly administered diltiazem 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 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 concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and the 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 one-week course of cimetidine at 1200 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.
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.
Digitalis Administration of diltiazem 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 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.
Statins 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 twice daily diltiazem SR resulted in a 5-fold higher mean simvastatin AUC compared with simvastatin alone.
High average steady-state exposures of diltiazem would result in a greater increase in simvastatin exposure.
A daily dose of 480 mg of diltiazem would be expected to result in an 8-fold higher mean simvastatin AUC compared with simvastatin alone.
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 twice daily diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3-to 4- fold higher mean lovastatin AUC and Cmax values compared with lovastatin alone.
In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration.
OVERDOSAGE
Several literature reports have identified cases of diltiazem hydrochloride overdose, some with multiple drug ingestion, with both fatal and nonfatal 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).
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.
DESCRIPTION
Diltiazem 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 450.99.
Its structural formula is as follows: Diltiazem hydrochloride, USP 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-a-Day Dosage), for oral administration, contain multiple units of diltiazem hydrochloride extended-release 60 mg, resulting in the 120 mg, 180 mg or 240 mg dosage strengths allowing for the controlled release of diltiazem hydrochloride over a 24-hour period.
In addition, each capsule contains the following inactive ingredients: ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, hypromellose, magnesium stearate, maltodextrin, microcrystalline cellulose, oleic acid, polyethylene glycol and sodium lauryl sulfate.
The empty hard-shell gelatin capsules contain FD&C Blue No.
1, FD&C Red No.
40 Aluminum Lake, gelatin, sodium lauryl sulfate and titanium dioxide.
In addition, the 120 mg and 180 mg empty hard-shell gelatin capsules contain D&C Red No.
28.
The imprinting ink contains black iron oxide, D&C Yellow No.
10 Aluminum Lake, FD&C Blue No.
1 Aluminum Lake, FD&C Blue No.
2 Aluminum Lake, FD&C Red No.
40 Aluminum Lake, propylene glycol and shellac glaze.
Diltiazem Hydrochloride Extended-release Capsules, USP (Once-a-Day Dosage) 120 mg, 180 mg and 240 mg meet USP Drug Release Test 8.
MM1
HOW SUPPLIED
Diltiazem Hydrochloride Extended-release Capsules, USP (Once-a-Day Dosage) are available in 120 mg, 180 mg and 240 mg.
The 120 mg capsule is a pink opaque cap/flesh opaque body, hard-shell gelatin capsule filled with two white to off-white, round tablets with no markings.
The capsule is radially printed with MYLAN over 5220 in black ink on the cap.
They are available as follows: NDC 0378-5220-01 bottles of 100 capsules NDC 0378-5220-05 bottles of 500 capsules The 180 mg capsule is a lavender opaque cap/flesh opaque body, hard-shell gelatin capsule filled with three white to off-white, round tablets with no markings.
The capsule is radially printed with MYLAN over 5280 in black ink on the cap.
They are available as follows: NDC 0378-5280-01 bottles of 100 capsules NDC 0378-5280-05 bottles of 500 capsules The 240 mg capsule is a light blue opaque cap/flesh opaque body, hard-shell gelatin capsule filled with four white to off-white, round tablets with no markings.
The capsule is radially printed with MYLAN over 5340 in black ink on both the cap and body.
They are available as follows: NDC 0378-5340-01 bottles of 100 capsules NDC 0378-5340-05 bottles of 500 capsules
INDICATIONS AND USAGE
INDICATIONS & USAGE Diltiazem hydrochloride extended-release capsules (once-a-day dosage) are indicated for the treatment of hypertension.
Diltiazem hydrochloride extended-release capsules (once-a-day dosage) may be used alone or in combination with other antihypertensive medications, such as diuretics.
Diltiazem hydrochloride extended-release capsules (once-a-day dosage) are indicated for the management of chronic stable angina.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Teratogenic Effects 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 q.d.
or 8 mg/kg q.d.
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 in pregnant women only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
NURSING MOTHERS Diltiazem is excreted in human milk.
One report suggests that concentrations in breast milk may approximate serum levels.
If use of diltiazem is deemed essential, an alternate method of infant feeding should be instituted.
INFORMATION FOR PATIENTS
Diltiazem hydrochloride extended-release capsules (once-a-day dosage) should be taken on an empty stomach.
Patients should be cautioned that the diltiazem hydrochloride extended-release capsules (once-a-day dosage) should not be opened, chewed or crushed, and should be swallowed whole.
DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION Hypertension Dosages must be adjusted to each patient’s needs, starting with 180 mg or 240 mg once daily.
Based on the antihypertensive effect, the dose may be adjusted as needed.
Individual patients, particularly60 years of age, may respond to a lower dose of 120 mg.
The usual dosage range studied in clinical trials was 180 mg to 480 mg once daily.
Current clinical experience with the 540 mg dose is limited, the dose may be increased to 540 mg with little or no increased risk of adverse reactions.
Doses should not exceed 540 mg once daily.
While a dose of diltiazem hydrochloride extended-release capsules given once daily may produce an antihypertensive effect similar to the same total daily dose given in divided doses, individual dose adjustment may be needed.
Angina Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 mg once daily, which may be titrated to doses of up to 480 mg once daily.
When necessary, titration may be carried out over a 7 to 14 day period.
Concomitant Use with Other Cardiovascular Agents Sublingual Nitroglycerin Sublingual nitroglycerin may be taken as required to abort acute anginal attacks during diltiazem therapy.
Prophylactic Nitrate Therapy Diltiazem hydrochloride extended-release capsules (once-a-day dosage) may be safely coadministered with short- and long-acting nitrates.
Beta-Blockers (See WARNINGS and PRECAUTIONS .) Antihypertensives Diltiazem 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.