Logimax (long-acting tablet 5mg/50mg No. 30)

A country

Sweden
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Active substance

Metoprolol + Felodipine

Compound

Active ingredients: felodipine + metoprolol.

pharmachologic effect

Hypotensive. Blocks myocardial beta1-adrenergic receptors (metoprolol) and inhibits the entry of calcium ions into vascular smooth muscle cells (felodipine). Completely absorbed from the gastrointestinal tract. The half-life of felodipine is 25 hours, metoprolol is 3-5 hours. The active substances are metabolized in the liver. Metoprolol reduces the stimulating effect of catecholamines on the myocardium, cardiac output and blood pressure. Felodipine relaxes the smooth muscles of the vascular wall, reduces total peripheral vascular resistance and potentiates (mutually) metoprolol-induced hypotension. The hypotensive effect is stable for 24 hours.

Indications for use

Hypertension, symptomatic arterial hypertension.

Mode of application

Inside, in the morning, without chewing, with liquid, 1 tablet. 1 time per day; if necessary, 1 table. 2 times a day.

Interaction

Calcium channel blockers such as verapamil potentiate the negative ino- and chronotropic effect. It enhances the negative ino- and dromotropic effect of antiarrhythmic drugs (quinidine analogues, amiodarone), and the cardiodepressive effect of inhalational anesthetics. The concentration of metoprolol in plasma is increased by cimetidine, hydralazine, and alcohol, and decreased by rifampicin. Indomethacin and other prostaglandin synthetase inhibitors weaken the hypotensive effect.

Side effect

From the nervous system and sensory organs: headache, weakness, dizziness, paresthesia, depression, decreased concentration, drowsiness or insomnia, nervousness, anxiety, blurred vision, dry or irritated eyes, conjunctivitis, amnesia, confusion, hallucinations, noise in ears, impaired taste. From the cardiovascular system and blood (hematopoiesis, hemostasis): facial flushing, bradycardia, palpitations, postural disturbances, cold extremities, peripheral edema, tachycardia, AV block of the first degree, pain in the heart, syncope, gangrene in patients with severe peripheral circulatory disorders, thrombocytopenia. From the respiratory system: shortness of breath on exertion, rhinitis. From the gastrointestinal tract: nausea, abdominal pain, diarrhea or constipation, vomiting, weight loss; dry mouth, changes in liver function tests, hyperplasia of the mucous membrane, increased concentration of liver enzymes. From the genitourinary system: impotence, sexual dysfunction. From the musculoskeletal system: myalgia, arthralgia. From the skin: rash (in the form of urticaria psoriasiform ), dystrophic skin lesions, hair loss; photosensitivity. Allergic reactions: angioedema.

Contraindications

Hypersensitivity, acute myocardial infarction, unstable angina, severe sinus bradycardia, AV block II-III degree, sick sinus syndrome, severe peripheral circulatory disorders, decompensated heart failure, cardiogenic shock, pregnancy, breastfeeding.

Overdose

Symptoms: hypotension, sinus bradycardia, AV block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, nausea, vomiting, cyanosis. Treatment: induction of vomiting, gastric lavage; symptomatic therapy.

special instructions

Should not be prescribed to patients with suspected acute myocardial infarction, with a heart rate less than 45 beats/min, with systolic blood pressure less than 100 mm Hg. Careful medical supervision is required when used simultaneously with ganglion blockers, other beta-blockers, and MAO inhibitors. When used concomitantly with clonidine and it is necessary to discontinue the latter, treatment with Logimax should be interrupted several days before discontinuation of clonidine. Before surgery, you should warn the anesthesiologist about taking the drug. Cancel gradually, over 1.5-2 weeks.

Dispensing conditions in pharmacies

On prescription

Logimax, prolong tablets. covered. captivity. about. 50 mg+5 mg, 30 pcs.

Toxicity

When using felodipine at a dose of 10 mg in a 2-year-old child, minor intoxication was noted. Felodipine at a dose of 150-200 mg in a 17-year-old patient and at a dose of 250 mg in an adult caused minor to moderate toxicity. It is likely that felodipine has a more significant effect on the peripheral circulation than on the heart, compared with other drugs in this therapeutic group.

Metoprolol at a dose of 7.5 g in an adult caused intoxication with a fatal outcome. A 5-year-old child who took 100 mg of metoprolol showed no signs of intoxication after gastric lavage. Taking metoprolol at a dose of 450 mg by a 12-year-old child resulted in moderate intoxication. Administration of metoprolol at doses of 1.4 g and 2.5 g to adults caused moderate and severe intoxication, respectively. Taking metoprolol in a dose of 7.5 g by adults led to extremely severe intoxication.

Symptoms

In case of overdose with long-acting drugs, symptoms of intoxication appear 12-16 hours after administration; severe symptoms may occur several days after administration.

With an overdose of felodipine, the greatest effect on the cardiovascular system is observed: bradycardia (sometimes tachycardia), marked decrease in blood pressure, AV block, ventricular extrasystole, atrioventricular dissociation, asystole, ventricular fibrillation, headache, dizziness, impaired consciousness (or coma) , convulsions, shortness of breath, pulmonary edema (not cardiac) and apnea; possible development of respiratory distress syndrome in adults; acidosis, hypokalemia, hyperglycemia, hypocalcemia, hot flashes, hypothermia, nausea and vomiting.

In case of an overdose of metoprolol, the most serious symptoms are from the cardiovascular system, but sometimes, especially in children and adolescents, symptoms from the central nervous system and suppression of pulmonary function, bradycardia, AV block I-III degrees, asystole, a pronounced decrease in blood pressure, may predominate. weak peripheral perfusion, heart failure, cardiogenic shock, depression of pulmonary function, apnea, as well as increased fatigue, impaired consciousness, loss of consciousness, tremor, convulsions, increased sweating, paresthesia, bronchospasm, nausea, vomiting, possible esophageal spasm, hypoglycemia (especially in children) or hyperglycemia, hyperkalemia; effects on the kidneys; transient myasthenic syndrome. Concomitant use of alcohol, antihypertensive drugs, quinidine or barbiturates may worsen the patient's condition. The first signs of overdose can be observed 20 minutes - 2 hours after taking the drug.

Treatment

Felodipin

The administration of activated carbon, and, if necessary, gastric lavage, is in some cases effective even at the late stage of intoxication. Symptomatic therapy is carried out.

Atropine (0.25-0.5 mg IV for adults, 10-20 mcg/kg for children) should be given before gastric lavage (due to the risk of vagus nerve stimulation). ECG monitoring is carried out. If necessary, maintain airway patency and adequate ventilation. Correction of acid-base status and serum electrolytes is indicated. In case of bradycardia and AV blockade, atropine 0.5-1 mg is prescribed intravenously for adults (20-50 mcg/kg for children), repeat the administration if necessary, or isoprenaline is initially administered at a dose of 0.05-0.1 mcg/kg/min. In case of acute intoxication at an early stage, it may be necessary to install an artificial pacemaker. Arterial hypotension is corrected with intravenous fluid administration. If necessary, adrenaline or dopamine is infused. In case of acute intoxication, glucagon may be prescribed. Cardiac arrest due to an overdose may require resuscitation for several hours. For convulsions, diazepam is prescribed. Other symptomatic treatment is carried out.

Metoprolol

Prescription of activated carbon and, if necessary, gastric lavage.

Atropine (0.25-0.5 mg IV for adults, 10-20 mcg/kg for children) should be given before gastric lavage (due to the risk of vagus nerve stimulation). If necessary, maintain airway patency (intubation) and adequate ventilation. Replenishment of blood volume and glucose infusion. ECG monitoring is carried out. Prescribe atropine at a dose of 1-2 mg IV, repeat the administration if necessary (especially in the case of vagal symptoms). In case of (suppression of) myocardial depression, infusion of dobutamine or dopamine is indicated. You can also use glucagon at a dose of 50-50 mcg/kg IV at intervals of 1 minute. In some cases, adding epinephrine to therapy may be effective. For arrhythmia and a widened ventricular (QRS) complex, solutions of sodium chloride or sodium bicarbonate are infused. It is possible to install an artificial pacemaker. Cardiac arrest due to an overdose may require resuscitation for several hours. Terbutaline (injected or inhaled) can be used to relieve bronchospasm. Symptomatic treatment is carried out.

Logimax® (Logimax)

Co-administration with substances that interact with the cytochrome P450 enzyme system may affect the concentration of felodipine and metoprolol in the blood plasma. There is no interaction between felodipine and metoprolol, since they are metabolized by various isoenzymes of the cytochrome P450 system.

Felodipin

Felodipine is a substrate for CYP3A4. Drugs that induce or inhibit CYP3A4 have a significant effect on felodipine plasma concentrations.

Drugs that induce isoenzymes of the cytochrome P450 system (phenytoin, carbamazepine, phenobarbital and rifampicin, as well as St. John's wort tincture) increase the metabolism of felodipine. The combined use of phenytoin, carbamazepine, phenobarbital and rifampicin leads to a decrease in felodipine AUC by 93% and Cmax by 82%. Co-administration with CYP3A4 inducers should be avoided.

Azole antifungals (itraconazole, ketoconazole), macrolide antibiotics (eg, erythromycin) and HIV protease inhibitors are inhibitors of the CYP3A4 enzyme system. When co-administered with itraconazole, the Cmax of felodipine increases by 8 times, and the AUC by 6 times. When erythromycin is co-administered, the Cmax and AUC of felodipine increases approximately 2.5 times. Co-administration of felidipine and CYP3A4 inhibitors should be avoided.

Grapefruit juice inhibits the CYP3A4 enzyme system. The use of felodipine with grapefruit juice increases the Cmax and AUC of felodipine by approximately 2 times. Concomitant use should be avoided.

Felodipine may cause an increase in tacrolimus plasma concentrations. When used together, it is recommended to monitor the concentration of tacrolimus in the blood serum; a dose adjustment of tacrolimus may be required.

When cyclosporine and felodipine are co-administered, Cmax of felodipine increases by 150%, AUC increases by 60%. However, the effect of felodipine on the pharmacokinetic parameters of cyclosporine is minimal.

The combined use of cimetidine and felodipine leads to an increase in Cmax and AUC of felodipine by 55%.

Metoprolol

Co-administration of Logimax with the following drugs should be avoided:

Barbiturates (study conducted with phenofarbital) slightly increase the metabolism of metoprolol due to enzyme induction.

When propafenone was prescribed to 4 patients treated with metoprolol, there was an increase in the plasma concentration of metoprolol by 2-5 times, while 2 patients experienced side effects characteristic of metoprolol. This interaction was confirmed in a study on 8 volunteers. The interaction is likely due to propafenone's inhibition, like quinidine, of the metabolism of metoprolol via the CYP2D6 isoenzyme. Taking into account the fact that propafenone has beta-blocker properties, the joint administration of Logimax and propafenone does not seem appropriate.

The combination of beta-blockers (atenolol, propranolol and pindolol) and verapamil can cause bradycardia and lead to a decrease in blood pressure. Verapamil and beta-blockers have complementary inhibitory effects on AV conduction and sinus node function.

The combination of Logimax with the following drugs may require dose adjustment.

Class I antiarrhythmics and beta blockers may result in additive negative inotropic effects, which may lead to serious hemodynamic side effects in patients with impaired left ventricular function. This combination should also be avoided in patients with sick sinus syndrome and impaired AV conduction. The interaction is described using disopyramide as an example.

Diphenhydramine reduces the clearance of metoprolol to α-hydroxymetoprolol by 2.5 times. At the same time, an increase in the effect of metoprolol is observed.

Hypertensive reactions during abrupt withdrawal of clonidine may be exacerbated by concomitant use of beta-blockers. When used together, if clonidine is discontinued, discontinuation of beta-blockers should begin several days before discontinuation of clonidine.

Diltiazem and beta-blockers mutually enhance the inhibitory effect on AV conduction and sinus node function. When metoprolol was combined with diltiazem, cases of severe bradycardia were observed.

NSAIDs weaken the antihypertensive effect of beta-blockers. This interaction is best documented for indomethacin. There is no reported interaction observed for sulindac. In studies with diclofenac, the described reaction was not observed.

Phenylpropanolamine (norephedrine) in a single dose of 50 mg can cause an increase in diastolic blood pressure to pathological values in healthy volunteers. Propranolol mainly prevents the increase in blood pressure caused by phenylpropanolamine. However, beta-blockers may cause paradoxical hypertension reactions in patients receiving high doses of phenylpropanolamine. Several cases of hypertensive crisis have been reported while taking phenylpropanolamine.

Ten cases of severe hypertension and bradycardia have been reported in patients taking non-selective beta blockers (including pindolol and propranolol) and receiving epinephrine (adrenaline). The interaction was also observed in the group of healthy volunteers. It is assumed that similar reactions can be observed when epinephrine is used together with local anesthetics if it accidentally enters the vascular bed. It is assumed that this risk is much lower with the use of cardioselective beta-blockers.

Quinidine inhibits the metabolism of metoprolol in a special group of patients with rapid hydroxylation (in Sweden, approximately 90% of the population), causing mainly a significant increase in plasma concentrations of metoprolol and increased beta-adrenergic receptor blockade. It is believed that such an interaction is also typical for other beta-blockers, the metabolism of which involves the CYP2D6 isoenzyme.

The combined use of amiodarone and metoprolol can lead to severe sinus bradycardia. Taking into account the extremely long T1/2 of amiodarone (50 days), the possible interaction should be considered long after discontinuation of amiodarone.

Rifampicin may increase the metabolism of metoprolol, reducing plasma concentrations of metoprolol.

The concentration of metoprolol in the blood plasma may increase when combined with cimetidine, hydralazine, selective serotonin inhibitors such as paroxetine, fluoxetine and sertraline.

Patients concomitantly taking metoprolol and other beta-blockers (eye drops) or MAO inhibitors should be closely monitored.

While taking beta-blockers, inhalational anesthetics enhance the cardiodepressive effect.

While taking beta-blockers, patients receiving oral hypoglycemic agents may require dose adjustment of the latter.

Logimax®

Co-administration with drugs that interact with the cytochrome P450 enzyme system may affect the concentration of metoprolol and felodipine in the blood plasma. There is no interaction between metoprolol and felodipine, since they are metabolized by various isoenzymes of the cytochrome P450 system.

Interactions with metoprolol

Metoprolol is a substrate for the CYP2D6 isoenzyme. Medicines that inhibit CYP2D6, such as quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine, may alter the plasma concentrations of metoprolol. It may be necessary to reduce the dose of Logimax® when used in combination with these drugs.

Quinidine:

Quinidine inhibits the metabolism of metoprolol in a special group of patients with “rapid” hydroxylation (in Sweden, approximately 90% of the population), causing mainly a significant increase in plasma concentrations of metoprolol and increased beta-blockade. It is believed that a similar interaction is typical for other beta-blockers, the metabolism of which involves cytochrome P4502D6.

Propaphenone:

when using propafenone in 4 patients treated with metoprolol, there was an increase in the plasma concentration of metoprolol by 2-5 times, while 2 patients had side effects characteristic of metoprolol. This interaction was confirmed in a study in 8 volunteers. The interaction is likely due to propafenone's inhibition, like quinidine, of the metabolism of metoprolol via the cytochrome P4502D6 system. Taking into account the fact that propafenone has beta-blocker properties, the combined use of Logimax® and propafenone does not seem appropriate.

Diphenhydramine:

diphenhydramine reduces the clearance of metoprolol to alpha-hydroxymetoprolol by 2.5 times. At the same time, an increase in the effect of metoprolol is observed.

Antiarrhythmics
:
Class I antiarrhythmics and beta-blockers, when used concomitantly, may result in additive negative inotropic effects, leading to serious hemodynamic side effects in patients with left ventricular dysfunction. The use of this combination should also be avoided in patients with sick sinus syndrome and impaired AV conduction. The interaction is described using disopyramide as an example.

Barbituric acid derivatives:

barbiturates (the study was conducted with phenobarbital) slightly increase the metabolism of metoprolol due to the induction of microsomal liver enzymes.

Nonsteroidal anti-inflammatory drugs (NSAIDs):

NSAIDs weaken the antihypertensive effect of beta-blockers. This interaction has been most studied for indomethacin. No reported interaction was observed for sulindac. This reaction was not observed in studies with diclofenac.

Phenylpropanolamine:

Epinephrine:

10 cases of severe hypertension and bradycardia were reported in patients taking non-selective beta-blockers (including pindolol and propranolol) and receiving epinephrine. The interaction was also observed in the group of healthy volunteers. It is assumed that similar reactions can be observed when epinephrine is used together with local anesthetics if it accidentally enters the vascular bed. It is assumed that this risk is much lower with the use of cardioselective beta-blockers.

Amiodarone:

Concomitant use of amiodarone and metoprolol can lead to severe sinus bradycardia. Given the extremely long half-life of amiodarone (50 days), a possible interaction should be considered long after discontinuation of amiodarone.

Rifampicin:

Rifampicin may increase the metabolism of metoprolol, reducing plasma concentrations of metoprolol.

Clonidine:

The increase in blood pressure upon abrupt withdrawal of clonidine may be more pronounced when taken together with beta-blockers. When used together, if clonidine is discontinued, discontinuation of beta-blockers should begin several days before discontinuation of clonidine.

Verapamil and diltiazem:

when beta-blockers are used together with BMCCs such as verapamil and diltiazem, an increase in negative inotropic and chronotropic effects may be observed. BMCCs such as verapamil should not be administered intravenously.

Cardiac glycosides:

in combination with beta-blockers, they can disrupt AV conduction and cause bradycardia.

The concentration of metoprolol in blood plasma may increase when combined with cimetidine, hydralazine, selective serotonin reuptake inhibitors such as paroxetine, fluoxetine and sertraline. Patients concomitantly taking metoprolol and other beta-blockers (in the form of eye drops) or monoamine oxidase inhibitors (MAOIs) should be closely monitored. While taking beta-blockers, inhalational anesthetics enhance the cardiodepressive effect. While taking beta-blockers, patients receiving oral hypoglycemic agents may require dose adjustment of the latter.

Interactions with felodipine

Felodipine is a substrate for the CYP3A4 isoenzyme. Drugs that induce or inhibit the CYP3A4 isoenzyme have a significant effect on the plasma concentration of felodipine.

Drugs that induce the cytochrome P450 system:

phenytoin, carbamazepine, phenobarbital and rifampicin, as well as St. John's wort preparations enhance the metabolism of felodipine due to the induction of the cytochrome P450 system. The combined use of phenytoin, carbamazepine, phenobarbital and rifampicin leads to a decrease in the area under the concentration-time curve (AUC) by 93% and Cmax of felodipine by 82%. Avoid combined use with inducers of the CYP3A4 isoenzyme.

Drugs that inhibit the cytochrome P450 system:

Azole antifungals (itraconazole, ketoconazole), macrolide antibiotics (for example, erythromycin, clarithromycin) and HIV protease inhibitors are inhibitors of the CYP3A4 isoenzyme. When used together with itraconazole, felodipine Cmax increases 8 times, AUC increases 6 times. When co-administered with erythromycin, the Cmax and AUC of felodipine increase approximately 2.5-fold. The combined use of felodipine and inhibitors of the CYP3A4 isoenzyme should be avoided.

Grapefruit juice inhibits the enzyme system of the CYP3A4 isoenzyme. The use of felodipine with grapefruit juice increases the Cmax and AUC of felodipine by approximately 2 times. Concomitant use should be avoided.

Tacrolimus:

felodipine may cause an increase in tacrolimus plasma concentrations. When used together, it is recommended to monitor the concentration of tacrolimus in the blood serum; a dose adjustment of tacrolimus may be required.

Cyclosporine:

when cyclosporine and felodipine are used together, felodipine Cmax increases by 150%, AUC increases by 60%. However, the effect of felodipine on the pharmacokinetic parameters of cyclosporine is minimal.

Cimetidine:

The combined use of cimetidine and felodipine leads to an increase in Cmax and AUC of felodipine by 55%.