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Tarka®

Interactions due to verapamil:

In vitro studies

indicate that verapamil is metabolized by the isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 of cytochrome P450.

Verapamil is an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein. Clinically significant interactions were observed with simultaneous use with inhibitors of the CYP3A4 isoenzyme, and an increase in the concentration of verapamil in the blood plasma was observed, while inducers of the CYP3A4 isoenzyme decreased the concentration of verapamil in the blood plasma. Accordingly, when using such agents simultaneously, the possibility of this interaction should be taken into account.

Co-administration of trandolapril/verapamil and a drug that is primarily metabolized by CYP3A4 or is a P-gp substrate may be accompanied by an increase in the concentration of such drug. This may result in increased or prolonged duration of both therapeutic and side effects of the drug used in conjunction with trandolapril/verapamil.

The table summarizes the data on drug interactions caused by verapamil content.

Other possible interactions with verapamil

Dabigatran

When dabigatran etexilate was co-administered with verapamil administered orally, the Cmax and AUC values ​​of dabigatran increased depending on the time of use and the dosage form of verapamil. The greatest increase in dabigatran values ​​was observed when the first dose of immediate-release verapamil was taken 1 hour before dabigatran etexilate (Cmax increased by 180% and AUC increased by 150%).

When using the sustained release formulation of verapamil, this effect was progressively reduced (Cmax increased by 90% and AUC by 70%), as well as when using multiple doses of verapamil (Cmax increased by 60% and AUC by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil.

When verapamil was administered 2 hours after taking dabigatran etexilate, no clinically significant interaction was observed (Cmax increased by 10% and AUC by 20%), since dabigatran was completely absorbed after 2 hours. In a study in patients with atrial fibrillation, dabigatran concentrations increased by no more than 21%, and no increase in the risk of bleeding was observed.

There are no data on the interaction of dabigatran etexilate with verapamil administered parenterally; no clinically significant interaction is expected.

With regard to the prolongation of blood coagulation, the use of verapamil, as a rule, did not affect the plasma concentration-effect relationship of dabigatran. No unexpected safety data were obtained when dabigatran etexilate was co-administered with verapamil.

Drugs that bind to plasma proteins

Verapamil, as a drug that is highly bound to plasma proteins, should be used with caution when taken simultaneously with other drugs that have a similar ability. It is possible to increase the concentrations in the blood plasma of drugs characterized by a high degree of protein binding (including coumarin and indanedione derivatives, non-steroidal anti-inflammatory drugs, quinine, salicylates, sulfinpyrazone).

Flecainide

A study involving healthy volunteers showed that the combined use of verapamil and flecainide may have an additive effect with a decrease in myocardial contractility, a slowdown in atrioventricular conduction and myocardial repolarization.

Disopyramide

Pending data on a possible interaction between verapamil and disopyramide, disopyramide should not be administered 48 hours before or 24 hours after use.

Ivabradin

Due to its moderate inhibitory effect on CYP3A4, verapamil (at a dose of 120 mg 2 times a day) when used simultaneously led to an increase in the AUC of ivabradine by 2-3 times.

Both verapamil and ivabradine are heart rate depressants and, therefore, co-administration may worsen the patient's heart rate. The simultaneous use of verapamil with ivabradine is contraindicated due to the development of an additional negative chronotropic effect.

Procainamide, quinidine and other drugs known to prolong the QT interval

Increased risk of developing QT prolongation.

Valproic acid

Verapamil increases the concentration of valproic acid in the blood due to suppression of metabolism involving cytochrome P450.

Nicotine

Nicotine accelerates metabolism in the liver, leads to a decrease in the concentration of verapamil in the blood, and reduces the severity of antianginal, antihypertensive and antiarrhythmic effects.

Ranitidine

Increases the level of verapamil in the blood plasma.

Calcium preparations

Reduced effectiveness of verapamil.

Sympathomimetics

Sympathomimetics reduce the antihypertensive effect of verapamil.

Estrogens

Estrogens reduce the antihypertensive effect of verapamil due to fluid retention in the body.

Antihypertensives, diuretics, vasodilators

Strengthening the antihypertensive effect.

Medicines for the treatment of HIV infection

Some drugs used to treat HIV infection, such as ritonavir, may inhibit the metabolism of verapamil, resulting in increased plasma concentrations of verapamil. Caution should be exercised or the dose of verapamil should be reduced.

Lithium

Increased lithium neurotoxicity has been observed during concomitant administration of verapamil and lithium, with no change or increase in serum lithium concentrations. However, additional administration of verapamil also led to a decrease in serum lithium concentrations in patients regularly taking lithium by mouth. Patients taking both drugs should be closely monitored.

β-blockers for intravenous administration

β-blockers for intravenous administration should not be used during treatment with Tarka® (see section "Contraindications"). Combined treatment with verapamil and beta-blockers can cause severe impairment of AV conduction, which, in some cases, can cause the development of severe bradycardia and cardiac depression.

Muscle relaxants

The effect of muscle relaxants may be enhanced.

Clinical data and preclinical studies suggest that verapamil may enhance the activity of muscle relaxants (such as curare and depolarizing agents).

Dantrolene

In patients susceptible to malignant hyperthermia, intravenous administration of dantrolene with simultaneous administration of calcium channel blockers led to hyperkalemia and myocardial depression.

The simultaneous use of both drugs in the treatment of malignant cardiac tachyarrhythmias caused by hyperthermia should be avoided.

The combination of dantrolene sodium and calcium channel blockers is not recommended in the treatment of malignant hyperthermia.

The combined use of the muscle relaxant dantrolene (IV) and verapamil is potentially dangerous (can cause fatal ventricular fibrillation). Concomitant use of verapamil and dantrolene is not recommended during the treatment of malignant hyperthermia.

In experimental studies in animals, coadministration of verapamil and dantrolene (IV) resulted in fatal ventricular fibrillation. This combination is potentially dangerous.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

When taken together with all antihypertensive drugs, NSAIDs (including acetylsalicylic acid, used in high doses as an anti-inflammatory drug, for example, to relieve pain) may reduce the antihypertensive effect of trandolapril. Increase blood pressure monitoring when adding or discontinuing any NSAID in a patient taking trandolapril.

In addition, NSAIDs and ACE inhibitors have been shown to further increase serum potassium, while renal function may be impaired. This effect is usually reversible and occurs more often in patients with impaired renal function.

NSAIDs, including acetylsalicylic acid, except when acetylsalicylic acid is used as an antiplatelet agent, should not be taken together with ACE inhibitors by patients with heart failure. The simultaneous use of acetylsalicylic acid and verapamil may lead to an increase in the number and severity of adverse events from taking acetylsalicylic acid (the risk of bleeding may increase).

Ethanol (alcohol)

Increased concentration of ethanol in blood plasma. Ethanol increases the risk of developing arterial hypotension.

HMG-CoA reductase inhibitors (statins)

Simvastatin/atorvastatin/lovastatin

In patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin/atorvastatin/lovastatin) should be started with the lowest possible doses and gradually increased during therapy. It has been noted that the simultaneous use of verapamil and high doses of simvastatin increases the risk of developing myopathy/rhabdomyolysis. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors, then it is necessary to review and reduce their doses according to the concentration of cholesterol in the blood serum.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by the CYP3A4 isoenzyme, so their interaction with verapamil is least likely.

Inhalational anesthetics

When inhaled anesthetics and calcium antagonists, such as verapamil hydrochloride, are used concomitantly, the dose should be carefully selected to avoid excessive depression of the cardiovascular system.

Interactions due to trandolapril:

Neutral endopeptidase inhibitors (NEP)

Concomitant use of ACE inhibitors and NEP inhibitors, such as sacubitril (available as a fixed-dose combination with valsartan) and racecadotril, is contraindicated as concomitant inhibition of ACE and neprilysin (neutral endopeptidase, NEP) may increase the risk of angioedema (see Contraindications sections). " and "Special instructions").

The simultaneous use of ACE inhibitors (trandolapril) and dipeptidyl peptidase type IV (DPP-IV) inhibitors (gliptins), for example, sitagliptin, saxagliptin, vildagliptin, linagliptin, may be accompanied by an increased risk of developing angioedema.

The simultaneous use of ACE inhibitors (trandolapril) and racecadotril (an enkephalinase inhibitor used to treat acute diarrhea) may be accompanied by an increased risk of developing angioedema.

The simultaneous use of ACE inhibitors (trandolapril) and estramustine may be accompanied by an increased risk of developing angioedema.

Diuretics

Diuretics or other antihypertensive agents may enhance the antihypertensive effect of trandolapril. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, eplerenone) or potassium supplements may increase the risk of hyperkalemia, especially in patients with renal impairment. Trandolapril may reduce potassium loss when used concomitantly with thiazide diuretics.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients taking co-trimoxazole (trimethoprim/sulfamethoxazole) may have an increased risk of developing hyperkalemia (see section "Special Instructions").

Angiotensin II receptor blockers, aliskiren

Data from clinical trials have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of side effects such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with the use of a single drug acting on the RAAS (see sections “Contraindications”, “Special instructions”).

The simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Hypoglycemic agents

Concomitant use of trandolapril, like any ACE inhibitors, with hypoglycemic agents (insulin or oral hypoglycemic agents) may enhance the hypoglycemic effect and lead to an increased risk of hypoglycemia.

Lithium

Trandolapril may impair lithium excretion. Monitoring the concentration of lithium in the blood serum is necessary.

Gold

There have been reports of rare cases of nitrate-like reactions (symptoms include facial flushing, nausea, vomiting and hypotension) in patients receiving intravenous gold preparations (sodium aurothiomalate) and concomitant use of ACE inhibitors, including Tarka®.

Other

Anaphylactoid reactions have been described when high-flux polyacrylonitrile membranes were used during hemodialysis in patients receiving ACE inhibitors. Patients receiving ACE inhibitors should avoid the use of this type of membrane during hemodialysis.

ACE inhibitors may enhance the antihypertensive effect of some inhalational anesthetics.

Allopurinol, cytostatics, immunosuppressive agents and systemic corticosteroids or procainamide may increase the risk of leukopenia when treated with ACE inhibitors. Antacids may reduce the bioavailability of ACE inhibitors.

The antihypertensive effect of ACE inhibitors may be reduced when sympathomimetics are co-administered. In such cases, careful monitoring is necessary.

As with the use of any other antihypertensive drugs, co-administration of antipsychotics or tricyclic antidepressants increases the risk of developing orthostatic hypotension.

Concomitant use of angiotensin-converting enzyme and mTOR kinase inhibitors (for example, sirolimus, everolimus, temsirolimus) may be accompanied by an increased risk of developing angioedema.

Contraindications to the use of Tarka

Hypersensitivity to trandolapril or any other ACE inhibitor and/or verapamil or any of the excipients; history of angioedema associated with treatment with ACE inhibitors; hereditary/idiopathic angioedema; cardiogenic shock; acute myocardial infarction with complications; AV block II-III degree without a functioning artificial pacemaker; sick sinus syndrome in patients without a functioning artificial pacemaker; decompensated heart failure; atrial fibrillation/flutter in the presence of additional pathways (for example, Wolff-Parkinson-White syndrome); During pregnancy and breastfeeding; simultaneous intravenous use of β-adrenergic receptor blockers (except for the need for intensive care).

Tarka drug overdose, symptoms and treatment

In case of an overdose of Tarka, the following signs and symptoms due to verapamil : hypotension, bradycardia, AV block, asystole and decreased force of heart contractions (as a result of negative inotropic effects). Deaths have been reported due to overdose. trandolapril may occur : severe arterial hypotension, shock, stupor, bradycardia, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, dizziness, anxiety and cough. Treatment : includes supportive measures. Treatment of verapamil hydrochloride overdose includes parenteral calcium supplementation, β-adrenergic stimulation and gastric lavage. Due to the possible delayed absorption of verapamil due to the slow release, patients may require medical observation and hospitalization for up to 48 hours. Verapamil hydrochloride is not eliminated by hemodialysis.

Side effects of Tarka

Adverse reactions of the drug Tarka correspond to known reactions when using its active components or drugs of this group. The most commonly reported symptoms were cough, headache, constipation, vertigo, dizziness and hot flashes. Side effects, spontaneous and obtained during clinical trials, are presented below. For each organ system, adverse reactions are classified as follows depending on the frequency of reports: often (1/100, but ≤1/10), sometimes (1/1000, but ≤1/100), rarely (1/10,000, but ≤ 1/1000), very rare (≤1/10,000), including isolated cases. Disorders of the blood and lymphatic system : very rarely - leukopenia, pancytopenia, thrombocytopenia. Immune system disorders : sometimes - nonspecific allergic reactions; very rarely - increased gammaglobulin levels, nonspecific hypersensitivity. Metabolic and nutritional disorders: sometimes - hyperlipidemia; very rarely - anorexia. Mental disorders : sometimes drowsiness; very rarely - aggressiveness, anxiety, depression, irritability. Central nervous system disorders : often - dizziness, vertigo; sometimes - tremor; rarely - collapse; very rarely - imbalance, insomnia, paresthesia or hyperesthesia, syncope or acute circulatory failure with loss of consciousness, change in taste, weakness. Visual disturbances : very rarely - blurred/blurred vision. From the cardiovascular system : often - hot flashes; sometimes - 1st degree AV block, palpitations; very rarely - angina pectoris, atrial fibrillation, complete AV block of unknown origin, bradycardia, cardiac arrest, cerebral hemorrhage, peripheral edema of unknown origin, hot flashes, heart failure, hypotension, including orthostatic hypotension or blood pressure fluctuations, tachycardia. Respiratory disorders, disorders of the chest and mediastinum : often - cough; very rarely - asthma, bronchitis, dyspnea, congestion in the sinuses of the lungs. Gastrointestinal disorders : often - constipation; sometimes - abdominal pain, diarrhea, gastrointestinal disorders of unknown origin, nausea; very rarely - dry mouth/throat, pancreatitis, vomiting. Disorders of the hepatobiliary system : very rarely - cholestasis, hepatitis, increased levels of γ-glutamyltransferase, lactate dehydrogenase, lipase, jaundice. From the skin and subcutaneous tissue : sometimes - swelling of the face, itching, rash, increased sweating; rarely - alopecia, herpes simplex; very rarely - angioedema, erythema multiforme, exanthema or dermatitis, psoriasis, urticaria. From the musculoskeletal system : very rarely - arthralgia, myalgia, myasthenia. From the kidneys and excretory system : sometimes - polyuria; very rarely - acute renal failure. From the reproductive system and mammary glands : very rarely - gynecomastia, impotence. General disorders : often - headache; sometimes - chest pain; rarely - fatigue or asthenia. Laboratory indicators: sometimes - changes in liver function tests; rarely - hyperbilirubinemia; very rarely - increased levels of potassium, transaminases, alkaline phosphatase in the blood serum. The following adverse reactions have not been reported with Tarka, but are common with ACE inhibitors. From the blood and lymphatic system : decrease in hemoglobin and hematocrit levels; in isolated cases - agranulocytosis. Isolated cases of hemolytic anemia have been reported in patients with congenital glucose-6-phosphate dehydrogenase (G-6-PDH) deficiency. From the mental side : sometimes - confusion. From the nervous system: rarely - sleep disturbance. From the organ of hearing : rarely - disturbance of the sense of balance, ringing in the ears. From the cardiovascular system : isolated cases of arrhythmia, myocardial infarction and transient ischemic attacks, which were associated with arterial hypotension. From the respiratory system : rarely - sinusitis, rhinitis, glossitis and bronchospasm. From the gastrointestinal tract: rarely - indigestion; in isolated cases - intestinal obstruction. From the hepatobiliary system : in isolated cases – cholestatic jaundice. On the part of the skin and subcutaneous tissue : allergic reactions and hypersensitivity reactions sometimes occur, such as Stevens-Johnson syndrome, toxic epidermal necrolysis. These conditions may be accompanied by fever, myalgia, arthralgia, eosinophilia, and/or increased antinuclear antibody (ANA) titers. Laboratory indicators : sometimes increased levels of urea and creatinine in the blood plasma, symptomatic or severe arterial hypotension. The following adverse reactions have not been reported in association with Tarka but are common with phenylalkylamine calcium channel blockers. From the nervous system: extrapyramidal symptoms (Parkinson's disease, choreoathetosis, dystonic syndrome), isolated reports of exacerbation of myasthenia gravis, Lambert-Eaton syndrome and progression of Duchenne muscular dystrophy. From the gastrointestinal tract : gingival hyperplasia. Skin and subcutaneous tissue disorders : cases of Stevens-Johnson syndrome and erythromelalgia have been described. In isolated cases, allergic skin reactions such as erythema occurred. From the reproductive system and mammary glands : the development of hyperprolactinemia and galactorrhea has been described.