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

Diltiazem is a derivative of benzothiazepines; has antiarrhythmic, antianginal and hypotensive activity. The blocker of "slow" calcium channels (BCCI), reduces the intracellular content of calcium ions in cardiomyocytes and smooth muscle cells of blood vessels, expands coronary and peripheral arteries and arterioles, reduces the overall peripheral vascular resistance (OPSS), the tone of smooth muscles, strengthens the coronary, cerebral and renal blood flow, reduces heart rate (Heart rate).

The antiarrhythmic effect is caused by the suppression of the ionized calcium transport in the heart tissues, which leads to an increase in the effective refractory period and prolongation of the time spent in the atrioventricular (AV) node (has clinical significance in patients with sinus node weakness syndrome, elderly patients whose calcium channel blockade may prevent the generation of a pulse in the sinus node and cause a sinoatrial (SA) blockade .Normal atrial action potential or intraventricular conduction (the normal sinus rhythm is usually unaffected), but with a decrease in the amplitude of atrial contraction, the rate of depolarization and the rate of conduction decrease.The anterograde effective refractory period in additional bypass beams of conduction may be shortened.The antianginal effect is due to the expansion of peripheral vessels,and decrease in systemic arterial pressure (afterload), which leads to a decrease in myocardial wall tension and its oxygen demand. 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.

Antihypertensive action is caused by dilatation of resistive vessels and a decrease in OPSS. The degree of decrease in blood pressure (BP) correlates with its baseline level (in "normotonics" there is a minimal effect on blood pressure). Reduction of blood pressure is noted in both the "lying" and "sitting" positions. 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, coronary heart disease, hypertrophic cardiomyopathy, reduces platelet aggregation.

Has a minimal effect on the smooth muscles of the gastrointestinal tract (GIT). 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 maximum severity of the hypotensive effect is achieved within 2 weeks.

Pharmacokinetics:

- suction: when ingested quickly and almost completely absorbed in the gastrointestinal tract,intestinal tract (GIT) - 90%. The maximum concentration in the blood plasma is reached in 4-6 hours after administration. Values of plasma concentrations in individual patients are very different.

- distribution: the connection with plasma proteins is 70-80%. The volume of distribution of the drug in the body is about 5.3 l / kg body weight. Penetrates into breast milk.

- metabolism: is subjected to intensive metabolism in the liver by deacetylation and demethylation (with the participation of isoenzymes CYP3A4, CYP3A5 and CYP3A7) with the formation of an active metabolite of deacetylldithiasem, which is determined in plasma 5-10 times less than that of diltiazem, and has 2-4 times less activity. The therapeutic concentration is 20-40 ng / ml. Bioavailability - 40% (the effect of "first passage" through the liver).

- excretion: It is excreted from the body through the intestine with bile (65%), and to a lesser extent by the kidneys (35%). The half-life of plasma is 3.2-6.6 hours. 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 the half-life is prolonged. In the elderly also can be reduced clearance diltiazem.

It is not excreted in hemodialysis and peritoneal dialysis.

Indications:Arterial hypertension; prevention of angina attacks, including Prinzmetal angina pectoris; prevention of attacks of supraventricular arrhythmias (paroxysmal tachycardia, flicker or atrial flutter).

Contraindications:

If you have any of these diseases, consult a doctor before taking the drug.

Hypersensitivity to the drug and other benzothiazepine derivatives, lactose intolerance, lactase deficiency and glucose-galactose malabsorption, cardiogenic shock, sinoatrial and atrioventricular blockade of grade II and III (with the exception of patients with a pacemaker), Wolff-Parkinson-White syndrome, Launa- Ganong-Levin combined with flutter or atrial fibrillation (except for patients with a pacemaker), chronic heart failure (in the stage of decompensation), acute heart failure, in Myocardial infarction with signs of left ventricular failure, sinus node weakness syndrome without the use of an artificial pacemaker, pronounced arterial hypotension (systolic BP less than 90 mmHg), pronounced bradycardia, ventricular tachycardia with a wide QRS complex, pregnancy, lactation, age under 18 years (efficiency and safety not established).

Carefully:

If you have any of these diseases, consult a doctor before taking the drug.

Caution should be used in patients with severe impairment of liver and kidney function, acute porphyria, severe stenosis of the aortic orifice, mild to moderatedegree of arterial hypotension, atrioventricular blockade of the 1st degree, in the acute phase of myocardial infarction (without signs of left ventricular failure), hypertrophic obstructive cardiomyopathy, with simultaneous application with beta-adrenoblockers or digoxin compensated for chronic heart failure, with a tendency to bradycardia, in old age.

Diltiazem reduces the conductance of the myocardium, so it is with particular caution prescribed to patients with AV blockade of the I degree and with bradycardia. Caution is also needed when appointing patients with a violation of the function of the left ventricle of the heart.

Diltiazem with caution appoint patients already receiving other drugs, in particular, blockers β-adrenergic receptors for oral administration. In this group of patients, the treatment process should be carried out under the close supervision of the cardiologist!

Diltiazem with caution appoint to patients with renal or hepatic insufficiency; In this group of patients, if necessary, reduce the prescribed doses of the drug and control the urea content in the urine, creatinine, and liver function.In patients with impaired liver function, the daily dose should not exceed 90 mg and it is recommended to regularly monitor liver function. For elderly patients, the standard dose should be adjusted.

As diltiazem reduces overall peripheral vascular resistance and can cause secondary arterial hypotension, it is necessary to monitor blood pressure, in particular, at the beginning of the course treatment, while therapeutic doses are not yet specified.

In the case of persistent skin rashes, growing in polymorphic erythema and exfoliative dermatitis - the drug should be discontinued.

If during the therapy the patient is required to undergo surgery under general anesthesia, it is necessary to inform the anesthetist about the nature of the therapy. In elderly patients, the half-life of diltiazem may increase.

Pregnancy and lactation:

With caution should be used in patients with severe violations of the liver and kidney function, acute porphyria, severe stenosis of the aortic aorta, mild or moderate degree of arterial hypotension, atrioventricular blockade of the I degree,in the acute phase of myocardial infarction, (without signs of left ventricular failure), hypertrophic obstructive cardiomyopathy, with simultaneous use with beta-adrenoblockers or digoxin compensated for chronic heart failure, with a tendency to bradycardia, in old age.

Dosing and Administration:

Tablets are taken orally, wholly, with a small amount of water. Tablets can not be crushed or chewed.

Usually appoint 90 mg (1 tablet) 2 times a day. The average daily dose is 180-240 mg. The maximum daily dose is 360 mg. Correction of the dosing regimen can be carried out only after two weeks.

Side effects:

The most frequently observed (in many cases, the relationship with the drug is not established): edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash ( 1,3%), asthenia (1,2%).

With a frequency of less than 1%: from the cardiovascular system: stenocardia, arrhythmia, bradycardia (less than 50 / min) or tachycardia, AV blockade, bundle branch blockade, development or exacerbation of heart failure, changes in the electrocardiogram, blood flushes,marked decrease in blood pressure, palpitations, fainting, orthostatic hypotension, ventricular extrasystole.

From the digestive system: dryness of the oral mucosa, anorexia, constipation or diarrhea, a taste disorder, dyspepsia, a moderate increase in the activity of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, thirst, vomiting, weight gain, hepatitis.

From the central nervous system and sensory organs: headache, general weakness, asthenia, fatigue, anxiety, dizziness, drowsiness, insomnia, depression, condition of pathological fear, extrapyramidal disorders, parkinsonism (ataxia, "masked" face, shuffling gait, stiffness of hands or feet, trembling of hands and fingers, difficulty swallowing);

When used in high doses - paresthesia, visual impairment (transient blindness).

Allergic reactions: reactions of increased photosensitivity, itching, skin rash, hyperemia of the facial skin. Very rarely - polymorphic erythema, exfoliative dermatitis.

Other: amblyopia, increased activity of creatine phosphokinase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, convulsions muscle, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual dysfunction, ringing in the ears.

Postmarketing experience: allergic reactions, alopecia, angioedema, including edema of the face and periorbital edema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis, extrapyramidal syndrome, gingival hyperplasia, hemolytic anemia, lengthening bleeding time, leukopenia, purpura, retinopathy, myopathy, thrombocytopenia, exfoliative dermatitis.

There were cases of generalized rash, which in some cases was a manifestation of leukocytoclastic. vasculitis; reported cases of myocardial infarction, which is not always easy to distinguish from the manifestations of the existing disease.

If any of the side effects indicated in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

Symptoms: bradycardia, marked decrease in blood pressure, which leads to collapse, violation of atrioventricular conduction, heart failure, cardiogenic shock, asystole.

Treatment: gastric lavage, Activated carbon, symptomatic therapy.

When AV blockade II and III degree - atropine in / in (0.6-1.0 mg). If the reaction is unsatisfactory, isoprenaline. With arterial hypotension - increase fluid intake and prescribe vasoconstrictor. With heart failure symptomatic therapy, diuretics, drugs with a positive inotropic effect. Hemodialysis and peritoneal dialysis are ineffective.

Interaction:

Simultaneous use of diltiazem with antihypertensive drugs can lead to a sharp decrease in blood pressure.

Diltiazem has a suppressive effect on the cardiac conduction system, in particular AV transmission, therefore, this interaction should be kept in mind when it is concomitantly administered with cardiodepressive drugs and / or with beta-blockers or antiarrhythmics, since there may be a mutual enhancement of pharmacological effects.

When used simultaneously with adenosine, increased risk of developingprolonged bradycardia.

Salicylates additionally inhibit the ability to aggregate platelets.

Simultaneous use with ethanol can lead to an additional vasodilating effect.

The risk of myopathy and rhabdomyolysis increases with the simultaneous use of diltiazem with statins metabolized via CYP3A4 (for example, atorvastatin, lovastatin, fluvastatin, and simvastatin).

Simultaneous use with cimetidine leads to a significant increase in plasma concentrations of diltiazem, which in turn can lead to its toxic effect on the cardiovascular system.

Diltiazem increases the concentration of theophylline and carbamazepine in blood plasma (40-70%) and increases the risk of adverse reactions, including. ataxia, nystagmus, diplopia, headache, vomiting, confusion, and increases the concentrations of cyclosporine, digoxin (up to 50%), imipramine, lithium and midazolam.

Increased the effect of hypoglycemic agents for oral administration (eg, clorppropamide and glipizide).

With the simultaneous use of diltiazem and cyclosporine in patients with a transplanted kidney, it is possible to develop intoxication last, paresthesia.Therefore, it is necessary to closely monitor the plasma concentrations of cyclosporine in this group of patients. Food intake increases the absorption and bioavailability of diltiazem up to 20-30%.

Procainamide, quinidine and other drugs that cause prolongation of the QT interval, increase the risk of its significant lengthening.

May increase the bioavailability of propranolol.

Means for inhalation anesthesia (derivatives of hydrocarbons), thiazide diuretics and other drugs that reduce blood pressure increase the hypotensive effect of diltiazem.

Phenobarbital, diazepam, rifampicin reduce the concentration of diltiazem.

Increases the concentration in the blood of quinidine, valproic acid (a dose reduction may be required).

The simultaneous administration of nitrates (including prolonged forms) is possible.

Strengthens the cardiodepressive effect of general anesthetics.

Lithium preparations can enhance the neurotoxic effect of diltiazem (nausea, vomiting, diarrhea, ataxia, tremor and / or tinnitus).

Indomethacin and other non-steroidal anti-inflammatory drugs, glucocorticosteroids and estrogens, as well as symptomatic drugs, reduce the hypotensive effect.

With the simultaneous use of diltiazem and inducers CYP3A4 (phenytoin), it is possible to reduce the level of diltiazem in serum.

Simultaneous use with moracizin leads to an increase in the concentration of moracisin and a decrease in the concentration of diltiazem in the blood.

Simultaneous use of diltiazem with antipsychotic drugs can enhance the hypotensive effect.

When used simultaneously with nifedipine diltiazem slows the excretion of nifedipine from the body by 50%.

Antiviral drugs (atazanavir, ritonavir): increase in diltiazem concentration in blood plasma.

Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Particular attention should be paid to the administration of short-acting benzodiazepines metabolized via CYP3A4 in patients receiving diltiazem.

Special instructions:

Features of the drug at the first reception:

Features of the drug during its cancellation:

Do not stop taking the medication until the doctor notifies you. It is very important not to stop taking the drug, even if you feel better. If you stop taking the pill without a doctor's advice, your condition may get worse.

Features of the actions of a doctor (paramedic), a patient with a missed intake of one or more doses of the drug:

It is necessary to take the missed dose as soon as an omission is discovered. Then continue the reception according to the established scheme. Do not take a double dose to make up for the missed appointment.

Effect on the ability to drive transp. cf. and fur:Until now, it has not been established that taking diltiazem in recommended doses affects the motor and mental activity of the patient. In patients with hypersensitivity, it can (in particular at the beginning of the course of treatment) cause excessive lowering of blood pressure, dizziness and a transient decrease in the ability to drive vehicles.

Form release / dosage:

Tablets of prolonged action of 90 mg.

Packaging:

10 tablets per blister are perforated from aluminum foil and PVC film.

3 blisters (30 tablets) are placed in a cardboard box together with instructions for use.

Storage conditions:

In the dark place at a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:3 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N016190 / 01

Date of registration:13.11.2009

The owner of the registration certificate:Alkaloid, JSCAlkaloid, JSC Macedonia

Manufacturer: & nbsp

ALKALOID, AD Macedonia

Representation: & nbspALKALOID, AOALKALOID, AO

Information update date: & nbsp26.12.15

Illustrated instructions

Instructions

Diltiazem (Diltiazem)