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Diltiazem

(dil tye' a zem)

PCI  : Contraindicated in pregnancy

LCI  : Contraindicated in lactation

Molecule Info

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Description

Diltiazem hydrochloride is a calcium ion cellular 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-.

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. Each tablet of Diltiazem contains 30 mg, 60 mg, 90 mg, or 120 mg diltiazem hydrochloride. Also contains: colloidal silicon dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake (30 mg and 90 mg), FD&C Yellow #6 Aluminum Lake (60 mg and 120 mg), hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, and polyethylene glycol.
Diltiazem tablets are indicated for oral use.

Indication(s) & Dosage

Diltiazem is indicated for the management of chronic stable angina and angina due to coronary artery spasm.

ANGINA PECTORIS 

Adult: Initially, 60 mg tid, increased to 360 mg daily or up to 480 mg daily, if necessary. Renal impairment: Dosage adjustment may be needed.  Initial dose of 120 mg daily, as a single dose or in 2 divided doses depending on the formulation and titrated carefully as required.  Do not increase dose if the heart rate drops <50 beats/min. Hepatic impairment: Dosage adjustment may be needed.  Initial dose of 120 mg daily, as a single dose or in 2 divided doses depending on the formulation and titrated carefully as required.  Do not increase dose if the heart rate drops <50 beats/min. Oral  Hypertension  Adult: Initially, 60-120 mg bid increased if needed.  Max: 360 mg daily. Renal impairment: Dosage adjustment may be needed.  Initial dose of 120 mg daily, as a single dose or in 2 divided doses depending on the formulation and titrated carefully as required.  Do not increase dose if the heart rate drops <50 beats/min. Hepatic impairment: Dosage adjustment may be needed.  Initial dose of 120 mg daily, as a single dose or in 2 divided doses depending on the formulation and titrated carefully as required.  Do not increase dose if the heart rate drops <50 beats/min.

Intravenous route

 Cardiac arrhythmias  Adult: Initially, 250 mcg/kg by bolus IV Inj over 2 mins, if necessary, after 15 min, may administer another dose of 350 mcg/kg.  Individualsie subsequent doses.  In patients with atrial fibrillation or flutter: 5-10 mg/hr infusion, increased in increments of 5 mg/hr up to a rate of 15 mg/hr continued for 24 hr.  Renal impairment: Dosage adjustment may be needed.  Hepatic impairment: Dosage adjustment may be needed.

Administration

Normal release prep: May be taken with or without food.  Admin instructions for modified release prep may vary according to brands, refer to literatures.

Overdosage

Common Symptoms:

Altered mental status, shock, bradycardia, hypotension, ECG changes, arrhythmias, heart block, cardiac arrest and heart failure.  

Management: Treatment is supportive and symptomatic.  Gastric lavage and administration of activated charcoal may help to reduce drug absorption.  Haemodialysis and peritoneal unlikely to be useful.  Charcoal haemoperfusion may be useful.

Contraindications

Diltiazem is contraindicated in 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 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 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 (six of 1243 patients for 0.48%). 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). Experience with the use of Diltiazem alone or in combination with beta-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients.
3. Hypotension. Decreases in blood pressure associated with Diltiazem therapy may occasionally result in symptomatic hypotension.
4. Acute Hepatic Injury. 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 have been reversible upon discontinuation of drug therapy. The relationship to Diltiazem is uncertain in most cases, but probable in some.

Special Precautions

Elderly.  Hepatic or renal impairment; impaired left ventricular function; prolonged AV periods; DM; hypotension.  Avoid abrupt withdrawal and long-term use.  Patients with sick-sinus syndrome, preexisting AV block, bradycardia and those taking beta-blockers or digitalis are at risk of developing AV block, bradycardia, asystole or sinus arrest.

Adverse Drug Reaction(s)

Headache, ankle oedema, hypotension, dizziness, fatigue, flushing, nausea, GI discomfort, gingival hyperplasia, rashes, erythema multiforme, exfoliative dermatitis, photosensitivity, occasionally hepatitis. Potentially Fatal: AV block, bradycardia, asystole, sinus arrest.

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 . Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Diltiazem .
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 this 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.
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. Benzodiazepines. Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to
4-fold and the Cmax 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 and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly 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 .

Buspirone. In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax 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 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.
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 trough dose ranging from 15% to 48% was necessary to maintain 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 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.
Quinidine. Diltiazem significantly increases the AUC of quinidine by 51%, T1/2 by 36%, and decreases its CLoral 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 may be increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events. In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID diltiazem SR 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 fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If co-administration 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, co-administration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.

Pregnancy safety-
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 some reduction in early individual pup weights and survival rates. 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.

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.

Pediatric Use
Safety and effectiveness in pediatric patients 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. 

Food Interaction

Serum levels may be elevated if taken with food.

Pregnancy Category (FDA)

Category C: Either studies in animals have revealed adverse effects on the foetus and there are no controlled studies in women or studies in women and animals are not available.  Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Storage

Intravenous or Oral: Store at 15-30°C.

Pharmacology

CLINICAL PHARMACOLOGY

The therapeutic benefits achieved with Diltiazem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Mechanisms of Action
Although precise mechanisms of its antianginal action are still being delineated, Diltiazem is believed to act in the following ways:
1. Angina Due to Coronary Artery Spasm. Diltiazem has been shown to be a potent dilator of coronary arteries both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasm are inhibited by Diltiazem.

2. Exertional Angina. Diltiazem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal exercise workloads. In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.

Diltiazem relaxes coronary vascular smooth muscles by inhibiting influx of calcium ions during depolarisation of the vascular smooth muscles and myocardium.  It increases myocardial O2 delivery in patients with vasospastic angina and inhibits cardiac conduction, particularly at the SA and AV nodes.  

Absorption: Rapidly and almost completely absorbed from the GI tract. Distribution: Enters breast milk.  Protein-binding: 80%.  Metabolism: Hepatic: Extensive first-pass effect; yields desacetyldiltiazem.  Excretion: Via urine, via bile; 3-5 hrs.

ATC Classification

C08DB01 - diltiazem; Belongs to the class of benzothiazepine derivative selective calcium-channel blockers with direct cardiac effects.  Used in the treatment of cardiovascular diseases.

Brand/Product Info


Total Products : 6      
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
CARDIL IBN SINA Pharmaceutical Industry Ltd. Diltiazem hydrochloride 30mg, 60mg Tablet 30mg x 100's, 60mg x 100's: 225.00 IP, 400.00 IP
CARDIZEM Drug International Ltd Diltiazem hydrochloride 30mg, 60mg Tablet 30mg x 100's, 60mg x 100's: 300.00 & 500.00 MRP
CARDIZEM-SR Drug International Ltd Diltiazem hydrochloride 90mg, 120mg Sustained Release Capsule Capsule 50's each: 250.00 & 400.00 MRP
DIAL Nipa Pharmaceuticals Ltd. Diltiazem hydrochloride 60mg Tablet 60mg x 100's: 380.00 MRP
DILTIZEM 90 Square Pharmaceuticals Ltd. Diltiazem 90mg Tablet 4x10's: 225.20 MRP
EVASCON Renata Limited Diltiazem hydrochloride 30mg, 60mg Tablet 30mg x 100's, 60mg x 100's: 202.00 & 385.00 MRP

Gen. MedInfo

Why this medication is prescribed?

Diltiazem is used to treat high blood pressure and to control angina.  Diltiazem is in a class of medications called calcium-channel blockers. It works by relaxing the blood vessels so the heart does not have to pump as hard.  It also increases the supply of blood and oxygen to the heart.

How this medicine should be used?

Diltiazem may come as a tablet, an extended-release tablet, and an extended-release capsule to take by mouth.  The regular tablet is usually taken three or four times a day.  The extended-release capsule and tablet are usually taken one or two times a day.  Ask your Doctor if you should take diltiazem with or without food, because instructions may vary with each product.  Take diltiazem at around the same time every day.  Follow the directions on your prescription label carefully, and ask your Doctor to explain any part you do not understand.  Take diltiazem exactly as directed.  Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the extended-release capsules and tablets whole; do not chew or crush them.Your doctor will probably start you on a low dose of diltiazem and gradually increase your dose, not more than once every 7 to 14 days if you are taking the extended-release tablet or capsule and not more than once every 1 to 2 days if you are taking the regular tablet.

If taken regularly, diltiazem may control chest pain, but it does not stop chest pain once it starts.  Your doctor may give you a different medication to take when you have chest pain.

Diltiazem controls high blood pressure and chest pain but does not cure them.  It may take up to 2 weeks before you feel the full benefit of diltiazem.  Continue to take diltiazem even if you feel well.  Do not stop taking diltiazem without talking to your doctor.

Other uses

Diltiazem is also sometimes used to treat certain types of arrhythmias.  Talk to your doctor about the risks of using this medication for your condition.

This medication may be prescribed for other uses; ask your Doctor for more information.

What special precautions to follow?

Before taking diltiazem, 

  • inform your Doctor if you are allergic to diltiazem, any other medications, or any of the ingredients in diltiazem.  Ask your Doctor for a list of the ingredients.
  • inform your Doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.  Be sure to mention any of the following: atazanavir; benzodiazepines such as midazolam and triazolam; beta blockers such as atenolol, labetalol, metoprolol, nadolol, and propranolol; buspirone; carbamazepine; cimetidine; cyclosporine; digoxin; lovastatin; quinidine; and rifampin.  Your doctor may need to change the doses of your medications or monitor you carefully for side effects.  Many other medications may also interact with diltiazem, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you have or have ever had a myocardial infarction; a narrowing or blockage of your digestive system or any other condition that causes food to move through your digestive system more slowly; low blood pressure; or heart, liver, or kidney disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding.  If you become pregnant while taking diltiazem, consult your doctor.
  • if you are having surgery, including dental surgery, tell your doctor or dentist that you are taking diltiazem.

What special dietary instructions to follow?

If your doctor prescribes a low-salt or low-sodium diet, follow these directions carefully.

What to do if I forget a dose?

Take the missed dose as soon as you remember it.  However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule.  Do not take a double dose to make up for a missed one.

What side effects can this medication cause?

Diltiazem may cause side effects.  Tell your doctor if any of these symptoms are severe or do not go away:
  • dizziness or lightheadedness
  • flushing
  • headache
  • weakness
  • slow heartbeat
  • vomiting
  • diarrhea
  • constipation
  • nasal congestion
  • cough
  • swelling of the face, eyes, lips, tongue, hands, arms, feet, ankles, or lower legs
  • difficulty breathing or swallowing
  • fainting
  • rash
  • yellowing of the skin or eyes
  • nausea
  • extreme tiredness
  • unusual bleeding or bruising
  • lack of energy
  • loss of appetite
  • pain in the upper right part of the stomach
  • flu-like symptoms
  • increase in frequency or severity of chest pain
Some side effects can be serious.  If you experience any of the following symptoms, consult your doctor immediately:

If you experience a serious side effect, you or your doctor may send a report to the Office of Directorate General, Drugs Administration.

What storage conditions are needed for this medicine?

Keep this medication in the container it came in, tightly closed, and out of reach of children.  Store it at room temperature and away from excess heat and moisture.  Throw away any medication that is outdated or no longer needed.  Talk to your Doctor about the proper disposal of your medication.

In case of emergency/overdose

In case of overdose, consult your Doctor.  If the victim has collapsed or is not breathing, consult local medical emergency services..

Symptoms of overdose may include:

  • slow, fast, or irregular heartbeat
  • fainting
  • difficulty breathing
  • seizures
  • dizziness
  • confusion
  • nausea
  • vomiting
  • increased sweating

What other information to know? 

Keep all appointments with your doctor and the laboratory.  Your blood pressure should be checked regularly to determine your response to diltiazem.

Your doctor may ask you to check your pulse daily and will tell you how fast it should be.  If your pulse is slower than it should be, consult your doctor for directions on taking diltiazem that day.  Ask your Doctor to teach you how to check your pulse.

Do not let anyone else take your medication.  

It is important for you to keep a written list of all of the prescription and nonprescription medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements.  You should bring this list with you each time you visit a doctor or if you are admitted to a hospital.  It is also important information to carry with you in case of emergencies. 

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