Cardil CR

Cardil CR

diltiazem

Manufacturer:

Orion

Distributor:

Harn Thai

Marketer:

Orion Pharma Thai
Full Prescribing Info
Contents
Diltiazem hydrochloride.
Description
Each 120 mg CR tablet of Cardil CR contains lactose 114 mg and approximately sucrose 0.8 mg.
Cardil also contains the following excipients: Tablet Core: Lactose monohydrate, hydrogenated castor oil, dried aluminium hydroxide gel, polyacrylate, talc, magnesium stearate. Film Coating: Hypromellose, sucrose, glycerol, titanium dioxide (E171), magnesium stearate, polysorbate 80.
Action
Pharmacotherapeutic Group: Benzothiazepine derivatives. ATC Code: C08DB01.
Pharmacology: Pharmacodynamics: Diltiazem a benzothiazepine derivative that effectively blocks the slow calcium channels (L channels) of vascular smooth muscle and cardiac muscle cells. Slow calcium channels play an important role especially in the regulation of sinoatrial and atrioventricular node function in the cardiac muscle cells. Diltiazem possesses both peripheral and coronary vasodilator properties. However, diltiazem-induced fall in blood pressure is not commonly followed by reflectory tachycardia which is probably due to the depressive effect of the drug on the stimulation of sinoatrial node function. Diltiazem slows atrioventricular conduction. It also has a weak negative inotropic effect on the heart. Diltiazem improves relaxation of the cardiac muscle and diastolic function which together with decreased afterload improves the left ventricular function. In spite of coronary dilatation, the total flow in healthy coronary arteries does not usually change, but some improvement in the circulation of contracted arteries has been observed. Diltiazem relaxes smooth muscle also elsewhere in the body eg, the lower oesophageal sphincter muscle. Diltiazem has not been shown to have effect on electrolyte-, lipid- or glucose balance in healthy or diabetic persons.
Pharmacokinetics: Absorption: Diltiazem is completely absorbed after oral administration, but owing to its first-pass metabolism in the liver, the absolute bioavailability of diltiazem hydrochloride is only about 40% (with interindividual variability ranging from 24-74%).
Distribution: The bioavailability is independent of formulation or therapeutic dose. A diet rich in fat and protein slightly increases the bioavailability of a sustained-release capsule formulation, but this has no clinical significance.
The peak concentration in plasma is reached in about 3-4 hrs after administration of a conventional diltiazem tablet. The absorption is slower from a sustained-release tablet.
About 80% of diltiazem is bound to proteins, about 40% of this to plasma albumin. Diltiazem is widely distributed to various tissues. The apparent volume of distribution is 5 L/kg and the volume of central compartment is 0.9 L/kg. In the blood, diltiazem is evenly distributed to the plasma and blood cells. Steady state is reached within 3 days with the dosage of one 60 mg tablet 3 times daily.
Metabolism: Diltiazem is extensively metabolised and <4% is excreted unchanged in the urine. The total clearance of diltiazem is between 0.7 and 1.3 L/kg/hr. Five (5) unconjugated metabolites have been found in the urine, 2 of them also in conjugated forms. Diltiazem is metabolised through deacetylation, N-demethylation, and O-demethylation. Deacetyldiltiazem is an active metabolite (40-50% of the activity of diltiazem) with concentrations of about 15-35% of those of diltiazem. The pharmacodynamic significance of this metabolite is minor. Diltiazem is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Diltiazem and its N-demethylated metabolites also act as inhibitors of CYP3A4 enzyme.
Excretion: According to 3-compartment model, the half-life (t½) of diltiazem ranges from about 0.1 hrs in the first phase to 2.1 hrs in the middle and 9.8 hrs in the terminal phase. The elimination t½ varies between 4 and 7 hrs.
The pharmacokinetics of diltiazem has not been observed to change after repeated administrations. The drug is not accumulated and it does not induce its own metabolism. Studies with renal insufficiency and angina pectoris patients did not show difference in the pharmacokinetic profile of diltiazem as compared with studies on healthy volunteers.
Toxicology: Preclinical Safety Data: The acute toxicity of diltiazem was low (oral LD50 >500 mg/kg) in toxicity studies on rodents. The toxicity of diltiazem was mainly directed to the heart [transient electrocardiogram (ECG) changes]. In teratogenicity studies, diltiazem induced increased fetal mortality and malformations.
Indications/Uses
Angina pectoris, Prinzmetal's angina, hypertension.
Dosage/Direction for Use
1-1½ tablets once or twice daily.
Dosage depends on the condition being treated and must be adjusted by titration to individual patients needs. The starting dose should be reduced in the elderly patients and in patients with impaired hepatic function. There are no data available on use of diltiazem in children.
Administration: The tablets should be taken orally and ingested whole. CR tablets can be halved.
Overdosage
Symptoms: Overdose may cause pronounced hypotension possibly leading to collapse, sinus bradycardia with or without isorhythmic dissociation, and atrioventricular conduction disturbances. Other symptoms eg, tiredness, irritability, somnolence, hypothermia, hyperglycaemia, and nausea may occur.
Treatment: There is no specific antidote for diltiazem. Absorption should be prevented by eg, with gastric lavage, osmotic diuresis and/or administration of activated charcoal. Respiration, hemodynamics and fluid and electrolyte balance should be monitored. Hypotension can be treated with IV dopamine or calcium chloride. Bradycardia and severe atrioventricular block have been treated with atropine or cardiac pacing. Vasopressors, inotropic agents and glucagon may also be used. Otherwise the treatment is symptomatic.
Contraindications
Hypersensitivity to diltiazem hydrochloride or to any of the excipients of Cardil CR. Sick sinus syndrome or evidence of 2nd- or 3rd-degree AV block except in the presence of a functioning pacemaker. Hypotension. Severe bradycardia (<40 bpm). Wolff-Parkinson-White syndrome. Decompensated cardiac insufficiency. Cardiogenic shock. Digitalis intoxication. Left ventricular failure with pulmonary congestion. Concomitant use of dantrolene infusion.
Use in Lactation: Diltiazem is excreted in breastmilk. Women should not breastfeed while on diltiazem treatment. If use of diltiazem is considered medically essential, breastfeeding should be terminated.
Special Precautions
Close observation is necessary in patients with reduced left ventricular function, bradycardia or with a 1st degree AV block detected on the electrocardiogram or aortic stenosis. In addition, caution should be used if diltiazem is used concomitantly with β-blockers or other medicaments that impair cardiac conduction or contractility.
The anaesthesist must be informed of ongoing diltiazem treatment. Depression of cardiac contractility, conductivity and automaticity, as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.
Increase of plasma concentrations of diltiazem may be observed in the elderly and in patients with renal or hepatic insufficiency. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.
Since diltiazem has shown porphyrogenic characteristics in in vitro and animal studies, caution should be exercised in the treatment of patients with acute porphyria.
Calcium channel blocking agents eg, diltiazem, may be associated with mood changes, including depression.
Like other calcium channel antagonists, diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk to develop an intestinal obstruction.
Tablets and controlled-release tablets contain lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Cardil CR.
Effects on the Ability to Drive or Operate Machinery: At the beginning of treatment with diltiazem, the decrease in blood pressure may induce dizziness especially when standing up. If this occurs, the patient should refrain from driving and using machines. After the treatment effects have been stabilised, it is unlikely that diltiazem should affect these capabilities.
Use in Pregnancy: There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been observed to induce increased fetal mortality and malformations in certain animal species. Diltiazem is therefore not recommended during pregnancy, as well as in women of childbearing potential not using effective contraception.
Use In Pregnancy & Lactation
Use in Pregnancy: There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been observed to induce increased fetal mortality and malformations in certain animal species. Diltiazem is therefore not recommended during pregnancy, as well as in women of childbearing potential not using effective contraception.
Use in Lactation: Diltiazem is excreted in breastmilk. Women should not breastfeed while on diltiazem treatment. If use of diltiazem is considered medically essential, breastfeeding should be terminated.
Adverse Reactions
The most common adverse effects of diltiazem include headache, dizziness, AV block (may be of 1st-, 2nd- or 3rd-degree; bundle branch block may occur), palpitations, peripheral oedema, flushing of face, nausea, constipation, dyspepsia, gastric pain, malaise, erythema and pruritus.
Other adverse effects of diltiazem include thrombocytopenia, leukopenia, weight gain, anorexia, nervousness, insomnia, mood changes (including depression), smell and taste disturbances, extrapyramidal syndrome, bradycardia, sinus arrest, aggravated angina pectoris, sinoatrial block, congestive heart failure, orthostatic hypotension, vasculitis (including leukocytoclastic vasculitis), vomiting, diarrhoea, dryness of mouth and throat, gingival hyperplasia, hepatic enzymes increased [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP)], hepatitis, urticaria, rash, angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reactions, exfoliative dermatitis, lupus erythematosus, acute generalised exanthematous pustulosis (AGEP), gynecomastia and polyuria.
Drug Interactions
Concomitant Use Contraindicated: Dantrolene (Infusion): Lethal ventricular fibrillation is regularly observed in animals when IV verapamil and dantrolene are administered concomitantly. The combination of a calcium antagonist and dantrolene is therefore potentially dangerous (see Contraindications).
Concomitant Use Requiring Caution: Lithium: Lithium neurotoxicity may occur in concomitant use with diltiazem. Therefore lithium concentrations in serum should be monitored.
Nitrate Derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects). In all the patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.
Theophylline: Increase in circulating theophylline levels.
Alpha-Antagonists: Increased antihypertensive effects.
Concomitant treatment with α-antagonists may produce or aggravate hypotension. The combination of diltiazem with an α-antagonist should be considered only with the strict monitoring of the blood pressure.
Amiodarone, Digoxin: Increased risk of bradycardia. Caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.
Beta-Blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.
Other Antiarrhythmic Agents: Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended (additive risk of increased cardiac adverse effects). This combination should only be used under close clinical and ECG monitoring.
Carbamazepine: Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
Rifampicin: Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.
Anti-H2 Agents (Ranitidine): Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H2 agents. An adjustment in diltiazem daily dose may be necessary.
Ciclosporin: Increase in circulating cyclosporin levels. It is recommended that the cyclosporin dose be reduced, renal function be monitored, circulating cyclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation. Diltiazem may increase the cardiac depressant effect of halothane and isoflurane.
General Information To Be Taken Into Account: Due to the potential for additive effects, caution and careful titration are necessary in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction. The effect of other antihypertensive agents may be potentiated if used concomitantly with diltiazem. Diltiazem is metabolized by CYP3A4. A moderate (<2-fold) increase of diltiazem plasma concentration in cases of co-administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other CYP3A4 substrates (eg, macrolide antibiotics, phenytoin, buspirone, nifedipine, sirolimus, tacrolimus, alfentanil, cisapride and HIV protease inhibitors) may result in an increase in plasma concentration of either co-administered drug. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
Benzodiazepines (Midazolam, Triazolam, Alprazolam):
Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their t½. Special care should be taken when prescribing short-acting benzodiazepines metabolized by the CYP3A4 pathway in patients using diltiazem. Diltiazem may also increase the effect of alprazolam.
Corticosteroids (Methylprednisolone): Inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein. The patient should be monitored when initiating methylprednisolone treatment. An adjustment in the dose of methylprednisolone may be necessary.
Statins: Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins (eg, simvastatin, lovastatin, atorvastatin). The risk of myopathy and rhabdomyolysis due to statins metabolised by CYP3A4 may be increased with concomitant use of diltiazem. When possible, a non-CYP3A4 metabolised statin should be used together with diltiazem, otherwise close monitoring for signs and symptoms of a potential statin toxicity is required.
Incompatibilities: None known.
Caution For Usage
Instructions for Use, Handling and Disposal: Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. In the controlled-release tablets, the medication is contained within a non-absorbable shell that has been specially designed to slowly release the drug so the body can absorb it. When this process is completed, the empty tablet is eliminated from the body.
Storage
Store at room temperature (+15°C to +25°C).
Shelf-Life: 3 years.
MIMS Class
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.
Presentation/Packing
CR tab 120 mg (controlled-release, white, capsule-shaped, scored, coded DL 120) x 100's.
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