diltiazem HCl 120 MG 24HR Extended Release Oral Capsule
WARNINGS
1.
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 (13 of 3,290 patients or 0.40%).
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.
(See ADVERSE REACTIONS section.) 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 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 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, 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 is uncertain in some cases, but probable in some.
(See PRECAUTIONS .)
DRUG INTERACTIONS
Drug Interactions Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem 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 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, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.
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 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 .) Cimetidine:A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per 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 P-450, the enzyme system responsible for the first-pass metabolism of diltiazem.
Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine.
An adjustment in the diltiazem dose may be warranted.
Digitalis:Administration of diltiazem 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 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 blockers should be titrated carefully.
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.
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.
OVERDOSAGE
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, gastric lavage, 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.
Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose.
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 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 (eg, 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.
DESCRIPTION
Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist).
Chemically, diltiazem hydrochloride is 1,5-benzothiazepin-4(5 H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-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.
It has a molecular weight of 450.98.
Diltiazem hydrochloride is formulated as a once-a-day extended release capsule containing either 120 mg, 180 mg, 240 mg, or 300 mg diltiazem hydrochloride.
Each diltiazem extended-release capsule, for oral administration, contains the following inactive ingredients: 120 mg — ammonio methacrylate copolymer NF, type A, ammonio methacrylate copolymer NF, type B, ammonium hydroxide, black iron oxide, gelatin, hydroxypropyl cellulose, pharmaceutical glaze, propylene glycol, silicon dioxide, simethicone, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, triethyl citrate.
180 mg — ammonio methacrylate copolymer NF, type A, ammonio methacrylate copolymer NF, type B, ammonium hydroxide, D&C yellow #10, FD&C blue #1, FD&C green #3, gelatin, hydroxypropyl cellulose, pharmaceutical glaze, propylene glycol, silicon dioxide, simethicone, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, triethyl citrate.
240 mg — ammonio methacrylate copolymer NF, type A, ammonio methacrylate copolymer NF, type B, ammonium hydroxide, D&C yellow #10, FD&C green #3, gelatin, hydroxypropyl cellulose, pharmaceutical glaze, propylene glycol, silicon dioxide, simethicone, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, triethyl citrate.
300 mg— ammonio methacrylate copolymer NF, type A, ammonio methacrylate copolymer NF, type B, ammonium hydroxide, black iron oxide, D&C yellow #10, FD&C green #3, gelatin, hydroxypropyl cellulose, pharmaceutical glaze, propylene glycol, silicon dioxide, simethicone, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, triethyl citrate.
This drug product conforms to USP Drug release test #11.
chemical structure
HOW SUPPLIED
Diltiazem Hydrochloride Extended-release Capsules, USP are supplied as follows: 120 mg — Each #2 capsule with light gray opaque cap and body printed with and 2588 on both cap and body in white ink contains 120 mg of diltiazem hydrochloride, USP.
Capsules are supplied in: Overbagged with 10 Capsules per bag, NDC 55154-6836-0 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59°-86°F).
Avoid excessive humidity.
Manufactured by: Actavis Elizabeth LLC 200 Elmora Avenue Elizabeth, NJ 07207 USA Distributed By: McKesson Packaging Concord, NC 28027 Repackaged By: Cardinal Health Zanesville, OH 43701 L50113330317 Revised — January 2008 IS-283-M13-01-A-R3 Imprint Symbol
INDICATIONS AND USAGE
Diltiazem hydrochloride extended-release capsules are indicated for the treatment of hypertension.
They may be used alone or in combination with other antihypertensive medications.
Diltiazem hydrochloride extended-release capsules are indicated for the management of chronic stable angina and angina due to coronary artery spasm.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Pregnancy Category C.
Reproduction studies have been conducted in mice, rats, and rabbits.
Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality.
These doses, in some studies, have been reported to cause skeletal abnormalities.
In the perinatal/postnatal studies, there was an increased incidence of stillbirths at doses of 20 times the human dose or greater.
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 alternative method of infant feeding should be instituted.
DOSAGE AND ADMINISTRATION
Patients controlled on diltiazem alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release capsules at the nearest equivalent total daily dose.
Higher doses of diltiazem hydrochloride extended-release capsules may be needed in some patients.
Patients should be closely monitored.
Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted.
There is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been studied in clinical trials.
The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.
Hypertension: Dosage needs to be adjusted by titration to individual patient needs.
When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses.
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 240 to 360 mg once daily.
Individual patients may respond to higher doses of up to 480 mg once daily.
Angina: Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 or 180 mg once daily.
Individual patients may respond to higher 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: 1.
Sublingual NTG – May be taken as required to abort acute anginal attacks during diltiazem hydrochloride extended-release capsules therapy.
2.
Prophylactic Nitrate Therapy – Diltiazem hydrochloride extended-release capsules may be safely coadministered with short-and long-acting nitrates.
3.
Beta-Blockers: (See WARNINGS and PRECAUTIONS ).
4.
Antihypertensives – Diltiazem hydrochloride extended-release capsules have an additive antihypertensive effect when used with other antihypertensive agents.
Therefore, the dosage of diltiazem hydrochloride extended-release capsules or the concomitant antihypertensives may need to be adjusted when adding one to the other.