Cardil - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate, hydrogenated castor oil, aluminum colloidal hydroxide, polyacrylate, talc, magnesium stearate, hydroxypropyl methylcellulose, sucrose, titanium dioxide (E 171), polysorbate 80, glycerin 85%.

Description:

Tablets 60 mg: white capsular, coated tablets with a dividing risk on both sides and code DL / 60 on one side.

Tablets 120 mg: white capsular, coated tablets with a dividing risk on both sides and code DL / 120 on one side.

Pharmacotherapeutic group:Blocks of "slow" calcium channels

ATX: & nbsp

C.08.D.B.01 Diltiazem

C.05.A.E.03 Diltiazem

Pharmacodynamics:

Diltiazem is a derivative of benzodiazepines; has antiarrhythmic, antianginal and hypotensive activity.

The "slow" calcium channel blocker reduces the intracellular content of Ca2 + in cardiomyocytes and smooth muscle cells, expands the coronary and peripheral arteries and arterioles, reduces the overall peripheral vascular resistance (OPSS), smooth muscle tone, strengthens coronary, cerebral and renal blood flow, reduces heart rate.

The antiarrhythmic effect is due to the suppression of Ca2 + transport in the heart tissues, which leads to an elongation of the effective refractory period and a slowing down of the atrioventricular (AV) node (it is clinically important in patients with sinus node weakness syndrome, elderly people whose calcium channel blockage may interfere with generation pulse in the sinus node and call the sinoatrial (SA) blockade). The normal atrial action potential or intraventricular conduction does not change (normal sinus rhythm is usually unaffected), but with a decrease in the amplitude of atrial contraction, the rate of depolarization and speed of conduction decrease.Anterograde effective refractory period in additional bypass beams of conduction may be shortened.

Antianginal action is due to the expansion of peripheral vessels and a decrease in systemic blood pressure (afterload), which leads to a decrease in the stress of the wall of the myocardium and its need for oxygen. In concentrations that do not lead to the appearance of a negative inotropic effect, it causes the relaxation of the smooth muscles of the coronary vessels and the dilatation of both large and small arteries.

The hypotensive effect is due to dilatation of the resistive vessels and a decrease in the OPSS. The degree of decrease in blood pressure (BP) correlates with its baseline level (in "normotonics" there is a minimal effect on blood pressure). Reduces blood pressure in both horizontal and vertical position. Rarely causes postural arterial hypotension and reflex tachycardia. Does not change or slightly reduces the maximum heart rate under the load. Long-term therapy does not lead to hyperkatecholamineemia, an increase in the activity of the renin-angiotensin-aldosterone system. Reduces the renal and peripheral effects of angiotensin II.Improves diastolic relaxation of the myocardium with arterial hypertension, ischemic heart disease, hypertrophic cardiomyopathy, reduces platelet aggregation.

Has a minimal effect on the smooth muscles of the gastrointestinal tract. During a long (8 months) therapy, tolerance does not develop. Does not affect the lipid profile of the blood. It is able to cause regression of left ventricular hypertrophy in patients with arterial hypertension.

The onset of action with oral administration: prolonged action tablets - 2-3 hours, tablets - 30-60 minutes.

The maximum severity of the hypotensive effect is achieved within 2 weeks. Duration of action with oral administration: tablets prolonged action - 12-24 h, tablets - 4-8 h.

Pharmacokinetics:

Diltiazem completely absorbed from the gastrointestinal tract after ingestion. Absolute bioavailability is about 40% (individual variations 24 - 74%). Bioavailability is the same for all dosage forms and is not dose-dependent when taking therapeutic doses. The maximum concentration in the blood plasma is achieved approximately 2-3 hours after taking the drug inside (with a single dose of 90 mg C_max is 50 to 65 ng / ml). For tablets 60 mg - the maximum concentration in the blood plasma is reached approximately 3-4 hours after taking the drug inside (with a single dose of 60 mg C_max is 39 to 120 ng / ml).

About 80% of diltiazem binds to blood plasma proteins (about 40% - with albumin). Diltiazem evenly distributed in various tissues. In the blood, the drug is quickly distributed between the plasma and the blood cells. Penetrates into breast milk.

Half-life (T_1/2) when ingested biphasic; tablets: early - 20-30 minutes, final - 3.5 hours (5-8 hours with high and repeated doses).

Is extensively metabolized in the liver by deacetylation and demethylation with participation of cytochrome P450 to the active metabolite dezatsetildiltiazema which is defined in the plasma at a concentration of 15 - 35% of the concentration of the parent drug and is 40 - 50% of diltiazem activity (expressed effect of "first pass" through the liver ).

It is excreted with bile (65%) and kidney (35%). In the unchanged form, 0.1-4% diltiazem is excreted in the urine; in urine there are five unconjugated metabolites, two of them are found in conjugated form.

The total clearance of diltiazem is 0.7 - 1.3 l / kg / h.

The pharmacokinetics of diltiazem for prolonged use does not change. The drug does not cumulate or induce its own metabolism.

In patients with angina and impaired renal function, the pharmacokinetics of diltiazem does not change. In patients with hepatic insufficiency, bioavailability increases and lengthens T_1/2. In the elderly, the diltiazem clearance can also be reduced.

Indications:

Treatment of arterial hypertension.

Treatment and prevention:

- Stenocardia of stress;

- Prinzmetal angina.

Prevention of heart rhythm disturbances:

paroxysmal tachycardia;

- flutter and atrial fibrillation;

- prevention of attacks of supraventricular arrhythmias.

Contraindications:

- Hypersensitivity to the drug and other benzodiazepine derivatives;

- pronounced bradycardia;

- Sinoauric blockade;

- sinoatrial and atrioventricular blockade of II and III degree (except for patients with a pacemaker);

- syndrome of weakness of the sinus node without the use of an artificial pacemaker;

- Wolff-Parkinson-White syndrome;

- heart failure (in the stage of decompensation);

- Myocardial infarction with signs of left ventricular failure;

- heart failure (including during a recent myocardial infarction);

- arterial hypotension (systolic blood pressure below 90 mm Hg);

- pregnancy and the period of breastfeeding;

- Ventricular tachycardia with a wide complex of QRS;

- age under 18 years (effectiveness and safety not established);

- cardiogenic shock;

- Intoxication with cardiac glycosides;

- Insufficiency of the left ventricle with stagnation of blood in the lungs;

- simultaneous use with dantrolene (for intravenous administration);

- galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;

- fructose intolerance and glucose / galactose absorption impairment syndrome or sucrose / isomaltase deficiency.

Carefully:With caution should be used in patients with severe violations of liver and kidney function, acute porphyria, violations of intraventricular conduction, AV blockade of 1 degree.

Pregnancy and lactation:

The drug is contraindicated for use during pregnancy and lactation.

There are very limited data on the use of diltiazem in pregnant patients. In some animal species, under the influence of diltiazem, there was an increase in intrauterine mortality and the incidence of developmental malformations. Therefore, it is not recommended to take Cardil to women of childbearing age who do not use effective methods of contraception.

Diltiazem is excreted in breast milk. Breastfeeding is contraindicated during treatment with Cardil. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Tablets are taken orally, swallowed, not chewed and washed down with a small amount of water.

Doses of the drug must be selected individually.

The average daily dose is 180 - 240 mg. The daily dose above 360 mg should be used with caution (in a hospital setting).

Cardil 120 mg tablets prolonged action, coated: one tablet 2 times a day. Applicable and the initial dose of 90 mg 2 times a day. The dose can be increased in accordance with the therapeutic effect up to 180 mg 2 times a day.

If necessary, the tablets can be divided in half without losing their prolonged action.

Cardil 60 mg tablets, coated: one tablet 3 or 4 times a day. Usually, an initial dose of 60 mg is administered 3 or 4 times a day. The dose can be increased in accordance with the therapeutic effect up to 120 mg 3 times a day.

Cardil in a dose of 60 mg is prescribed for people over 60 years 3 times a day.

In elderly patients or patients with impaired liver function is recommended to begin treatment with lower doses (half tablets), 2 times a day.

Experience in the treatment of children is absent.

Side effects:

Usually Cardile is well tolerated by patients.

There are: headache, dizziness, feeling of weakness, fatigue, palpitations, discomfort, dyspepsia, "tides" of blood to the skin, allergic skin reactions, such as itching, redness, rash, and peripheral edema. In some cases, possible allergic reactions such as exudative erythema multiforme, limfoadenopanii and eosinophilia.

In rare cases marked effects on the gastrointestinal tract: nausea, vomiting, heartburn, diarrhea,constipation; reversible increase in the activity of liver enzymes (alkaline phosphatase (SHT), aspartate aminotransferase (ACT), alanine aminotransferase (ALT), lactate dehydrogenase (LDH)), as a sign of acute liver damage, hepatitis. Therefore, a regular study of liver function is necessary.

Very rarely: thrombocytopenia, leukopenia, weight gain, anorexia, taste and smell, vasculitis (including allergic vasculitis), angioedema, dryness of the oral and throat mucosa, erythema polymorph, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis , systemic lupus erythematosus, acute generalized exanthematous pustulosis, gynecomastia and polyuria. With the use of diltiazem in high doses, severe bradycardia, conduction disorders (atrioventricular and sinouricular blockade), excessive decrease in arterial pressure, the appearance or aggravation of symptoms of heart failure, blockage of the bundle branch, pulmonary edema, paresthesia, tremor and visual impairment may occur.

In some cases, there may be: insomnia, depression, hallucinations,violation of potency. With long-term therapy, isolated cases of hyperplasia of the mucosa have been noted.

Overdose:

Diltiazem in a dose of 0,9 - 1,8 g can cause intoxication of different severity in adults. Diltiazem in a dose of 2.6 g in elderly patients and in a dose of 5.9 g in adults can cause serious intoxication, and in a dose of 10.8 g - very serious. Symptoms of poisoning occur within 8 hours after taking the drug. The clinical picture of acute intoxication is accompanied by excessive or pronounced decrease in blood pressure, which results in a collapse, sinus bradycardia with / without isorhythmic dissociation of the atrioventricular rhythm, and a decrease in AV conduction.

With these effects, gastric lavage, osmotic diuresis are shown.

With a marked decrease in blood pressure with clinical manifestations, intravenous administration of dopamine (dopamine) or dobutamine, calcium chloride, isoproterenol (isadrine) or norepinephrine (norepinephrine) is indicated.

With tachycardia, a rapid ventricular rhythm in patients with anterograde in fluttering or atrial fibrillation and with additional beams of conduction in Wolff-Parkinson-White syndrome or in Laun-Ganong-Levin syndrome, direct electropulse therapy is shown,intravenous injection of lidocaine or procainamide, slow intravenous drip of fluids.

With bradycardia (rarely - atrioventricular blockade of II and III degree with progression in some patients to asystole), intravenous administration of atropine, isoproterenol or calcium chloride or the use of an electrocardiostimulator is indicated.

Interaction:

May enhance the effect of other antihypertensive drugs and diuretics. Strengthening the AV conduction blockade and increasing the risk of bradycardia with concomitant administration with beta-blockers.

Dantrolene: in animal experiments fatal fibrillation of the ventricles was constantly observed with the simultaneous administration of intravenous verapamil and dantrolene. Therefore, the combination of blockers of "slow" calcium channels and dantrolene is potentially dangerous.

Nifedipine: diltiazem reduces the clearance of nifedipine, in some cases by more than 50%.

Propranolol, metoprolol: diltiazem increases the concentration of propranolol and metoprolol in the blood plasma by reducing their metabolism in the liver.

Digoxin: diltiazem increases the concentration of digoxin in the blood plasma from 20% to 50% by reducing its clearance (monitoring the concentration of digoxin in the blood serum). There is a risk of severe bradyarrhythmia.

Midazolam, triazolam: diltiazem increases or prolongs the sedative effect of midazolam and triazolam by reducing metabolism in the liver.
Diazepam: diazepam reduces the concentration of diltiazem in the blood plasma to about 20% by reducing its absorption.

Cimetidine: cimetidine increases the absorption of diltiazem by reducing the metabolism of the "primary passage" through the liver of diltiazem (the clinical significance of the interaction is unclear).

Amiodarone: diltiazem in combination with amiodarone affects AV conduction, there is a risk of developing severe bradyarrhythmia;

Calcium preparations: intravenous administration of calcium preparations reduces the effect of diltiazem.

Carbamazepine, imipramine: diltiazem increases the concentration of carbamazepine and imipramine in blood plasma.

Buspirone: diltiazem significantly increases the concentration of buspirone in the blood plasma.

Lithium: with simultaneous use with diltiazem, neurotoxicity of lithium may appear.Derivatives of nitrates: increased antihypertensive effect and a tendency to fainting (due to summation of vasodilator action).

Theophylline: increased theophylline concentration in the blood.

Alpha-blockers: increased antihypertensive action.

Simultaneous treatment with alpha-blockers can lead to the emergence or increase of arterial hypotension.

Beta-adrenoblockers: the possibility of rhythm disturbances (severe bradycardia, complete inhibition of sinus node activity, sinus arrest), violations of sinoatrial and atrioventricular conduction of impulse and heart failure (mutually reinforcing effect).

Other antiarrhythmic drugs: since diltiazem has antiarrhythmic properties, its simultaneous appointment with other antiarrhythmic drugs is not recommended (the probability of developing unwanted effects on the heart is summarized).

Rifampicin: decreased diltiazem concentration in the blood plasma after the initiation of rifampicin treatment.

Blockers H₂-gistaminovyh receptors (ranitidine): an increase in the concentration of diltiazem in the blood plasma.

Cyclosporine: diltiazem increases the concentration of cyclosporine in the blood plasma to 50%, while increasing the nephrotoxicity of cyclosporine by decreasing the metabolism of cyclosporine.

Diltiazem can enhance the depressive effect on the heart of halothane and isoflurane.

Experimentally diltiazem reduces the clearance of theophylline to 25% in male smokers.

In animal studies, the cardiosuppressive effect of halothane and isoflurane. In patients this interaction was not noted.

Due to the possibility of summation of effects, caution and gradual titration of the dose to patients who receive diltiazem simultaneously with other drugs with a known effect on contractility and / or conduction of the heart. The effect of other antihypertensive drugs may be enhanced when combined with diltiazem. Diltiazem is metabolized by the CYP3A4 isoenzyme. A moderate (less than twofold) increase in the concentration of diltiazem in the blood plasma was documented in the case of its simultaneous administration with a stronger inhibitor of the isoenzyme CYP3A4. Diltiazem is also an inhibitor of the isoenzyme CYP3A4. Simultaneous administration with other substrates of CYP3A4 (such as macrolide antibiotics, phenytoin, buspirone, nifedipine, sirolimus, tacrolimus, alfentacicisapride and HIV protease inhibitors) can lead to an increase in the plasma concentration of each of the combined drugs. The joint administration of diltiazem with inducers of the isoenzyme CYP3A4 can lead to a decrease in the concentration of diltiazem in the blood plasma. Benzodiazepines (midazolam, triazolam, alprazolam): diltiazem significantly increases the concentrations of midazolam and triazolam in blood plasma, and also lengthens their half-lives. With extreme caution, short-acting benzodiazepines should be administered that are metabolized along the pathway of the CYP3A4 isoenzyme, to patients who take diltiazem.

Diltiazem can also enhance the effects of alprazolam.

Corticosteroids (methylprednisolone): inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein. A dose adjustment of methylprednisolone may be required.

HMG-CoA reductase inhibitors (statins): significantly increases the AUC (area under the concentration-time curve) of certain HMG-CoA reductase inhibitors (simvastatin, lovastatin, atorvastatin). When used simultaneously with diltiazem inhibitors of HMG-CoA reductase, metabolized with the isozyme CYP3A4, increases the likelihood of development of myopathy and rhabdomyolysis.If possible, HMG-CoA reductase inhibitors should be used together with diltiazem, which are not metabolized by the CYP3A4 isoenzyme, otherwise careful monitoring of the possible occurrence of symptoms and signs of the toxic effect of HMG-CoA reductase inhibitors is necessary.

Special instructions:

Careful observation of patients with weakened left ventricular function, bradycardia or atrioventricular blockade of degree I, revealed on an electrocardiogram, as well as with aortic stenosis is required. With extreme caution, Cardil should be used concomitantly with beta-blockers or other drugs that can cause conduction disorders. It is necessary to inform the anesthesia doctor about the ongoing treatment with Cardil. Reduction of contractility, conduction and automatism of the heart, as well as vasodilation caused by anesthetics, can be enhanced by blockers of "slow" calcium channels.

An increase in Cardiol concentration in the blood plasma can be observed in elderly patients and in patients with renal or hepatic insufficiency. At the beginning of treatment, you should carefully read the contraindications,take appropriate precautions, you need regular monitoring of heart rate.

Since Cardil in studies in vitro and in animal studies has shown the ability to cause porphyria, caution should be applied to its patients with acute porphyria. "Slow" calcium channel blockers, such as Cardil, can be associated with mood changes, including depression.

Like other blockers of "slow" calcium channels, Cardil has a depressing effect on intestinal peristalsis. Therefore, it should be used with caution in patients with the possibility of intestinal obstruction.

In isolated cases, when performing extracorporeal fertilization with the use of blockers of "slow" calcium channels, reversible biochemical changes in the sperm head were noted, which led to a disruption of the sperm function. With unsuccessful attempts of in vitro fertilization and with the exclusion of other causes of infertility, one should take into account the probability of influence on the semen of blockers of "slow" calcium channels, provided they are used.

Effect on the ability to drive transp. cf. and fur:At the very beginning of treatment, dizziness may occur, especially when the position of the body changes. At this stage, it is necessary to avoid the management of mechanical vehicles and perform work that requires a high rate of mental and physical reactions. At a later stage of treatment, when good therapeutic control is achieved, the effect of diltiazem on the ability to drive and work is unknown.

Form release / dosage:Pills.

Packaging:For 30 or 100 tablets in a vial of HDPE with a lid of HDPE and a ring of the first opening. For 1 bottle with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of 15 - 25 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiration date printed on the package!

Terms of leave from pharmacies:On prescription

Registration number:П N015009 / 02-2003

Date of registration:31.07.2008

Expiration Date:Unlimited

Date of cancellation:2017-02-07

The owner of the registration certificate:Orion CorporationOrion Corporation Finland

Manufacturer: & nbsp

ORION CORPORATION Finland

Representation: & nbspOrion Pharma LLCOrion Pharma LLC

Information update date: & nbsp10.12.2017

Illustrated instructions

Instructions

Cardil (Cardil)