Pramilet
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRAILET® (PRAMILET®)
Composition:
Active substances: amlodipine (amlodipine), lisinopril (lisinopril);
Tablets 5 mg/10 mg: each tablet contains amlodipine besylate equivalent to amlodipine 5 mg and lisinopril dihydrate equivalent to lisinopril 10 mg;
Tablets 5 mg/20 mg: each tablet contains amlodipine besylate equivalent to amlodipine 5 mg and lisinopril dihydrate equivalent to lisinopril 20 mg;
Tablets 10 mg/20 mg: each tablet contains amlodipine besylate equivalent to amlodipine 10 mg and lisinopril dihydrate equivalent to lisinopril 20 mg;
Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.
Pharmaceutical form. Tablets.
Main physico-chemical properties:
for strength 5 mg/10 mg: tablets are white or almost white, round, flat, with an engraving "K" on one side and smooth on the other side;
for strength 5 mg/20 mg: tablets are white or almost white, round, flat, with engravings "5" and "20" separated by a line on one side and smooth on the other side;
for strength 10 mg/20 mg: tablets are white or almost white, round, flat, with engravings "10" and "20" separated by a line on one side and smooth on the other side.
Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors in combination with calcium antagonists. Lisinopril and amlodipine. ATC code C09B B03.
Pharmacological Properties
Pramilet**®** is a fixed-dose combination medicinal product containing two active substances: lisinopril and amlodipine.
Lisinopril
Lisinopril is an inhibitor of peptidyl dipeptidase enzyme. It inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I into the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE leads to reduced concentrations of angiotensin II, resulting in decreased vasoconstrictor activity and reduced aldosterone secretion. The latter reduction may lead to increased serum potassium levels.
Since the mechanism by which lisinopril lowers blood pressure involves suppression of the renin-angiotensin-aldosterone system, lisinopril reduces arterial pressure even in patients with low-renin hypertension. ACE is identical to kininase II, the enzyme responsible for bradykinin degradation. Whether increased concentrations of bradykinin, a potent vasodilator peptide, play a role in the therapeutic effects of lisinopril has not yet been established.
Amlodipine
Amlodipine is a dihydropyridine inhibitor of calcium ion influx (a slow calcium channel blocker, or calcium antagonist), which blocks calcium ion entry through cell membranes into vascular smooth muscle and myocardial cells.
The antihypertensive mechanism of amlodipine is due to its direct relaxant effect on vascular smooth muscle.
Reduction of total ischemic load occurs via two mechanisms:
- Amlodipine causes peripheral arteriolar dilation, thereby reducing total peripheral vascular resistance (afterload). Since heart rate remains stable, reduced cardiac workload leads to decreased energy consumption and myocardial oxygen demand.
- The mechanism of action of amlodipine may also involve dilation of coronary arteries and arterioles in both normal and ischemic myocardial zones. This increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal's angina, or variant angina).
Once-daily administration of amlodipine results in clinically significant reduction of arterial pressure in patients with arterial hypertension both in the upright and supine positions over 24 hours. Due to its slow onset of action, a rapid hypotensive effect does not occur.
In patients with angina, once-daily dosing of amlodipine increases exercise tolerance, prolongs the time to onset of angina, delays the development of ST-segment depression (by 1 mm), and reduces the frequency of angina attacks and nitroglycerin use.
Amlodipine has no adverse effects on metabolism or plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, type 2 diabetes, and gout.
Pharmacokinetics
Lisinopril
Lisinopril is an orally active ACE inhibitor that does not contain a sulfhydryl group.
Absorption
After oral administration, peak plasma concentrations are reached within 7 hours, although in patients with acute myocardial infarction a slight delay in time to peak serum concentration has been observed. Based on urinary excretion data, the average extent of absorption of lisinopril is approximately 25%, with interpatient variability ranging from 6% to 60% within the studied dose range (5 to 80 mg). In patients with heart failure, the absolute bioavailability of lisinopril is reduced to approximately 16%. Absorption of lisinopril is not affected by food intake.
Distribution
Lisinopril does not bind to plasma proteins except for circulating ACE. Preclinical studies have shown that penetration of lisinopril across the blood-brain barrier is minimal.
Elimination
Lisinopril is not metabolized in the body and is excreted unchanged in urine. With repeated administration, the effective elimination half-life of lisinopril is 12.6 hours. Renal clearance of lisinopril in healthy volunteers is approximately 50 mL/min. Serum lisinopril concentrations decline with a prolonged terminal elimination half-life, which does not favor accumulation of the active substance in the body. This terminal half-life likely reflects saturable binding to ACE and is not dose-dependent.
Pharmacokinetic characteristics in special patient populations
Hepatic impairment
Impaired liver function in patients with hepatic cirrhosis resulted in reduced absorption of lisinopril (approximately 30% lower based on urinary excretion data), but the drug effect was increased (approximately 50%) compared to healthy volunteers due to reduced clearance.
Renal impairment
Impaired renal function reduces the elimination of lisinopril, which is primarily excreted by the kidneys, but this reduction becomes clinically significant only when glomerular filtration rate is less than 30 mL/min. In mild to moderate renal impairment (creatinine clearance of 30–80 mL/min), the mean area under the concentration-time curve (AUC) increases by only 13%, whereas in severe renal impairment (creatinine clearance of 5–30 mL/min), the mean AUC increases by 4.5-fold. Lisinopril can be removed from the body by hemodialysis. After 4 hours of hemodialysis, plasma lisinopril concentration decreases by approximately 60%, and dialysis clearance ranges from 40 to 55 mL/min.
Heart failure
In patients with heart failure, higher plasma concentrations of lisinopril are observed compared to healthy volunteers (mean AUC increased by approximately 125%), but based on urinary excretion data, absorption of lisinopril is reduced by approximately 16% compared to healthy individuals.
Elderly patients
In elderly patients, increased blood concentrations of lisinopril and higher (approximately 60%) AUC values are observed compared to younger patients.
Amlodipine
Absorption, distribution, plasma protein binding
After administration of therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentrations within 6–12 hours. Absolute bioavailability is estimated to be between 64% and 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Food intake does not affect the bioavailability of amlodipine.
Metabolism and elimination
The terminal plasma elimination half-life is approximately 35–50 hours, consistent with once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites. Only 10% of the parent compound and 60% of metabolites are excreted in urine.
Pharmacokinetic characteristics in special patient populations
Hepatic impairment
Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, clearance of amlodipine is reduced, leading to an increase in elimination half-life and AUC by approximately 40–60%.
Elderly patients
Time to peak plasma concentration of amlodipine is practically the same in elderly and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, resulting in increased AUC and elimination half-life.
Increased AUC and elimination half-life in patients with congestive heart failure are consistent with expectations for this age group.
Fixed-dose combination product
No pharmacokinetic interactions between the active components of the medicinal product Pramilet**®**, tablets, have been described. Pharmacokinetic parameters (AUC, Cmax, tmax, t1/2) were not different from those observed after administration of the active components separately.
Food intake does not affect the gastrointestinal absorption of the medicinal product Pramilet**®**, tablets.
Clinical characteristics.
Indications.
Essential arterial hypertension in adults.
Pramilet® is indicated for patients whose blood pressure is adequately controlled with concomitant administration of lisinopril and amlodipine at appropriate doses.
Contraindications.
Associated with lisinopril:
- Hypersensitivity to lisinopril or to any other angiotensin-converting enzyme (ACE) inhibitor;
- History of angioedema associated with previous ACE inhibitor therapy;
- Hereditary or idiopathic angioedema;
- Pregnancy or planned pregnancy, breastfeeding (see section "Use in pregnancy or lactation");
- Concomitant use of Pramilet**®** with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
- Concomitant use with sacubitril/valsartan; initiation of Pramilet**®** is not recommended within 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
Associated with amlodipine:
- Hypersensitivity to amlodipine or to any other dihydropyridine derivatives;
- Severe arterial hypotension;
- Shock (including cardiogenic shock);
- Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
- Hemodynamically unstable heart failure following acute myocardial infarction.
Associated with the medicinal product Pramilet**®** :
- All contraindications listed above related to the use of individual components also apply to the combined medicinal product Pramilet**®** ;
- Hypersensitivity to any of the excipients of Pramilet**®** (see section "Composition").
Interaction with other medicinal products and other forms of interaction.
Interactions related to lisinopril
Antihypertensive agents
Concomitant use of lisinopril with other antihypertensive agents (e.g., nitroglycerin and other nitrates or other vasodilators) may result in additional reduction of blood pressure.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren is associated with an increased risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure) compared to monotherapy (see sections "Contraindications" and "Special precautions for use").
Medicinal products that may increase the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").
Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neprilysin inhibitors (e.g., racecadotril), tissue plasminogen activator, or vildagliptin may increase the risk of angioedema (see section "Special precautions for use").
Diuretics
The antihypertensive effect is usually enhanced when a diuretic is added to lisinopril therapy. In patients already receiving diuretics, particularly those recently initiated on diuretic therapy, excessive reduction in blood pressure may rarely occur upon addition of lisinopril. The risk of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to starting lisinopril (see sections "Special precautions for use" and "Method of administration and dosage").
Potassium-containing dietary supplements or salt substitutes, potassium-sparing diuretics, and other medicinal products that may increase serum potassium levels
Although serum potassium levels usually remain within normal limits during lisinopril therapy, hyperkalemia may occur in some patients. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to significant increases in serum potassium, particularly in patients with impaired renal function. Caution should be exercised when lisinopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim has effects similar to potassium-sparing diuretics like amiloride. Therefore, concomitant use of lisinopril with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, the products should be used with caution and with periodic monitoring of serum potassium levels (see section "Special precautions for use").
Cyclosporine
Concomitant use of ACE inhibitors and cyclosporine may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.
Heparin
Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.
When lisinopril is administered concomitantly with potassium-sparing diuretics, diuretic-induced hypokalemia may be reduced.
Lithium preparations
Elevated and potentially toxic serum lithium concentrations have been reported during concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and may exacerbate lithium toxicity already present due to ACE inhibitor use. Concomitant use of lisinopril and lithium preparations is not recommended; however, if use of this combination is deemed necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").
Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day
Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 [COX-2] inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and hyperkalemia, particularly in patients with reduced renal function. These effects are reversible. Caution is advised when using combination therapy, especially in elderly patients. Adequate hydration is recommended, and renal function should be carefully monitored at the start of and during combination therapy.
Gold
Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness, and hypotension, which may be severe) have been reported more frequently in patients receiving ACE inhibitors after administration of injectable gold preparations (e.g., sodium aurothiomalate).
Tricyclic antidepressants/antipsychotics/anesthetics
Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions for use").
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Hypoglycemic agents
It is known that concomitant use of ACE inhibitors with hypoglycemic medicinal products (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.
Medicinal products that suppress bone marrow function (immunosuppressants, allopurinol, procainamide)
Concomitant use with lisinopril increases the risk of neutropenia and/or agranulocytosis (see section "Special precautions for use").
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers, and/or nitrates.
Interactions related to amlodipine
Effects of other medicinal products on amlodipine
CYP3A4 enzyme inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine concentration, increasing the risk of hypotension. The clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, medical monitoring is recommended, and dose adjustment of amlodipine may be necessary.
Clarithromycin is a CYP3A4 inhibitor. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Strict medical monitoring is recommended when amlodipine is used concomitantly with clarithromycin.
CYP3A4 enzyme inducers
When used concomitantly with known inducers of CYP3A4 enzyme, amlodipine blood concentrations may vary. Therefore, blood pressure should be monitored and doses adjusted as needed during and after combination therapy, especially when using potent CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum).
Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this may increase the bioavailability of amlodipine, thereby enhancing its hypotensive effect.
Dantrolene (infusion)
In animal studies, ventricular fibrillation and cardiovascular collapse with concomitant hyperkalemia and fatal outcome were observed after verapamil administration followed by intravenous dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and for the treatment of malignant hyperthermia.
Effects of amlodipine on other medicinal products
The hypotensive effect of amlodipine is enhanced by the corresponding effects of other medicinal products with antihypertensive properties.
Tacrolimus
Concomitant use of tacrolimus and amlodipine may increase tacrolimus blood concentrations; the mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, tacrolimus blood concentrations should be monitored during amlodipine therapy, and the tacrolimus dose adjusted if necessary.
Inhibitors of mammalian target of rapamycin (mTOR)
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. Concomitant use of amlodipine with mTOR inhibitors may enhance the effects of the latter.
Cyclosporine
No interaction studies between cyclosporine and amlodipine have been conducted in healthy volunteers or other populations, except in kidney transplant patients, in whom increased cyclosporine blood concentrations (on average by 0–40%) have been observed. Therefore, cyclosporine blood concentrations should be monitored during amlodipine therapy in such patients, and the cyclosporine dose reduced if necessary.
Simvastatin
Concomitant administration of repeated 10 mg doses of amlodipine and 80 mg of simvastatin resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. The simvastatin dose should be limited to 20 mg daily in patients taking amlodipine.
It is known from clinical interaction studies that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Special precautions for use.
All the special precautions for use listed below, related to the use of individual components, also apply to the combined medicinal product Pramilet®.
Special precautions for use related to lisinopril
Symptomatic hypotension
Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension.
A significant decrease in blood pressure may occur in patients with reduced circulating blood volume due to diuretic therapy, a strict low-salt diet, dialysis, diarrhea, vomiting, as well as in patients with pronounced renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").
Cases of symptomatic hypotension have been reported in patients with heart failure, with or without concomitant renal impairment. Such cases are most likely in patients with more severe degrees of heart failure due to high-dose loop diuretics, hyponatremia, or functional renal impairment. Patients at increased risk of symptomatic arterial hypotension should be monitored for hypotensive effects after the initial dose. These recommendations apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of arterial hypotension, the patient should be placed in a supine position with elevated lower limbs and fluid volume should be replenished (intravenous administration of physiological saline) if necessary. Transient arterial hypotension is not a contraindication for continued use of the drug, and further administration usually does not cause problems after blood pressure increases due to increased circulating blood volume.
In some patients with heart failure and normal or low blood pressure, lisinopril may cause additional reduction in systemic arterial pressure. This is a known effect and usually does not require discontinuation of therapy. If hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril may be necessary.
Arterial hypotension in acute myocardial infarction
Treatment with lisinopril should not be initiated in patients with acute myocardial infarction who are prone to further serious hemodynamic deterioration after vasodilator therapy. These are patients with systolic blood pressure of 100 mm Hg or lower or with cardiogenic shock. During the first 3 days after myocardial infarction, the dose should be reduced if systolic blood pressure is 120 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If arterial hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour), lisinopril should be discontinued.
Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy
As with all ACE inhibitors, lisinopril should be administered with caution to patients with mitral valve stenosis and left ventricular outflow tract obstruction, such as aortic stenosis or hypertrophic cardiomyopathy.
Renal impairment
In patients with impaired renal function (creatinine clearance < 80 mL/min), the initial dose of lisinopril should be adjusted according to the patient's creatinine clearance and subsequently based on the patient's response to treatment. Routine monitoring of serum potassium and creatinine concentrations is part of standard medical practice in treating such patients.
In patients with heart failure, arterial hypotension after initiation of ACE inhibitor therapy may lead to further deterioration of renal function. In such cases, acute renal failure, usually reversible, has been reported.
In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney receiving ACE inhibitors, increased blood urea nitrogen and serum creatinine concentrations may occur, usually reversible after discontinuation of the drug. This is particularly likely in patients with pre-existing renal impairment.
In patients with concomitant renovascular hypertension, there is an increased risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under close medical supervision with low doses and careful dose titration. Since diuretic therapy may promote the development of the above-mentioned conditions, diuretics should be discontinued, and renal function should be monitored during the first weeks of lisinopril therapy.
In some patients with arterial hypertension without prior pronounced renovascular hypertension, increases in blood urea and serum creatinine concentrations have been observed, usually mild and transient, especially when lisinopril is used concomitantly with diuretics. This is particularly likely in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of diuretics and/or lisinopril may be required.
In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with signs of renal impairment defined as serum creatinine concentration exceeding 177 µmol/L and/or proteinuria exceeding 500 mg/24 hours. If renal function impairment develops during lisinopril therapy (serum creatinine concentration exceeding 265 µmol/L or doubling the baseline value), the physician should consider discontinuing lisinopril.
Proteinuria
Rare cases of proteinuria have been reported, particularly with reduced renal function or after high doses of lisinopril. In cases of clinically significant proteinuria (over 1 g/day), the medicinal product should be administered only after evaluating the benefit-risk ratio and under continuous monitoring of clinical and biochemical parameters.
Hypersensitivity, angioedema
Isolated cases of angioedema of the face, hands, feet, lips, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including lisinopril. Angioedema may occur at any time during treatment. In such cases, lisinopril should be immediately discontinued, appropriate treatment initiated, and medical observation ensured until all symptoms resolve before patient discharge. Even in cases of tongue swelling without respiratory distress, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.
Very rarely, fatal cases due to angioedema associated with laryngeal or tongue swelling have been reported. Patients with involvement of the tongue, glottis, or larynx may develop airway obstruction, especially in patients who have previously undergone airway surgery. In such cases, immediate medical assistance is required, which may include administration of adrenaline and/or airway support. The patient should remain under close physician supervision until complete and stable resolution of symptoms.
ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races.
Patients who previously experienced angioedema unrelated to ACE inhibitor therapy may be more prone to developing angioedema when using an ACE inhibitor (see section "Contraindications").
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of lisinopril. Treatment with lisinopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (such as sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., swelling of the airways or tongue with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Patients already taking ACE inhibitors should initiate treatment with racecadotril, mTOR inhibitors, and vildagliptin with caution.
Anaphylactoid reactions in patients undergoing hemodialysis
Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux, highly permeable dialysis membranes (e.g., AN 69) and simultaneously receiving an ACE inhibitor. Consideration should be given to using a different type of dialysis membrane or antihypertensive drug of another class for such patients.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
In isolated cases, life-threatening anaphylactoid reactions occurred in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate. The occurrence of such reactions can be avoided by withholding ACE inhibitor therapy before each apheresis session.
Desensitization
Sustained anaphylactoid reactions occur in patients receiving ACE inhibitors during desensitization to hymenoptera venom (e.g., Hymenoptera venom). Anaphylactoid reactions were avoided in such patients by temporarily discontinuing ACE inhibitors, but they recurred after accidental re-administration of the drug.
Hepatic impairment
Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice, progressing to fulminant necrosis, and sometimes resulting in death. The mechanism of this syndrome is unclear. Patients receiving lisinopril who develop jaundice or significantly elevated liver enzyme activity should discontinue lisinopril and remain under appropriate medical supervision.
Neutropenia/agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors. Neutropenia and agranulocytosis are reversible and resolve after discontinuation of the ACE inhibitor.
Lisinopril should be administered with particular caution to patients with connective tissue diseases, immunosuppressive therapy, allopurinol, or procainamide, or in combination with these complicating factors, especially with pre-existing renal impairment. Some of these patients developed serious infections, which in several cases were unresponsive to intensive antibiotic therapy. Periodic laboratory tests (blood count with leukocyte formula) are recommended during lisinopril therapy in such patients, and they should be warned to report the first signs of infection.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use with ACE inhibitors, ARBs, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
If dual RAAS blockade is absolutely indicated, careful specialist supervision and mandatory monitoring of renal function, fluid-electrolyte balance, and blood pressure are required.
ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
Race
ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races. As with other ACE inhibitors, lisinopril may be less effective in reducing blood pressure in patients of Black race compared to patients of other races, likely due to the higher prevalence of low-renin states in patients of Black race with arterial hypertension.
Cough
Cough has been reported with ACE inhibitor use. Cough is usually non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/anesthesia
In patients undergoing major surgery or under general anesthesia with agents causing arterial hypotension, lisinopril may block angiotensin II formation following compensatory renin release. If arterial hypotension develops, likely due to the above mechanism, correction can be achieved by increasing circulating blood volume.
Hyperkalemia
ACE inhibitors may cause hyperkalemia due to suppression of aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, in patients with impaired renal function, type II diabetes mellitus, and/or patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), as well as patients taking other drugs that may increase serum potassium levels (e.g., heparin, trimethoprim, or the combination drug co-trimoxazole (trimethoprim/sulfamethoxazole)), and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may develop. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients taking ACE inhibitors. If concomitant use of the above-mentioned drugs is necessary, regular monitoring of serum potassium levels and renal function is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Patients with diabetes mellitus
In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, careful monitoring of glycemia is required during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Lithium preparations
Combination of lithium preparations and lisinopril is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Special precautions for use related to amlodipine
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Heart failure
Amlodipine should be used with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III and IV), pulmonary edema was reported more frequently in the amlodipine group than in the placebo group.
Calcium channel blockers, including amlodipine, should be prescribed with caution to patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality in the future.
Hepatic impairment
In patients with hepatic impairment, prolonged elimination half-life and increased AUC of amlodipine have been observed, but corresponding dosing recommendations have not been established. Therefore, amlodipine therapy should be initiated with the lowest dose within the dosing range. Dose initiation and titration should be done cautiously. Slow dose titration and careful monitoring may be required for patients with severe hepatic impairment.
Elderly patients
Dose increases in elderly patients should be done cautiously (see sections "Pharmacokinetics" and "Dosage and administration").
Renal impairment
Amlodipine can be administered to such patients at usual doses. Plasma amlodipine concentrations do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.
Special precautions for use related to Pramilet®
This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., practically sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy
The medicinal product Pramilet® is contraindicated in pregnant women and women planning pregnancy (see section "Contraindications").
There is no adequate controlled clinical experience with the use of lisinopril and amlodipine in pregnant women. However, the use of both active substances is not recommended or contraindicated (see information on active substances in section "Composition").
If pregnancy is confirmed during treatment with Pramilet®, its use must be immediately discontinued, and if necessary, replaced with another medicinal product permitted for use during pregnancy (see section "Special precautions for use").
The use of Pramilet® should not be initiated during pregnancy. If continued treatment with Pramilet® is necessary, women planning pregnancy should be switched to alternative antihypertensive agents with a known safety profile during pregnancy.
Use of lisinopril
Epidemiological data on the risk of teratogenicity associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, although a slight increase in risk cannot be excluded. If continued ACE inhibitor therapy is deemed necessary, women planning pregnancy should be switched to alternative antihypertensive agents with a known safety profile during pregnancy. Upon confirmation of pregnancy, ACE inhibitor therapy should be immediately discontinued and alternative therapy initiated if needed.
It is known that ACE inhibitor use during the second and third trimesters of pregnancy induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If an ACE inhibitor is used from the second trimester of pregnancy, ultrasound monitoring of renal function and skull development is recommended. Newborns and infants whose mothers received ACE inhibitors should be closely monitored for timely detection of arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Use of amlodipine
The safety of amlodipine use in pregnant women has not been established.
It is known that reproductive toxicity has been observed in animal studies with high doses. Use during pregnancy is possible only in the absence of a safer alternative treatment and in cases where the disease itself poses a significant risk to the mother and fetus.
Lactation period
Information on the use of lisinopril during lactation is lacking. Amlodipine is excreted in breast milk. The amount of amlodipine received by the infant through breast milk is estimated at an interquartile range of 3–7%, maximum 15%. The effect of amlodipine on the infant has not been evaluated.
The medicinal product Pramilet® is contraindicated during breastfeeding; alternative drugs with established safety profiles should be used, especially when breastfeeding a newborn or preterm infant (see section "Contraindications").
Fertility
There are no adequate controlled clinical data on the effect of lisinopril and amlodipine on fertility.
Use of amlodipine
Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient.
Ability to affect reaction speed when driving vehicles or operating machinery.
Related to lisinopril
When driving vehicles or operating machinery, the possible development of dizziness or fatigue should be considered.
Related to amlodipine
Amlodipin may cause a slight or moderate effect on the ability to drive vehicles and operate machinery. In patients experiencing dizziness, headache, fatigue, or nausea, reaction ability may be impaired. Caution is recommended, especially at the beginning of treatment.
Accordingly, the medicinal product Pramilet® may affect the ability to drive vehicles and operate machinery (especially at the beginning of treatment).
Dosage and administration.
Doses
The recommended dose is 1 tablet per day. The maximum daily dose is 1 tablet.
Fixed-dose combination preparations are generally not suitable for initial therapy.
The choice of Pramilet® preparation (see table below) depends on the established optimal maintenance doses of lisinopril and amlodipine.
| Optimal maintenance doses |
Medicinal product Pramilet® |
|
| Amlodipine |
Lisinopril |
|
| 5 mg |
10 mg |
Pramilet®, tablets 5 mg/10 mg |
| 5 mg |
20 mg |
Pramilet®, tablets 5 mg/20 mg |
| 10 mg |
20 mg |
Pramilet®, tablets 10 mg/20 mg |
Patients with renal impairment
For selecting the optimal initial and maintenance dose in patients with renal impairment, dose titration should be performed individually using the separate components of the drug – lisinopril and amlodipine.
During therapy with the medicinal product Pramilet**®, renal function, and serum potassium and sodium levels should be monitored. If renal function deteriorates, treatment with Pramilet®** should be discontinued and replaced by appropriate doses of its individual components. Amlodipine is not removed by dialysis.
Patients with hepatic impairment
Dosage recommendations for patients with mild or moderate hepatic impairment have not yet been established; therefore, dose selection in such patients should be done cautiously, starting with the lowest dose within the dosing range (see sections "Pharmacokinetics" and "Special precautions"). For selecting the optimal initial and maintenance dose in patients with hepatic impairment, dose titration should be performed individually using lisinopril and amlodipine as separate tablets.
The pharmacokinetics of amlodipine in severe hepatic impairment has not been studied. Amlodipine administration in patients with severe hepatic impairment should start with the lowest dose, and dose titration should be performed slowly.
Elderly patients (aged 65 years and older)
The drug should be prescribed with caution in elderly patients.
Clinical studies have not shown any age-related differences in the efficacy and safety profile of amlodipine or lisinopril. To select the optimal maintenance dose for elderly patients, dose titration should be performed individually using lisinopril and amlodipine as separate tablets.
Method of administration
Oral. Since food does not affect drug absorption, the medicinal product Pramilet**®** can be taken independently of meals, i.e., before, during, or after food intake.
Children
The safety and efficacy of the medicinal product Pramilet**®** in children (under 18 years of age) have not been established.
Overdose
There are no data on Pramilet**®** overdose in humans.
Overdose of lisinopril
Data on human overdose are limited. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include arterial hypotension, circulatory shock, electrolyte imbalances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. In case of overdose, intravenous administration of physiological saline is recommended. If arterial hypotension develops, the patient should be placed in a supine position on their back. Infusion of angiotensin II and/or intravenous administration of catecholamines may also be considered.
If drug intake was recent, measures should be taken to remove lisinopril (e.g., induction of emesis, gastric lavage, administration of sorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Special precautions"). In case of bradycardia unresponsive to medical therapy, insertion of a pacemaker is indicated. Continuous monitoring of vital signs, serum electrolytes, and serum creatinine concentration is required.
Overdose of amlodipine
Data on intentional overdose in humans are limited.
Symptoms
Overdose may lead to excessive peripheral vasodilation with reflex tachycardia. Profound and prolonged systemic arterial hypotension has also been reported, progressing to shock with fatal outcome.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Factors contributing to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at supporting perfusion and cardiac output.
Treatment
In cases of clinically significant arterial hypotension due to amlodipine overdose, active measures are required to support cardiovascular function, including frequent monitoring of cardiovascular and respiratory parameters, placing the patient in a supine position with legs elevated above the head, and monitoring circulating blood volume and diuresis.
Administration of vasopressors may be necessary to restore vascular tone and arterial pressure, provided there are no contraindications to their use. Intravenous administration of calcium gluconate may have a beneficial effect in reversing effects caused by calcium channel blockade.
Gastric lavage may be effective in some cases. In studies involving healthy volunteers, administration of activated charcoal within 2 hours after ingestion of 10 mg amlodipine reduced the rate of amlodipine absorption.
Since amlodipine is highly bound to plasma proteins, dialysis is ineffective.
Overdose of the medicinal product Pramilet**®** may result in excessive peripheral vasodilation with marked arterial hypotension and acute circulatory failure, electrolyte imbalances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Symptomatic treatment is recommended (place the patient in a supine position, observe and, if necessary, support cardiovascular and respiratory functions, monitor arterial pressure, circulating blood volume, electrolyte balance, and serum creatinine concentration). In case of pronounced arterial hypotension, the patient should be placed in a supine position with legs elevated above the head. If fluid administration is insufficient, supportive therapy with peripheral vasopressors may be required, provided there are no contraindications to their use. Infusion of angiotensin II may also be considered. Intravenous administration of calcium gluconate may have a beneficial effect in reversing effects caused by calcium channel blockade.
Lisinopril can be removed from systemic circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes during dialysis is not recommended.
Adverse Reactions
The frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).
Within each frequency group, adverse reactions are listed in order of decreasing severity.
Adverse reactions observed and recorded during treatment with lisinopril and amlodipine separately:
Lisinopril
Blood and lymphatic system disorders: uncommon – decreased hemoglobin levels, decreased hematocrit; rare – bone marrow suppression, anemia, agranulocytosis (see section "Special precautions"), leukopenia, neutropenia, thrombocytopenia, hemolytic anemia, lymphadenopathy.
Immune system disorders: rare – autoimmune disorders; frequency not known – anaphylactic/anaphylactoid reaction.
Endocrine system disorders: uncommon – syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Metabolism and nutrition disorders: rare – hypoglycemia.
Psychiatric disorders: uncommon – mood changes, sleep disturbances, hallucinations; uncommon – confusion; frequency not known – depression.
Nervous system disorders: common – dizziness, headache; uncommon – vertigo, paresthesia, dysgeusia; uncommon – olfactory disturbances; frequency not known – syncope.
Cardiac disorders: uncommon – myocardial infarction, likely due to excessive reduction in blood pressure in high-risk patients (see section "Special precautions"), tachycardia, palpitations.
Vascular disorders: common – orthostatic effects (including orthostatic hypotension); uncommon – acute cerebrovascular accident (stroke), likely due to excessive reduction in blood pressure in high-risk patients (see section "Special precautions"), tachycardia, Raynaud's syndrome.
Respiratory, thoracic and mediastinal disorders: common – cough; uncommon – rhinitis; rare – bronchospasm, allergic alveolitis/eosinophilic pneumonia, sinusitis.
Gastrointestinal disorders: common – diarrhea, vomiting; uncommon – abdominal pain, nausea, dyspepsia; uncommon – dry mouth; rare – pancreatitis, angioneurotic intestinal edema.
Hepatobiliary disorders: rare – liver failure, hepatitis – hepatocellular or cholestatic, jaundice (see section "Special precautions").
Skin and subcutaneous tissue disorders: uncommon – rash, pruritus; uncommon – psoriasis, urticaria, alopecia, hypersensitivity / angioedema of the face, extremities, lips, tongue, glottis and/or larynx (see section "Special precautions"); rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, sweating, benign lymphadenosis of the skin*.
Renal and urinary disorders: common – renal function impairment; uncommon – acute renal failure, uremia; rare – oliguria/anuria.
Reproductive system and breast disorders: uncommon – impotence; uncommon – gynecomastia.
General disorders and administration site conditions: uncommon – fatigue, asthenia.
Investigations: uncommon – increased serum urea and creatinine concentrations, hyperkalemia, increased liver enzyme activity; uncommon – increased serum bilirubin, hyponatremia.
Amlodipine
Blood and lymphatic system disorders: rare – thrombocytopenia, leukopenia.
Immune system disorders: rare – allergic reactions.
Metabolism and nutrition disorders: rare – hyperglycemia.
Psychiatric disorders: uncommon – insomnia, mood changes (including anxiety), depression; uncommon – confusion.
Nervous system disorders: common – somnolence, dizziness, headache (especially at the beginning of treatment); uncommon – syncope, tremor, dysgeusia, hypesthesia, paresthesia; rare – hypertonia, peripheral neuropathy; frequency not known – extrapyramidal disorders.
Eye disorders: common – visual disturbances (including diplopia).
Ear and labyrinth disorders: uncommon – tinnitus.
Cardiac disorders: common – palpitations; uncommon – arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation); rare – myocardial infarction.
Vascular disorders: common – skin flushing; uncommon – arterial hypotension; rare – vasculitis.
Respiratory, thoracic and mediastinal disorders: common – dyspnea; uncommon – cough, rhinitis.
Gastrointestinal disorders: common – abdominal pain, nausea, dyspepsia, defecation disorders (diarrhea and constipation); uncommon – vomiting, dry mouth; rare – pancreatitis, gastritis, gingival hyperplasia.
Hepatobiliary disorders: rare – hepatitis, jaundice, increased liver enzyme levels**.
Skin and subcutaneous tissue disorders: uncommon – alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, rash, exanthema, urticaria; rare – Quincke's edema, exfoliative dermatitis, Stevens-Johnson syndrome, erythema multiforme, angioedema, photosensitivity; frequency not known – toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: common – ankle swelling (tarsal joint), muscle cramps; uncommon – arthralgia, myalgia, back pain.
Renal and urinary disorders: uncommon – micturition disorder, nocturia, increased frequency of urination.
Reproductive system and breast disorders: uncommon – impotence, gynecomastia.
General disorders and administration site conditions: very common – edema; common – fatigue, asthenia; uncommon – chest pain, pain, malaise.
Investigations: uncommon – increased body weight, decreased body weight.
*A symptom complex has been reported, which may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody (ANA) test, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, skin rash, photosensitization, or other skin changes.
**Most frequently associated with cholestasis.
Clinical safety data suggest that lisinopril is generally well tolerated in children and adolescents with arterial hypertension, and the safety profile in this age group is comparable to that in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store at temperatures not exceeding 25 °C.
Keep out of reach of children.
Packaging.
10 tablets in a blister. 3 or 9 blisters in a cardboard package.
Prescription status.
Prescription only.
Manufacturer.
LLC "KUSUM PHARM".
Manufacturer's location and address of place of business.
40020, Ukraine, Sumy region, Sumy city, Skryabina St., 54.
or
Manufacturer.
LLC "GLEDPHARM LTD".
Manufacturer's location and address of place of business.
40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia St., 54.