MONO-TILDIEM LP

Diltiazem is a benzothiazepine derivative with antihypertensive and vasodilating properties.

Approved in by the

FDA, it is a member of the non-dihydropyridine calcium channel blockers drug class.

It works through various mechanisms of action, but it primarily works by inhibiting the calcium influx into cardiac and vascular smooth muscle during depolarization.

Compared to dihydropyridine drugs, such as nifedipine, that preferentially act on vascular smooth muscle and verapamil that directly acts on the heart muscle, diltiazem displays an intermediate specificity to target both the cardiac and vascular smooth muscle.

Being a potent vasodilator, diltiazem is used clinically as an antihypertensive, anti-arrhythmic, and as an anti-anginal agent for the management of cardiovascular conditions such as hypertension, chronic stable angina, atrial fibrillation, atrial flutter.

Apart from its main

FDA-approved indications, diltiazem has also been used for numerous off-label indications, such as anal fissures (in topical formulations), migraine prophylaxis, pulmonary hypertension, and rest-related cramps in the lower extremities.

Typically available in extended-release oral and intravenous formulations, diltiazem is marketed under various brand names with Cardizem and Tiazac being the most common ones.

Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents.

Indicated for use to improve exercise tolerance in patients with chronic stable angina.

Indicated for the management of variant angina (Prinzmetal's angina).

Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate.

Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm.

This includes

AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome.

Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, 9 idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy.

Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure.

This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization.

Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate).

It is also considered a rate-control drug as it reduces heart rate. 2, 8 Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow.

Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations.

In supraventricular tachycardia, diltiazem prolongs AV nodal refractories.

As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension.

In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively.

In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo.

In the

NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed.

When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group.

Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients.

L-type calcium channel subunit alpha-1C Blocker Voltage-dependent calcium channel gamma-1 subunit Blocker.

Diltiazem is readily absorbed from the gastrointestinal tract.

Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50-200 ng/mL.

Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3-4 hours and the peak plasma concentrations were reached between and 18 hours post-dose.

Diltiazem peak and systemic exposures were not affected by concurrent food intake.

Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, 12 with the value ranging from 24-74% due to high interindividual variation in the first pass effect.

The bioavailability may increase in patients with hepatic impairment.

The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers.

Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability.

It undergoes N-demethylation primarily mediated by

CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation.

There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers.

In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active.

Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound.

Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem.

N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem.

N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated.

Diltiazem can be O-demethylated by

CYP2D6 to form O-desmethyl diltiazem.

Hover over products below to view reaction partners Diltiazem N-monodesmethyl diltiazem Deacetyl N-monodesmethyl diltiazem Deacetyl N,O-didesmethyl diltiazem N,O-didesmethyl diltiazem Deacetyl diltiazem Deacetyl O-desmethyl diltiazem Deacetyl diltiazem N-oxide O-desmethyl diltiazem.

Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine.

The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites.

The plasma elimination half-life is approximately 3.0-4.5 hours following single and multiple oral doses.

The half-life may slightly increase with dose and the extent of hepatic impairment.

The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6-9 hours.

The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection.

The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem.

Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h.

After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h.

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Clinical Toxicity and Overdose The oral

LD 50 ranges from 415-740 mg/kg in mice and 560-810 mg/kg in rats.

The oral

LD in dogs is considered to be in excess of 50 mg/kg.

The intravenous

LD is 60 mg/kg in mice and 38 mg/kg in rats.

Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death.

Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue.

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination.

Bradycardia and heart block can be treated with atropine at doses ranging from 0.60-1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered.

Cardiac pacing can also be used to treat fixed high-degree AV block.

In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as isoproterenol, dopamine, or dobutamine.

Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.

Diltiazem does not appear to be removed by peritoneal or hemodialysis.

Non-clinical toxicity

In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity.

There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro bacterial assays.

No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day.

In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths.

There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women.

The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus.

Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother.

Use in special populations

As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve 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.

Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment.

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 3290 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.

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.

Decreases in blood pressure associated with diltiazem hydrochloride therapy may occasionally result in symptomatic hypotension.

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 hydrochloride is uncertain in some cases, but probable in some.

Diltiazem hydrochloride 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 hypotension (less than 90 mm Hg systolic), patients who have demonstrated hypersensitivity to the drug, and patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

Patients controlled on diltiazem alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release capsules, USP at the nearest equivalent total daily dose.

Higher doses of diltiazem hydrochloride extended-release capsules, USP may be needed in some patients.

Monitor patients closely.

Subsequent titration to higher or lower doses may be necessary.

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.

Adjust dosage to individual patient needs.

When used as monotherapy, reasonable starting doses are 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, schedule dosage adjustments accordingly.

The usual dosage range studied in clinical trials was to 360 mg once daily.

Individual patients may respond to higher doses of up to 480 mg once daily.

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.

When necessary, titration may be carried out over a 7.

• to 14-day period.

Concomitant Use with Other Cardiovascular Agents Sublingual NTG: May be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy.

P r ophylactic Nitrate Therapy

Diltiazem hydrochloride extended-release capsules, USP may be safely coadministered with short.

• and long-acting nitrates.

Diltiazem hydrochloride extended-release capsules, USP have an additive antihypertensive effect when used with other antihypertensive agents.

Therefore, the dosage of diltiazem hydrochloride extended-release capsules, USP or the concomitant antihypertensives may need to be adjusted when adding one to the other.

Diltiazem hydrochloride Extended-Release

Capsules, USP are Dark blue/Dark blue capsule (size 00) imprinted with N369 on one end and on the other end.

NDC: 71335-1897-1: 30 CAPSULEs in a BOTTLE NDC: 71335-1897-2: 90 CAPSULEs in a BOTTLE Storage Conditions: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Avoid excessive humidity.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504 image description.

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 hydrochloride in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Diltiazem is excreted in human milk.

One report suggests that concentrations in breast milk may approximate serum levels.

If use of diltiazem hydrochloride is deemed essential, an alternative method of infant feeding should be instituted.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of diltiazem did not include sufficient numbers of subjects aged 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.