Side Effects of Cardizem (diltiazem)

Cardizem (diltiazem) is a calcium channel blocker (CCB) used to treat heart pain (angina), high blood pressure, and abnormal heart rhythms. 

CCBs block the entry of calcium into muscle cells that make up the heart and that surround the arteries. It is the entry of calcium into these cells that causes the cells to contract, allowing the heart to pump blood, and the arteries to narrow. 

By blocking the entry of calcium, Cardizem decreases the force of contraction of the heart and its rate of contraction. It also relaxes the muscles surrounding the arteries, allowing the arteries to widen (dilate). In order to pump blood, the heart needs oxygen. The harder the heart works, the more oxygen it requires. 

Angina occurs when the supply of oxygen to the heart is inadequate for the amount of work the heart must do. By dilating arteries, Cardizem reduces the pressure in the arteries into which the heart must pump blood, and, as a result, the heart needs to work less and requires less oxygen. By reducing the heart's need for oxygen, Cardizem relieves or prevents angina. Dilation of the arteries also reduces blood pressure.

Common side effects of Cardizem include

• constipation,
• nausea,
• headache,
• rash,
• swelling of the legs and feet with fluid (edema),
• low blood pressure (hypotension),
• drowsiness,
• dizziness, and
• sexual dysfunction.

Serious side effects of Cardizem include

• liver dysfunction,
• overgrowth of the gums, and
• worsening symptoms of heart failure when given to individuals with heart failure. 

Drug interactions of Cardizem include digoxin, which can increase digoxin blood levels. Similarly, concurrent administration of Cardizem with an anti-seizure medication, carbamazepine, can increase blood levels of the seizure medication, and occasionally lead to toxicity.

• Cardizem increases blood levels of lovastatin, atorvastatin, and simvastatin, possibly increasing the risk of adverse effects.
• Cardizem may increase blood levels of buspirone, midazolam, triazolam, and diazepam by reducing their breakdown and elimination from the body by the liver. This can lead to toxicity from these drugs. Rifampin reduces the effect of Cardizem by reducing its levels in blood to undetectable levels. 

There are no well-controlled studies in pregnant women. Cardizem should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. 

Cardizem is excreted in breast milk. To avoid adverse effects in the infant, Cardizem should not be taken while breastfeeding.

Side effects include:

• constipation,
• nausea,
• headache,
• rash,
• edema (swelling of the legs and feet with fluid),
• low blood pressure (hypotension),
• drowsiness, and
• dizziness.

Liver dysfunction and overgrowth of the gums also may occur. Diltiazem can cause mildly abnormal liver tests that usually return to normal with discontinuation of the medication.

When diltiazem is given to individuals with heart failure, symptoms of heart failure may worsen because these drugs reduce the ability of the heart to pump blood. Like other drugs for high blood pressure, diltiazem is associated with sexual dysfunction.

Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities usually have been excluded.

In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during Cardizem therapy was not greater than that reported during placebo therapy.

The following represent occurrences observed in clinical studies of angina patients. In many cases, the relationship to Cardizem has not been established. The most common occurrences from these studies, as well their frequency of presentation, are

• edema (2.4%),
• headache (2.1%),
• nausea (1.9%),
• dizziness (1.5%),
• rash (1.3%), and
• asthenia (1.2%).

In addition, the following events were reported infrequently (less than 1 %):

Cardiovascular

• Angina, arrhythmia, AV block (first-degree), AV block, bradycardia, bundle branch block, congestive heart failure, ECG abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous System

• Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tremor.

Gastrointestinal

• Anorexia, constipation, diarrhea, dysgeusia, dyspepsia, mild elevations of alkaline phosphatase, SGOT, SGPT, and LDH, thirst, vomiting, weight increase.

Dermatological

• Petechiae, photosensitivity, pruritus, urticaria.

Other

• Amblyopia, CPK elevation, dry mouth, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties, tinnitus.
• The following postmarketing events have been reported infrequently in patients receiving Cardizem:
  • acute generalized exanthematous pustulosis,
  • allergic reactions,
  • alopecia,
  • angioedema (including facial or periorbital edema),
  • asystole,
  • erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis),
  • extrapyramidal symptoms,
  • gingival hyperplasia,
  • hemolytic anemia,
  • increased bleeding time,
  • leukopenia,
  • photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas),
  • purpura,
  • retinopathy,
  • myopathy, and
  • thrombocytopenia.
• There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis.
• 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 definitive cause and effect relationship between these events and Cardizem therapy cannot yet be established.
• Exfoliative dermatitis (proven by rechallenge) has also been reported.

• Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Cardizem 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 Cardizem.
• 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 Cardizem 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 Cardizem (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.

Buspirone

• In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo.
• The T½ 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 Cardizem 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 Cardizem therapy to avoid possible over-or under-digitalization.

Quinidine

• Diltiazem significantly increases the AUC (0→infin;) of quinidine by 51%, T½ 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.