Instructions for Lercamen apf 10/10 tablets No. 28
Composition
active ingredients: lercanidipine, enalapril;
Lercamen® ACE 10/10: 1 film-coated tablet contains lercanidipine hydrochloride 10 mg, equivalent to lercanidipine 9.44 mg, and enalapril maleate 10 mg, equivalent to enalapril 7.64 mg;
Lercamen® ACE 10/20: 1 film-coated tablet contains lercanidipine hydrochloride 10 mg, equivalent to lercanidipine 9.44 mg, and enalapril maleate 20 mg, equivalent to enalapril 15.29 mg;
excipients:
lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, sodium bicarbonate, magnesium stearate;
tablet shell Lercamen® ACE 10/10: Opadry 02F29056 (hypromellose, titanium dioxide (E 171), talc, polyethylene glycol);
Tablet coating Lercamen® ACE 10/20: Opadry 02F22330 (hypromellose, titanium dioxide (E 171), talc, polyethylene glycol, quinoline yellow (E 104), iron oxide yellow (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties:
Lercamen® ACE 10/10: white, round, biconvex, film-coated tablets;
Lercamen® ACE 10/20: yellow, round, biconvex, film-coated tablets.
Pharmacotherapeutic group
ACE inhibitors and calcium channel blockers. Enalapril and lercanidipine. ATX code C09B B02.
Pharmacological properties
Pharmacodynamics
Lercamen® ACE inhibitor is a combination drug consisting of lercanidipine hydrochloride (a calcium channel blocker) and enalapril maleate (an ACE inhibitor), two antihypertensive agents with complementary mechanisms of action for the control of blood pressure in patients with essential hypertension.
Enalapril.
Enalapril maleate is the maleic acid salt of enalapril, which is a derivative of the two amino acids L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasopressor angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in plasma angiotensin II levels, which increases plasma renin activity (due to blocking the negative feedback mechanism of renin release) and to a decrease in aldosterone secretion.
Because ACE is identical to kinase II, enalapril may also inhibit the breakdown of bradykinin, a potent vasodepressor peptide. However, the role of this mechanism in the therapeutic action of enalapril has not yet been elucidated.
Although enalapril lowers blood pressure primarily by inhibiting the renin-angiotensin-aldosterone system, it is also effective in patients with low plasma renin levels.
In patients with arterial hypertension, the use of enalapril helps to reduce blood pressure in the supine and standing positions without a significant increase in heart rate.
In rare cases, symptomatic orthostatic hypotension has been observed. In some patients, normalization of blood pressure occurs within several weeks of treatment. Abrupt discontinuation of enalapril does not lead to a sharp increase in blood pressure.
Effective inhibition of ACE activity usually occurs within 2–4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive action is usually observed within 1 hour, with the maximum reduction in blood pressure occurring 4–6 hours after administration. The duration of action is dose-dependent, but at recommended doses, the antihypertensive and hemodynamic effects persist for at least 24 hours.
Hemodynamic studies in patients with essential hypertension have shown that the reduction in blood pressure is associated with a decrease in peripheral vascular resistance and an increase in cardiac output; no or little change in heart rate was observed. After the use of enalapril, renal blood flow increases, while the glomerular filtration rate remains unchanged. There is no evidence of sodium and water retention. However, in patients with low glomerular filtration rate before treatment, the indicators usually increase.
In short-term clinical studies, enalapril was used in diabetic and non-diabetic patients with renal disease to reduce albuminuria and urinary excretion of IgG and total urinary protein.
The combined use of ACE inhibitors and angiotensin II receptor blockers has been investigated in two large, randomized, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)).
These studies did not show a significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared with monotherapy. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
Therefore, the combined use of ACE inhibitors and angiotensin II receptor blockers is not indicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to investigate the benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was stopped early due to an increased risk of adverse events. Cardiovascular mortality and stroke were more common in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more common in the aliskiren group than in the placebo group.
Lercanidipine.
Lercanidipine is a calcium antagonist of the dihydropyridine group that inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of antihypertensive action is based on a direct relaxing effect on vascular smooth muscle, which leads to a decrease in total peripheral resistance. Despite the short half-life of lercanidipine, it has a prolonged antihypertensive effect due to its high membrane distribution coefficient and is devoid of negative inotropic effects due to its high vascular selectivity.
Because the vasodilation caused by lercanidipine develops gradually, acute hypotension with reflex tachycardia is rarely observed in patients with hypertension.
As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to the action of the (S)-enantiomer.
Enalapril/lercanidipine.
The combination of these substances has an additive antihypertensive effect, lowering blood pressure to a greater extent than when each of these components is taken separately.
Lerkamen® APF 10/10
In a pivotal (double-blind) additional phase III clinical study conducted in 342 patients without clinical response to lercanidipine 10 mg (defined as patients with a sitting diastolic blood pressure of 95-114 mmHg and as patients with a sitting systolic blood pressure of 140-189 mmHg), after 12 weeks of double-blind therapy, the residual reduction in sitting systolic blood pressure with the combination of enalapril 10 mg and lercanidipine 10 mg was 5.4 mmHg. higher than when taking lercanidipine alone at a dose of 10 mg (-7.7 mmHg compared to -2.3 mmHg, p (p = 0.032) for diastolic blood pressure in the sitting position. When taking the combination of drugs compared to monotherapy, normalization of systolic (39% compared to 22%, p 140/90 mmHg was observed significantly more often: the dose was increased in 133 patients out of 221, and after its increase, diastolic blood pressure in the sitting position of the patient normalized in ⅓ of the patients.
Lerkamen® APF 10/20
In a pivotal (double-blind) additional phase III clinical study conducted in 327 patients without clinical response to enalapril 20 mg (defined as patients with a sitting diastolic blood pressure of 95–114 mmHg and as patients with a sitting systolic blood pressure of 140–189 mmHg), the residual reduction in sitting systolic blood pressure with the combination of enalapril 20 mg and lercanidipine 10 mg was significantly greater than with monotherapy (-9.8 mmHg versus -6.7 mmHg, p = 0.013). A similar difference was also seen in the residual reduction in sitting diastolic blood pressure (-9.2 mmHg vs. -7.5 mmHg, p = 0.015). The proportion of patients with clinical response was not significantly higher with combination therapy than with monotherapy: 53% vs. 43% (p = 0.076) for sitting diastolic blood pressure and 41% vs. 33% (p = 0.116) for sitting systolic blood pressure. A slightly higher percentage of patients taking the combination therapy had normalization of sitting diastolic (48% vs. 37%, p = 0.055) and sitting systolic blood pressure (33% vs. 28%, p = 0.325) compared with monotherapy.
Pharmacokinetics
No pharmacokinetic interaction was observed when enalapril and lercanidipine were co-administered.
Absorption: After oral administration, enalapril is rapidly absorbed and its maximum serum concentration is reached within 1 hour. Based on the urinary content of enalapril, the extent of its absorption after oral administration as enalapril maleate is approximately 60%. The absorption of enalapril after oral administration is not affected by the presence of food in the gastrointestinal tract.
Distribution. After absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations occur approximately 4 hours after oral administration of enalapril maleate. The effective half-life of enalaprilat after multiple oral doses of enalapril is 11 hours. In subjects with normal renal function, steady-state serum concentrations are reached within 4 days of initiation of treatment. At therapeutically relevant concentrations, enalapril is less than 60% bound to plasma proteins.
Biotransformation: Apart from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.
Elimination: Enalaprilat is eliminated primarily by the kidneys. The major components of urine are enalaprilat (approximately 40% of the administered dose) and unchanged enalapril (approximately 20%).
Renal dysfunction. Exposure to enalapril and enalaprilat is increased in patients with renal impairment. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), steady-state AUC of enalaprilat was approximately 2-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increased approximately 8-fold. The effective half-life of enalaprilat after multiple doses of enalapril maleate is prolonged with this level of renal impairment, and the time to reach steady-state concentration is increased. Enalaprilat can be removed from the systemic circulation by hemodialysis. Dialysis clearance is 62 mL/min.
Lactation. After 4-6 hours of oral administration of 20 mg of enalapril, the mean peak concentration of enalapril in the breast milk of five postpartum women was 1.7 μg/L (range 0.54 to 5.9 μg/L). The mean peak concentration of enalaprilat was 1.7 μg/L (range 1.2 to 2.3 μg/L); peak concentrations occurred at different times during the 24-hour period. Based on data on the peak concentration in breast milk, it is estimated that an exclusively breastfed infant receives no more than 0.16% of the maternal dose adjusted on a per kg basis. In a woman who took 10 mg of enalapril orally daily for 11 months, peak enalapril concentrations (2 μg/L) occurred approximately 4 hours after dosing and peak enalaprilat concentrations (0.75 μg/L) occurred approximately 9 hours after dosing. The total daily amounts of enalapril and enalaprilat in breast milk were 1.44 μg/L and 0.63 μg/L, respectively. Enalaprilat levels in breast milk were below the limit of detection 4 hours after a single dose of enalapril 5 mg in one patient and a single dose of enalapril 10 mg in two patients (
Lercanidipine.
Absorption: Lercanidipine is completely absorbed after oral administration, with peak plasma concentrations achieved after approximately 1.5–3 hours.
The two enantiomers of lercanidipine showed identical plasma level profiles: the time to peak concentration is identical, and the peak plasma concentration and AUC are on average 1.2 times higher for the (S)-enantiomer. The elimination half-lives of the two enantiomers are essentially the same. In vivo interchangeability of the two enantiomers is not observed.
Due to extensive first-pass metabolism, the absolute bioavailability of orally administered lercanidipine under fasting conditions is approximately 10%. However, bioavailability in healthy volunteers under fasting conditions is reduced to ⅓ of the above value.
The bioavailability of orally administered lercanidipine is increased 4-fold when administered 2 hours after a high-fat meal. Accordingly, the drug should be taken before meals.
Distribution: Distribution from plasma to tissues and organs is rapid and extensive.
The degree of plasma protein binding of lercanidipine exceeds 98%. Since protein levels are reduced in patients with severe renal or hepatic dysfunction, the content of free fractions of lercanidipine may be higher.
Biotransformation: Lercanidipine is extensively metabolised by the enzyme CYP3A4; no related compounds are detected in urine or faeces. It is mainly converted to inactive metabolites and approximately 50% of the dose is excreted in the urine.
In vitro experiments with human liver microsomes have shown that lercanidipine slightly inhibits two enzymes, CYP3A4 and CYP2D6, at concentrations 160 and 40 times higher than its peak plasma concentrations achieved after a dose of 20 mg.
Elimination: Elimination occurs primarily by biotransformation. The mean terminal half-life is 8–10 hours; due to the high affinity for lipid membranes, therapeutic activity is prolonged to 24 hours. No accumulation was observed after repeated administration.
Linearity/non-linearity. The plasma levels of lercanidipine after oral administration are not directly proportional to the dose (non-linear kinetics). After administration of 10, 20 or 40 mg, the peak plasma concentrations observed were in the ratio 1:3:8 and the areas under the plasma pharmacokinetic time-concentration curve were in the ratio 1:4:18, suggesting progressive saturation of the first-pass metabolism. Accordingly, the availability increases with increasing dose.
Additional information on special populations. The pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic dysfunction have been shown to be similar to that observed in the general patient population. In patients with severe renal dysfunction or in patients undergoing dialysis, drug concentrations were higher (approximately 70%). In patients with moderate or severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to be increased, since the drug is usually extensively metabolised in the liver.
Preclinical safety data.
Combination of enalapril and lercanidipine.
The potential toxicity of the combination of enalapril and lercanidipine was studied in rats: the drug was administered orally for 3 months, and two genotoxicity tests were performed. The toxicological profile of the combination drug did not differ from the profiles of its two components when administered separately.
Relevant data exist separately for the two components – enalapril and lercanidipine.
Enalapril.
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Data from reproductive toxicity studies suggest that enalapril does not affect fertility and reproductive function in rats and is not teratogenic. In the study, the drug was administered to female rats before mating and during pregnancy, and increased mortality of the offspring was observed during lactation. As it turned out, the drug penetrates the placenta and is excreted in milk. It has been shown that drugs of the angiotensin-converting enzyme inhibitor class have an adverse effect on late fetal development, which can lead to death, congenital pathologies of the skull. In addition, fetotoxicity, intrauterine growth retardation and non-union of the ductus arteriosus have been reported. These developmental disorders can be explained in part by the direct effect of ACE inhibitors on the fetal renin-angiotensin system, in part by ischemia associated with maternal arterial hypotension, as well as by a decrease in fetoplacental blood flow and a decrease in the supply of oxygen and nutrients to the fetus.
Lercanidipine.
Data obtained during non-clinical standard pharmacological safety studies, studies on repeated dose toxicity, genotoxicity, carcinogenic potential, as well as reproductive toxicity indicate the absence of a special hazard of the drug for humans.
The significant effects observed in long-term studies in rats and dogs were directly or indirectly related to the known effects of high doses of calcium antagonists, i.e. were a consequence of excessively high pharmacodynamic activity.
Lercanidipine treatment did not affect fertility and general reproductive function in rats, but high doses resulted in pre- and post-implantation fetal death and intrauterine growth retardation. No teratogenic effects of lercanidipine were observed in rat and rabbit studies, but teratogenicity of other dihydropyridines has been observed in animal studies. High doses of lercanidipine (12 mg/kg/day) during parturition may cause dystocia.
The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in milk have not been studied.
Indication
Lerkamen® ACE inhibitor 10/10:
Treatment of essential hypertension in patients whose blood pressure is not adequately controlled with lercanidipine hydrochloride monotherapy at a dose of 10 mg. Treatment of arterial hypertension should not be started immediately with the combined drug Lercamen® ACE 10/10.
Lerkamen® ACE 10/20:
Treatment of essential hypertension in patients whose blood pressure is not adequately controlled with enalapril maleate monotherapy at a dose of 20 mg. Treatment of arterial hypertension should not be started immediately with the combined drug Lercamen® ACE 10/20.
Contraindication
− Hypersensitivity to the active substances of the drug, to any ACE inhibitor or dihydropyridine calcium channel blockers, or to any of the excipients (see section “Composition”).
− History of angioedema resulting from previous treatment with an ACE inhibitor.
− Hereditary or idiopathic angioedema.
− The simultaneous use of Lercamen® ACE inhibitor and drugs containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacodynamics”).
− Obstruction of blood outflow from the left ventricle, including aortic stenosis.
− Congestive heart failure for which no treatment was given.
− Unstable angina.
− Within one month after a myocardial infarction.
− Severe renal insufficiency (creatinine clearance
− Severe liver failure.
− Concomitant use with:
− potent CYP3A4 inhibitors (see section “Interaction with other medicinal products and other types of interactions”);
− cyclosporine (see section “Interaction with other medicinal products and other types of interactions”);
− grapefruit juice (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
The antihypertensive effect of Lercamen® ACE inhibitor may be enhanced by other drugs that lower blood pressure, such as diuretics, β-blockers, α-blockers and other substances.
In addition, the following interactions have been observed with each of the active ingredients of this medicinal product.
Enalapril maleate.
Dual blockade of the renin-angiotensin-aldosterone system
Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) associated with the concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with the use of a single agent acting on the RAAS (see sections "Contraindications", "Special instructions for use" and "Pharmacodynamics").
Potassium-sparing diuretics and potassium supplements
ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or substances containing potassium salts may lead to significant increases in serum potassium. If such drugs are co-administered in patients with established hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).
Diuretics (thiazide and loop diuretics)
Previous treatment with high doses of diuretics may cause volume depletion and a risk of hypotension when initiating enalapril (see section 4.4). Hypotensive effects may be reduced by discontinuation of the diuretic, increased salt or fluid intake, or by starting on a low dose of enalapril.
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking concomitant mTOR inhibitors may be at increased risk of angioedema (see section 4.4).
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Patients concomitantly taking co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk of hyperkalemia (see section 4.4).
Other antihypertensive agents
Concomitant use with other antihypertensive agents may lead to increased effects of enalapril. Concomitant use of nitroglycerin and other nitrates or vasodilators may lead to additional reduction in blood pressure.
Lithium
During concomitant use of lithium with ACE inhibitors, reversible increases in serum lithium concentrations and increased toxicity have been observed. Concomitant use of thiazide diuretics may increase lithium concentrations and, consequently, potentiate the toxicity of lithium when used concomitantly with ACE inhibitors. Therefore, the use of enalapril with lithium preparations is not recommended, but if their concomitant use is necessary, careful monitoring of serum lithium levels is necessary (see section "Special instructions").
Tricyclic antidepressants/antipsychotics/anesthetics/narcotics
With the concomitant use of some anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors, an additional decrease in blood pressure is possible (see section "Special instructions").
Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors
The combined use of NSAIDs (including selective COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors is accompanied by an additive effect in the form of an increase in serum potassium concentration and may lead to a deterioration in renal function. As a rule, these effects are reversible. In rare cases, acute renal failure may develop, especially in patients with impaired renal function (for example, in elderly patients or dehydrated patients, including those receiving diuretic therapy). Therefore, the combined use of these drugs should be prescribed with caution, especially in patients with impaired renal function. Patients should receive sufficient fluid intake. Both after the start of joint therapy and subsequently, renal function should be periodically monitored.
Gold preparations
Rare nitrite-like reactions, accompanied by symptoms such as facial flushing, nausea, vomiting and hypotension, have been reported with concomitant use of ACE inhibitors, including enalapril, with injectable gold preparations (sodium aurothiomalate).
Sympathomimetics
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Antidiabetic agents
Epidemiological studies have suggested that the use of ACE inhibitors concomitantly with antidiabetic agents (insulin, oral hypoglycaemic agents) may lead to a decrease in blood glucose levels with a risk of hypoglycaemia. This phenomenon is most likely to occur during the first weeks of concomitant treatment and in patients with impaired renal function (see sections 4.4 and 4.8).
Alcohol
Alcohol enhances the hypotensive effect of ACE inhibitors.
Acetylsalicylic acid, thrombolytics and β-blockers
The simultaneous use of enalapril with acetylsalicylic acid (in cardiological doses), thrombolytics and β-blockers is not dangerous.
Lercanidipine.
CYP3A4 inhibitors
Since lercanidipine is metabolized by the CYP3A4 enzyme, concomitant use of CYP3A4 inhibitors and inducers may affect the metabolism and excretion of lercanidipine.
The combined use of lercanidipine and potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is contraindicated (see section "Contraindications").
In an interaction study with ketoconazole, a potent CYP3A4 inhibitor, a significant increase in lercanidipine plasma concentrations was observed (15-fold increase in area under the concentration-time curve (AUC) and 8-fold increase in Cmax of the S-lercanidipine eutomer).
Cyclosporine
Cyclosporine and lercanidipine should not be used together (see section "Contraindications").
After co-administration, an increase in plasma concentrations of both drugs was observed. A study in young volunteers showed that when cyclosporine was administered 3 hours after lercanidipine, the plasma level of lercanidipine did not change, but the AUC of cyclosporine increased by 27%. When lercanidipine and cyclosporine were administered simultaneously, a 3-fold increase in plasma levels of lercanidipine and an increase in the AUC of cyclosporine by 21% were observed.
Grapefruit juice
Lercanidipine should not be taken with grapefruit juice (see section "Contraindications").
As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit juice, with a subsequent increase in the systemic availability of lercanidipine and an increase in the hypotensive effect.
Alcohol
Alcohol should be avoided as it can enhance the vasodilating effect of antihypertensive drugs (see section "Special warnings and precautions for use").
CYP3A4 substrates
Caution should be exercised when administering lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmics (e.g. amiodarone, quinidine).
CYP3A4 inducers
Caution should be exercised when lercanidipine is used concomitantly with CYP3A4 inducers such as anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin, as the antihypertensive effect of lercanidipine may be reduced. Therefore, blood pressure should be monitored more frequently than usual.
Digoxin
The simultaneous use of 20 mg of lercanidipine in patients who were continuously taking β-methyldigoxin did not reveal any pharmacokinetic interaction. In healthy volunteers, the simultaneous use of 20 mg of lercanidipine with digoxin led to an increase in Cmax (mean maximum value) of digoxin by 33%, while there were no significant changes in either AUC (area under the curve) or renal clearance. Patients who are simultaneously using lercanidipine and digoxin should be closely monitored for possible clinical signs of digoxin intoxication.
Midazolam
In elderly volunteers, concomitant oral administration of midazolam at a dose of 20 mg increased the absorption of lercanidipine (by approximately 40%), but reduced its absorption rate (tmax increased from 1.75 to 3 hours). Midazolam concentrations were not affected.
Concomitant administration of lercanidipine and metoprolol (a β-blocker that is mainly eliminated by the liver) did not alter the bioavailability of metoprolol, while the bioavailability of lercanidipine was reduced by 50%. This effect may be due to the reduction in hepatic blood flow caused by β-blockers and may therefore also occur with other drugs of this class. However, lercanidipine can be safely administered at the same time as β-blockers.
Cimetidine
Concomitant use of cimetidine at a dose of 800 mg per day does not cause significant changes in lercanidipine plasma levels, but caution is required when using significantly higher doses of cimetidine, as the bioavailability and therefore the hypotensive effect of lercanidipine may be increased.
Fluoxetine
An interaction study of lercanidipine with fluoxetine, an inhibitor of CYP2D6 and CYP3A4, conducted in healthy volunteers aged 65±7 years (mean ± standard deviation), did not reveal any clinically significant modification of the pharmacokinetics of lercanidipine.
Simvastatin
When lercanidipine 20 mg was repeatedly co-administered with simvastatin 40 mg, the AUC of lercanidipine was slightly altered, while the AUC of simvastatin increased by 56% and the AUC of its main metabolite, the β-hydroxyacid, by 28%. These changes are unlikely to be clinically significant. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening, as is shown for drugs of this class.
Warfarin
Concomitant administration of lercanidipine at a dose of 20 mg in fasting healthy volunteers did not alter the pharmacokinetics of warfarin.
Children
Interaction studies were conducted only with the participation of adults.
Application features
Symptomatic arterial hypotension.
Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. When treating hypertensive patients with enalapril, the risk of symptomatic hypotension increases if fluid and electrolyte imbalance is disturbed and fluid loss occurs, for example, after diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting (see section "Interaction with other medicinal products and other forms of interaction"). Symptomatic hypotension has been observed in patients with heart failure (with or without concomitant renal failure). It occurs more often in patients with more severe heart failure, which is associated with the use of high doses of loop diuretics, hyponatremia or impaired renal function. Treatment of such patients should be initiated under medical supervision, and this supervision should be continued when the dose of enalapril and / or diuretic is changed. The same recommendations apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive lowering of blood pressure can lead to myocardial infarction or acute cerebrovascular accident.
In case of hypotension, the patient should be placed in the supine position and, if necessary, an intravenous infusion of saline should be given. The reversible hypotensive effect is not a contraindication to further use of the drug, which can be continued after the blood pressure has increased after volume replenishment.
In some patients with heart failure and normal or low blood pressure, enalapril may cause an additional decrease in blood pressure. This effect is expected and is not usually a reason for discontinuation of therapy. If hypotension becomes symptomatic, it may be necessary to reduce the dose and/or discontinue the diuretic and/or enalapril.
Sick sinus syndrome.
The drug should be prescribed with caution to patients with sick sinus syndrome unless an artificial pacemaker is implanted.
Left ventricular dysfunction and ischemic heart disease.
Although hemodynamically controlled studies have not revealed any impairment of ventricular function, calcium channel blockers should be used with caution in patients with impaired left ventricular function. It is assumed that the use of some short-acting dihydropyridines may be associated with an increased cardiovascular risk in patients with
