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Data Sheet

Cardizem CD

Diltiazem hydrochloride 120, 180 and 240 mg capsules

Presentation

120 mg capsule (light turquoise opaque) marked CARDIZEM CD 120 mg
180 mg capsule (half light turquoise/half blue) marked CARDIZEM CD 180mg
240 mg blue capsule marked CARDIZEM CD 240 mg

Uses

Actions

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

Diltiazem produces its antihypertensive effects primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.

Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem hydrochloride prevents spontaneous and ergometrine provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure and, in exercise tolerance studies in patients with ischaemic heart disease, reduces the heart rate-blood pressure product for any given work load. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction and left ventricular end diastolic pressure have not been affected. Increased heart failure has, however, been reported in occasional patients with pre-existing impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem.

Diltiazem produces antihypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects. Diltiazem decreases vascular resistance, increases cardiac output (by increasing stroke volume) and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually reduced. Heart rate at maximum exercise does not change or is slightly reduced. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem antagonises the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.

Intravenous diltiazem hydrochloride in doses of 20 mg prolongs AH conduction time and A-V node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of diltiazem hydrochloride in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree A-V block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of diltiazem to patients in doses of up to 540 mg/day has resulted in small increases in PR interval but has not usually produced abnormal prolongation (see WARNINGS).

Pharmacokinetics

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%. Diltiazem undergoes extensive metabolism in which 2 - 4% of the unchanged drug appears in the urine. In vitro ligand binding studies show diltiazem is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown diltiazem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of diltiazem appear to be in the range of 50 - 200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose.

A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single study in patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

When compared to a diltiazem tablet at steady-state, more than 95% of drug is absorbed from the CARDIZEM CD formulation. A single 360 mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours. When CARDIZEM CD was co-administered with a high fat content breakfast, the extent of diltiazem absorption was not affected. Dose-dumping does not occur. The apparent elimination half-life after single or multiple dosing is 5 to 8 hours. A departure from linearity similar to that seen with diltiazem tablets is observed. As the dose of CARDIZEM CD capsules is increased from a daily dose of 120 mg to 240 mg, there is an increase in the area under the curve of 2.7 times. When the dose is increased from 240 mg to 360 mg there is an increase in the area under the curve of 1.6 times.

No information is available on the pharmacokinetics and bioavailability of diltiazem in patients with hepatic or renal failure, or in elderly hypertensive patients.

Indications

CARDIZEM CD is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications such as diuretics.

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

Dosage and Administration

Patients controlled on diltiazem alone or in combination with other medications may be safely switched to CARDIZEM CD capsules at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited clinical experience with doses above 360 mg.

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 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 360 mg once daily. When necessary, titration may be carried out over a 7 to 14 day period.

Concomitant Use with Other Cardiovascular Agents

Sublingual glyceryl trinitrate may be taken as required to abort acute anginal attacks during CARDIZEM CD therapy.

CARDIZEM CD may be safely co-administered with short- and long-acting nitrates.

Beta-blockers (See WARNINGS AND PRECAUTIONS).

Antihypertensives - CARDIZEM CD has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of CARDIZEM CD or the concomitant antihypertensives may need to be adjusted when adding one to the other.

Contraindications

Warnings and Precautions

Cardiac Conduction

Close observation is necessary in patients with reduced left ventricular function, bradycardia or with a first degree AV block.

Diltiazem prolongs A-V 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 A-V block). Concomitant use of diltiazem with beta-blockers, amiodarone 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 hydrochloride.

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, haemodynamic 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). 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 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).

Impaired Hepatic or Renal Function

Plasma diltiazem concentrations can be increased in patients with renal or hepatic insufficiency. Diltiazem is extensively metabolised by the liver and excreted by the kidneys and in bile. As with any new drug given over prolonged periods, laboratory parameters should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Use in Diabetics

Diltiazem should be used with caution in patients suffering from diabetes. Like other calcium channel blockers, diltiazem influences insulin secretion and its peripheral action by inhibiting calcium influx into cells. In one study, increases in fasting and peak glucose levels were observed after 2-6 months diltiazem administration.

Concomitant Administration with Beta-blockers

Controlled and uncontrolled 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 (see INTERACTIONS).

Administration of diltiazem concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased by approximately 50%. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted.

In contrast, there appears to be no effect on the pharmacokinetics of atenolol, a renally cleared drug. In view of the known pharmacodynamic interactions between these classes of drugs, this effect may be of clinical relevance.

Use with Amiodarone

Amiodarone should be used with caution with diltiazem particularly if there is suspicion of underlying dysfunction of the sinus node, such as bradycardia or sick sinus syndrome or if there is partial A-V block (see INTERACTIONS).

Concomitant Use with Digoxin

Diltiazem has been shown to increase serum digoxin concentrations and to modify its pharmacokinetics (see INTERACTIONS). Patients with plasma digoxin levels in the upper therapeutic range (1.5 to 2.5 ng/mL) may develop toxic plasma concentrations and side effects. Therefore, digoxin plasma concentrations should be controlled 6 to 8 days after starting these drug combinations, at which time new steady state conditions develop and the digoxin dose can be reduced if there is evidence of toxicity.

Long Term Use

Data to support long-term use of CARDIZEM CD (longer than 1 year) with doses > 360 mg/day are limited. Treatment at doses above 360 mg/day does not offer increased efficacy but it is associated with a greater risk of adverse reactions. Therefore treatment with doses exceeding 360 mg/day is not recommended.

Abrupt Withdrawal

The sudden withdrawal of diltiazem has been associated with severe angina in anginal patients.

Paediatric Use

Safety and effectiveness in children have not been established.

Use in the Elderly

Plasma diltiazem concentrations can be increased in the elderly. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.

Use in Pregnancy and During Lactation

Reproduction studies have been conducted in mice, rats and rabbits. Administration of high doses has resulted in embryo and foetal 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 high doses.

There are no well controlled studies in pregnant women. Also, diltiazem is a calcium channel blocker and drugs listed in this class carry the potential for foetal hypoxia associated with maternal hypotension. Accordingly, diltiazem is not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.

Diltiazem levels were measured in both serum and milk in nursing women. Samples were taken simultaneously on the fourth day of the treatment with diltiazem, 60 mg four times a day. The peak level in milk was as high as 200 ng/mL and was almost the same as that in serum. These data show that diltiazem is freely diffusible in milk but it is not known whether it is harmful to the newborn. Therefore, breastfeeding while taking Cardizem CD is contraindicated. If use of Cardizem CD is considered medically essential, an alternative method of infant feeding should be instituted.

Adverse Effects

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

The following table presents the most common adverse reactions reported in placebo-controlled angina and hypertension trials in patients receiving CARDIZEM CD up to 360 mg with rates in placebo patients shown for comparison.

In clinical trials of CARDIZEM CD capsules, the most common events were oedema, headache, dizziness, asthenia, first-degree A-V block, bradycardia, flushing, nausea and rash.

Double Blind Placebo Controlled Hypertension Trials

ADVERSE REACTION CARDIZEM CD
N=269		 PLACEBO
N=119
Headache 18.2% 17.6%
Dizziness 3.7% 5.0%
Bradycardia 10.4% 2.5%
AV block first degree 3.7% -
Oedema 7.8% 5.0%
ECG abnormality 5.2% 5.0%
Asthenia 4.1% 3.4%


In addition, the following events were reported infrequently in hypertension trials:

Cardiovascular

Angina, arrhythmia, A-V block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous system

Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paraesthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal

Anorexia, constipation, diarrhoea, dry mouth, dysgeusia, dyspepsia, mild elevations of SGOT, SGPT, LDH and alkaline phosphatase (in rare cases, clinical hepatitis has been reported, reversible upon discontinuation of Cardizem CD; see hepatic warnings), thirst, vomiting, weight increase.

Dermatological

Petechiae, photosensitivity, pruritus, urticaria, sweating.

Other

Amblyopia, CPK increase, dyspnoea, epistaxis, eye irritation, hyperglycaemia, sexual difficulties, muscle cramp, nasal congestion, nocturia, osteoarticular pain, impotence, polyuria, hyperuricemia.

The following post-marketing events have been reported infrequently in patients receiving diltiazem: alopecia, gynaecomastia, vasculitis, musculo-cutaneous reactions such as simple erythema or occasionally desquamative erythema with or without fever, symptoms of vasodilation (such as flushing, lower limb oedema), erythema multiforme (including rare cases of Steven-Johnson's syndrome), exfoliative dermatitis, angioedema, swelling of the face, skin hyperpigmentation, acute generalised exanthematous pustulosis, sino-atrial block, orthostatic hypotension, malaise, gastric pain, extrapyramidal symptoms, gingival hyperplasia, haemolytic anaemia, increased bleeding time, leukopenia, myopathy, purpura, retinopathy and thrombocytopenia. Very rare cases of toxic epidermal necrolysis have also been reported. In addition, events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease of these patients. A number of well-documented cases of rash, characterised as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and diltiazem therapy is yet to be established.

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.

Diltiazem undergoes biotransformation by the cytochrome P450 system. Coadministration of diltiazem with other drugs which follow the same route of biotransformation may result in competitive inhibition or induction of metabolism. This may lead to an increased risk of adverse reactions.

Dantrolene infusion

Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and dantrolene are administered concomitantly. The combination of a calcium channel antagonist and dantrolene is therefore potentially dangerous.

Beta-blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and beta-blockers or digitalis 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 by approximately 50%. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (See also WARNINGS).

Due to the possibility of rhythm disturbances, combination therapy with diltiazem and beta-blockers must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.

Digoxin

Concomitant use of diltiazem and digoxin may result in an additive effect on conduction. Diltiazem has been shown to modify digoxin pharmacokinetics in healthy subjects, in patients with cardiac insufficiency and in patients with chronic atrial fibrillation. Increases in plasma digoxin concentrations ranged from 24 to 70%. The renal digoxin clearance was decreased from 86.9 ± 18.3 to 62.8 ± 15.4 mL/minute and digoxin elimination half-life was prolonged from 36.7 ± 11.2 to 44.5 ± 11.5 hours during conventional diltiazem co-administration. There is an increased risk of bradycardia with this combination. Caution is required when digoxin is combined with diltiazem, particularly in the elderly and when high doses are used.

Statins

In a ten-subject study, coadministration of diltiazem with lovastain resulted in a 3 - 4 fold increase in mean lovastatin AUC and Cmax versus lovastatin alone; no change in pravastatin AUC and Cmax was observed during diltiazem co-administration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Treatment with simvastatin in a patient taking CARDIZEM CD should be started at the lowest possible dose and titrated upwards. If CARDIZEM CD treatment is to be added to patients already taking simvastatin, consider a reduction in statin dose and re-titrate against serum cholesterol concentrations.

Nitrate Derivatives

Increased hypotensive effects and faintness may be seen due to additive vasodilatating effects. In patients treated with calcium channel antagonists, the addition of nitrate derivatives should only be carried out at gradually increasing doses.

H2 antagonists (cimetidine, ranitidine)

Concomitant use may result in increased plasma diltiazem concentrations. Patients receiving diltiazem concurrently with an H2 antagonist should be carefully monitored when initiating or discontinuing therapy with H2 antagonists. An adjustment in diltiazem daily dose may be necessary.

Concurrent administration of cimetidine produced an increase in diltiazem levels (approximately 50% over control). The plasma levels of diltiazem's metabolite desacetyldiltiazem were also increased.

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. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.

Lithium

There is an increased risk of lithium-induced neurotoxicity.

Rifampicin

Administration of diltiazem with rifampicin markedly reduced plasma diltiazem concentrations and the therapeutic effect of diltiazem. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.

Cyclosporin

Concomitant administration of diltiazem and cyclosporin has resulted in an increase in cyclosporin concentrations. If these agents are to be administered concurrently, cyclosporin concentrations should be monitored. Downward titration of the cyclosporin dose is recommended and renal function should be monitored.

Benzodiazepines

Diazepam has been reported to cause a significant decrease in diltiazem plasma levels. The average decrease in diltiazem concentration was between 20 and 30%. Three out of eight patients showed decreases that were greater than 50%.

Diltiazem significantly increases the peak plasma levels and the elimination half-life of triazolam and midazolam.

Theophylline

Concomitant use results in an increase in circulating theophylline levels.

Rimonabant

Co-administration with diltiazem results in an increase in serum rimonabant levels.

Alpha-blockers

Concomitant treatment with alpha-blockers may produce or aggravate hypotension. The combination of diltiazem with an alpha-blocker should only be considered with the strict monitoring of blood pressure due to the risk of increased antihypertensive effects.

Amiodarone

Sinus arrest and a life-threatening low cardiac output state developed when amiodarone was added to a regimen of diltiazem and a diuretic. It has been suggested that diltiazem and amiodarone have additive adverse effects on sinus node function and on myocardial contractility (see PRECAUTIONS). There is an increased risk of bradycardia with this combination. Caution is required when amiodarone is combined with diltiazem, particularly in the elderly and when high doses are used.

Other Antiarrhythmic Agents

Since diltiazem has antiarrhythmic properties, its concomitant use with other antiarrhythmic agents is not recommended. Such combination should only be used under close clinical and ECG monitoring.

Anaesthetic agents

Additive haemodynamic depressive effects are found when calcium channel blockers are combined with inhalation anaesthetic agents such as halothane, isoflurane or enflurane. These effects are related both to the anaesthetic concentration and to the dose of the calcium channel blocker. Depression of cardiac contractility, conductivity and automaticity, as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Prior to general anaesthesia, the anaesthetist must be informed of ongoing diltiazem treatment.

Overdosage

Overdosage experience with oral diltiazem has been limited. Single oral doses of 300 mg of diltiazem have been well tolerated by healthy volunteers. In the event of overdosage or exaggerated response, appropriate supportive measures should be employed in addition to gastric lavage. The following measures may be considered:

Bradycardia

Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade administer isoprenaline cautiously.

High-degree A-V block

Treat as for bradycardia above. Fixed high-degree A-V block should be treated with cardiac pacing.

Cardiac failure

Administer inotropic agents (isoprenaline, dopamine or dobutamine) and diuretics

Hypotension

Vasopressors (eg, dopamine or noradrenaline).

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

The oral LD50s in mice and rats ranged from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50s in these species were 60 and 38 mg/kg, respectively. The oral LD50 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. Overdoses with as much as 10.8 g of oral diltiazem have been survived following appropriate supportive care.

Pharmaceutical Precautions

Store below 25oC. Protect from light and moisture.

Medicine Classification

Prescription Medicine

Package Quantities

Capsules may be packaged in high density polypropylene bottles in packs of 30.

Capsules may be packaged in blister strip calendar packs.

Further Information

Nil

Name and Address

sanofi-aventis new zealand limited
Level 8, James & Wells Tower
56 Cawley Street
Ellersie
Auckland

Ph: (09) 580 1810

Date of Preparation

13 August 2007