Instructions for use Hartil AM capsules 5 mg/10 mg blister No. 30
Composition
active ingredients: ramipril; amlodipine;
1 capsule contains 5 mg of ramipril and 5 mg of amlodipine (equivalent to 6.95 mg of amlodipine besylate); or 5 mg of ramipril and 10 mg of amlodipine (equivalent to 13.9 mg of amlodipine besylate); or 10 mg of ramipril and 5 mg of amlodipine (equivalent to 6.95 mg of amlodipine besylate); or 10 mg of ramipril and 10 mg of amlodipine (equivalent to 13.9 mg of amlodipine besylate);
excipients: crospovidone, hypromellose, microcrystalline cellulose, glycerol dibehenate;
capsule composition (lid and base);
5 mg/5 mg capsules: Diamond Blue FCF+FD and C Blue 1 (E 133), Allura Red AC+FD and C Red 40 (E 129), titanium dioxide (E 171), gelatin;
5 mg/10 mg capsules: red iron oxide (E 172), titanium dioxide (E 171), azorubine, carmoisine (E 122), indigo carmine (E 132), gelatin;
10 mg/5 mg capsules: iron oxide red (E 172), titanium dioxide (E 171), diamond blue FCF+FD and C blue 1 (E 133), allura red AC+FD and C red 40 (E 129), gelatin;
10 mg/10 mg capsules: azorubine, carmoisine (E 122), indigo carmine (E 132), titanium dioxide (E 172), gelatin.
Dosage form
Capsules.
Main physicochemical properties:
5 mg/5 mg capsules:
hard gelatin capsules of the Coni Snap type, size 2, unmarked, self-closing, with an opaque amethyst (dark pink) body and an opaque amethyst (dark pink) cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white in color, odorless or almost odorless;
5 mg/10 mg capsules:
hard gelatin capsules of the Coni Snap type, size 0, unmarked, self-closing, with an opaque flesh-colored (light pink) body and an opaque dark maroon cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white in color, odorless or almost odorless;
10 mg/5 mg capsules:
hard gelatin capsules of the Coni Snap type, size 0, unmarked, self-closing, with an opaque flesh (light pink) body and an opaque amethyst (dark pink) cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white in color, odorless or almost odorless;
10 mg/10 mg capsules:
hard gelatin capsules of the Coni Snap type, size 0, unmarked, self-closing, with an opaque dark maroon body and an opaque dark maroon cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white in color, odorless or almost odorless.
Pharmacotherapeutic group
ACE inhibitors and calcium channel blockers.
ATX code C09BB07.
Pharmacological properties
Pharmacodynamics
Mechanism of action of ramipril.
Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase (synonyms: angiotensin-converting enzyme, kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. The reduction in the formation of angiotensin II and the inhibition of the breakdown of bradykinin lead to vasodilation.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat helps to reduce aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (African) hypertensive patients (usually with low-renin states) than in white patients.
Pharmacodynamic action.
The use of ramipril causes a pronounced decrease in peripheral arterial resistance. In general, no significant changes in renal plasma flow and glomerular filtration rate were observed. The use of ramipril in patients with arterial hypertension leads to a decrease in blood pressure in the horizontal and vertical positions, without a compensatory increase in heart rate. In most patients, the onset of the antihypertensive effect of a single dose of ramipril occurs 1-2 hours after oral administration of the drug. The maximum effect after a single dose is usually achieved 3-6 hours after oral administration. The antihypertensive effect persists for 24 hours.
The maximum antihypertensive effect of long-term treatment with ramipril is generally apparent after 3-4 weeks. The antihypertensive effect has been shown to be maintained for up to 2 years with long-term therapy.
Abrupt discontinuation of ramipril does not lead to a rapid and excessive rebound increase in blood pressure.
Mechanism of action of amlodipine
Amlodipine inhibits the transmembrane influx of calcium ions in heart cells and vascular smooth muscle (slow calcium channel blocker or calcium ion antagonist).
The mechanism of antihypertensive action is due to the direct relaxing effect of amlodipine on vascular smooth muscle, which contributes to a decrease in systemic peripheral vascular resistance.
The exact mechanism by which amlodipine relieves angina is not fully understood, but it may have two actions:
1) amlodipine dilates peripheral arterioles, thus reducing total peripheral resistance (after load).
2) due to the above-described mechanism of action, amlodipine increases the supply of oxygen to the myocardium even in the case of coronary artery spasm (Prinzmetal's angina or variant angina).
Pharmacodynamic properties
In patients with hypertension, a single dose of amlodipine provides a clinically significant reduction in blood pressure for 24 hours in both the supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute hypotension.
In patients with angina, the use of amlodipine once daily prolongs the total time of possible physical exertion, delays the onset of an angina attack and prolongs the time to significant ST segment depression, reduces the frequency of angina attacks and reduces the need for glyceryl trinitrate tablets.
Amlodipine does not have an adverse effect on metabolism and blood plasma lipids, therefore it is suitable for the treatment of patients with bronchial asthma, diabetes mellitus, and gout.
Pharmacokinetics
Ramipril
Absorption
After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: maximum plasma concentrations of ramipril are reached within 1 hour. Taking into account the urinary excretion of ramipril, the extent of absorption is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at a dose of 2.5 mg and 5 mg is 45%.
The maximum plasma concentration of ramiprilat, the only active metabolite of ramipril, is reached 2-4 hours after taking ramipril. Steady-state plasma concentrations of ramiprilat are reached by the 4th day of treatment at usual doses (once daily).
Distribution
The binding of ramipril to blood proteins is approximately 73%, and that of ramiprilat is 56%.
Metabolism
Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.
Breeding
Excretion of metabolites is carried out mainly by the kidneys.
The decrease in plasma ramiprilat concentration occurs in several phases. Due to the strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat is characterized by a prolonged terminal elimination phase at very low plasma concentrations.
After multiple doses of ramipril, the effective half-life of ramiprilat is 13-17 hours after doses of 5-10 mg and longer after lower doses of 1.25-2.5 mg. The difference is due to the saturable capacity of the enzyme to bind ramiprilat.
After a single oral dose, ramipril and its metabolite were not detected in breast milk. However, the effect of multiple doses is unknown.
Patients with renal impairment.
Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal clearance of ramiprilat is proportionally related to creatinine clearance. This results in increased plasma concentrations of ramiprilat, which decline more slowly than in subjects with normal renal function.
Patients with impaired liver function.
In patients with impaired hepatic function, the metabolism of ramipril to ramiprilat is slowed down, which is due to reduced activity of hepatic esterases, and plasma levels of ramipril in these patients are increased. However, the maximum concentration of ramiprilat in these patients did not differ from that in individuals with normal hepatic function.
Amlodipine
Absorption
After oral administration, amlodipine is almost completely absorbed, reaching maximum plasma concentrations 6-12 hours after administration. Food intake does not affect the bioavailability of the drug. Absolute bioavailability is 64-80%.
Distribution
The volume of distribution is 21 l/kg body weight. Steady-state plasma concentrations (5-15 ng/ml) are reached within 7-8 days of administration. In vitro studies have shown that 93-98% of circulating amlodipine is bound to plasma proteins.
Metabolism and excretion
Amlodipine is extensively metabolized in the liver (almost 90%) to inactive pyridine derivatives.
10% of the parent compound and 60% of inactive metabolites are excreted in the urine, 20-25% in the feces.
The decrease in plasma concentration is biphasic. The terminal plasma elimination half-life is approximately 35-50 hours, taking into account once-daily dosing.
The total clearance is 7 ml/min/kg body weight (for patients with a body weight of 60 kg – 25 l/h). In elderly patients – 19 l/h.
Use in the elderly
The time to reach maximum plasma concentrations of amlodipine is similar in both elderly and younger patients. There is a tendency for amlodipine clearance to decrease in the elderly, resulting in an increase in the area under the concentration-time curve (AUC) and half-life. An increase in AUC and half-life has been reported in patients with congestive heart failure.
Patients with renal impairment
Patients with impaired liver function.
The half-life of amlodipine is prolonged in patients with impaired liver function.
Indication
For the treatment of hypertension in patients whose blood pressure is adequately controlled by individual drugs, administered simultaneously at the same dose as in the combination, but as separate tablets.
Contraindication
Contraindications associated with the use of ramipril:
a history of angioedema (hereditary, idiopathic or due to previous use of ACE inhibitors or angiotensin II receptor antagonists);
simultaneous use of the drug with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or with impaired renal function (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacodynamics”);
Concomitant use with sacubitril/valsartan is contraindicated due to increased risk of angioedema;
extracorporeal treatment, which results in blood coming into contact with negatively charged surfaces;
severe bilateral renal artery stenosis or renal artery stenosis of a single kidney;
arterial hypotension or hemodynamically unstable conditions;
hypersensitivity to the active substance;
Use is contraindicated in pregnant women and women planning to become pregnant (see section "Use during pregnancy and breastfeeding").
Contraindications associated with the use of amlodipine:
hypersensitivity to the active substance;
severe arterial hypotension;
shock (including cardiogenic shock);
narrowing of the outlet of the left ventricle (for example, severe aortic stenosis);
hemodynamically unstable heart failure after acute myocardial infarction.
Contraindications associated with the use of ramipril/amlodipine:
hypersensitivity to the active substances, dihydropyridine derivatives, ACE inhibitors (angiotensin-converting enzyme) or to any of the excipients.
Interaction with other medicinal products and other types of interactions
Ramipril
Contraindicated combinations.
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration with certain membranes with high hydraulic permeability (e.g. polyacrylonitrile), and low-density lipoprotein apheresis with dextran sulfate, due to an increased risk of severe anaphylactoid reactions. If such treatments are required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections 4.3 and 4.4). Treatment with the drug should only be initiated 36 hours after the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan should only be initiated 36 hours after the last dose of ramipril.
Use with caution.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalaemia and worsening renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
mTOR inhibitors or vildagliptin: An increased incidence of angioedema has been observed in patients receiving concomitant ACE inhibitors and mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised when initiating therapy.
Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): hyperkalemia may occur, therefore careful monitoring of plasma potassium levels is necessary.
Trimethoprim and fixed-dose combinations with sulfamethoxazole (co-trimoxazole):
An increased incidence of hyperkalemia has been observed in patients receiving ACE inhibitors and trimethoprim, and fixed-dose combinations with sulfamethoxazole (co-trimoxazole).
Antihypertensive drugs (e.g. diuretics) and other agents that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): possible increased risk of arterial hypotension.
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: blood pressure monitoring is recommended.
Lithium salts: ACE inhibitors may reduce the excretion of lithium and therefore may increase its toxicity. Monitoring of lithium levels in the blood is recommended.
Antidiabetic agents, including insulin: hypoglycemic reactions possible. Monitoring of blood glucose levels is recommended.
Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: possible reduction of the antihypertensive effect of ramipril. Therefore, the combined use of ACE inhibitors and non-steroidal anti-inflammatory drugs may lead to an increased risk of deterioration of renal function and an increase in blood potassium levels.
Neprilysin inhibitors (NEP): An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors (such as ramipril) and NEP inhibitors (such as racecadotril).
Amlodipine
Amlodipine is safe when used concomitantly with thiazide diuretics,
β-blockers, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.
Effects of other drugs on amlodipine
CYP3A4 inhibitors: When amlodipine was co-administered with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, plasma concentrations of amlodipine increased by approximately 22% and 50%, respectively. However, the clinical significance of these findings is unknown. It cannot be excluded that strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution in combination with CYP3A4 inhibitors. However, no adverse events associated with this interaction have been reported.
CYP3A4 inducers: There are no data on the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (rifampicin, St. John's wort) may result in decreased plasma concentrations of amlodipine. Caution should be exercised when amlodipine is used with CYP3A4 inducers.
Clinical interaction studies have shown that cimetidine, aluminum/magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.
Tacrolimus
With simultaneous administration of the drug with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood.
In order to avoid tacrolimus toxicity, the administration of amlodipine to a patient being treated with tacrolimus requires monitoring of tacrolimus blood levels and adjustment of tacrolimus dosage as necessary.
mTOR (mammalian target of rapamycin) inhibitors
mTOR inhibitors such as sirolimus, temsirolimus and velolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When co-administered with mTOR inhibitors, amlodipine may increase the exposure of mTOR inhibitors.
Dantrolene (infusion)
Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that calcium channel blockers such as amlodipine be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.
Effect of amlodipine on other medicinal products
Amlodipine may enhance the effect of other antihypertensive drugs.
Clinical interaction studies have not shown an effect of amlodipine on the pharmacokinetics of atorvastatin, digoxin, ethanol, warfarin or cyclosporine. Amlodipine does not affect laboratory parameters.
Cyclosporine
No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations, except in renal transplant patients, where variable increases in cyclosporine trough concentrations (mean 0-40%) were observed. Monitoring of cyclosporine levels should be considered in renal transplant patients receiving amlodipine; if necessary, a reduction in the cyclosporine dose should be considered.
Simvastatin: Co-administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.
Application features
Ramipril.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and worsening of renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections 4.5 and 5.1).
If such dual blockade therapy is considered absolutely necessary, it should only be used under specialist supervision and with frequent monitoring of renal function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Pregnancy: Treatment with ACE inhibitors is contraindicated during pregnancy. When pregnancy is diagnosed, ACE inhibitors should be stopped immediately and, if necessary, alternative treatment should be started (see sections 4.3 and 4.4).
Patients at high risk of developing arterial hypotension.
Patients with a strongly activated renin-angiotensin-aldosterone system. Patients with a strongly activated renin-angiotensin-aldosterone system are at risk of a sudden significant fall in blood pressure and deterioration of renal function due to ACE inhibition, particularly when an ACE inhibitor or concomitant diuretic is given for the first time or when the dose is increased for the first time. A strongly activated renin-angiotensin-aldosterone system, requiring medical supervision, including regular monitoring of blood pressure, may be expected, for example, in patients:
with severe arterial hypertension;
with decompensated congestive heart failure;
with hemodynamically significant obstruction to the inflow or outflow of blood from the left ventricle (for example, with aortic or mitral valve stenosis);
with unilateral renal artery stenosis in the presence of a second functioning kidney;
who have or may develop fluid or electrolyte depletion (including those receiving diuretics);
with liver cirrhosis and/or ascites;
who perform extensive surgical interventions or during anesthesia with the use of drugs that cause arterial hypotension.
It is generally recommended that dehydration, hypovolemia, or electrolyte depletion be corrected before initiating treatment (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).
Transient or persistent heart failure after myocardial infarction.
Patients at risk of cardiac or cerebral ischemia in the event of acute arterial hypotension. Special medical supervision is required in the initial phase of treatment.
Elderly patients: See section "Method of administration and dosage".
Surgery: If possible, treatment with angiotensin-converting enzyme inhibitors such as ramipril should be discontinued 1 day before surgery.
Monitoring of renal function. Renal function should be assessed before and during treatment and the dose adjusted, especially in the first weeks of treatment. Particularly careful monitoring is required in patients with impaired renal function (see section "Method of administration and dosage"). There is a risk of deterioration of renal function, especially in patients with congestive heart failure or after kidney transplantation.
Angioedema. Angioedema has been reported in patients treated with ACE inhibitors, including ramipril (see section 4.8). If angioedema develops, Hartil®-AM should be discontinued. Emergency treatment should be initiated immediately. The patient should be kept under medical observation for at least 12-24 hours and may be discharged after complete resolution of symptoms.
Intestinal angioedema has been reported in patients treated with ACE inhibitors, including ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea/vomiting).
Anaphylactic reactions during desensitization. The use of ACE inhibitors increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Ramipril should be temporarily discontinued before desensitization.
Hyperkalemia: Hyperkalemia has been observed in some patients treated with ACE inhibitors, including ramipril. Patients at risk for hyperkalemia include patients with renal insufficiency, patients over 70 years of age, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute cardiac decompensation, or metabolic acidosis. If concomitant use of the above-mentioned drugs is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section 4.5).
Hyponatremia
Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been observed rarely. Bone marrow suppression has also been reported. Monitoring of the white blood cell count is recommended to detect possible leukopenia. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or in those taking other medicinal products that may cause changes in the blood picture (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).
Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in non-blacks. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients than in non-blacks. This may be because black hypertensive patients are more likely to have low-renin hypertension.
Cough. Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. The possibility of ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Amlodipine.
The safety and efficacy of amlodipine for the treatment of hypertensive crisis have not been established.
Patients with heart failure.
Patients with heart failure require special consideration. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine-treated group than in the placebo group, but this was not associated with worsening heart failure.
Use in patients with impaired liver function.
In patients with impaired liver function, the half-life of amlodipine is increased, but dosage recommendations have not yet been developed. For this reason, amlodipine should be used with caution in such patients.
Use in elderly patients.
For elderly patients, dose increases should be carried out with caution.
Patients with renal failure.
This category of patients should use the usual doses of the drug. Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of renal dysfunction. Amlodipine is not removed by dialysis.
Amlodipine does not affect the results of laboratory tests.
It is not recommended to use amlodipine with grapefruit or grapefruit juice, as bioavailability may be increased in some patients, leading to increased hypotensive effect of the drug.
Anaphylactic reactions during desensitization
In combination with amlodipine:
Others.
The capsule shell of the 5 mg/5 mg and 10 mg/5 mg capsules contains Allura Red AC+ FD and C Red 40 (E 129), and the capsule shell of the 5 mg/10 mg and 10 mg/10 mg capsules contains Azorubine, Carmoisine (E 122). These dyes may cause allergic reactions.
Use during pregnancy or breastfeeding
Ramipril
It is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is detected during therapy, the drug should be discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women (see section "Contraindications").
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increased risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ACE inhibitor treatment should be stopped immediately and alternative therapy should be started.
The use of ACE inhibitors during the second and third trimesters of pregnancy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If an ACE inhibitor is used during the second trimester of pregnancy, ultrasound examination of renal function and the skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. Because there is insufficient information regarding the use of ramipril during breastfeeding, its use is not recommended and alternative treatments are preferable, especially while nursing a newborn or preterm infant.
Amlodipine
Pregnancy.
Use during pregnancy is recommended only when there is no safer alternative and when the disease itself poses a greater risk to the mother and fetus.
Breast-feeding.
A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding for the child and the benefit of amlodipine therapy for the mother.
Given the above information, the use of Hartil®-AM during pregnancy or breastfeeding is contraindicated.
Ability to influence reaction speed when driving vehicles or other mechanisms
Some side effects (e.g. symptoms of low blood pressure such as dizziness) may impair the ability to concentrate and react, which may affect the speed of reaction when driving or using other machinery.
These adverse reactions have been observed at the beginning of treatment or when switching from other drugs. After taking the first dose or when increasing the dose, it is not recommended to drive or operate other machinery for several hours.
Method of administration and doses
Hartil®-AM is indicated for patients whose blood pressure is adequately controlled with separately prescribed monocomponent drugs at the same doses as recommended for the fixed combination.
The recommended initial daily dose is 1 capsule with a dosage of 2.5 mg/2.5 mg.
Hartil®-AM should be taken once a day at the same time every day, regardless of meals.
Do not chew or crush the capsule.
The fixed combination is not suitable for initial therapy.
If necessary, the dose of Hartil®-AM can be changed or the components of the free combination can be individually titrated.
The daily dose can be increased to the maximum - 10 mg/10 mg (1 capsule of Hartil®-AM 10 mg/10 mg once a day).
Adults
Caution should be exercised in patients treated with diuretics, as excessive fluid and/or sodium loss may occur. Renal function and serum potassium should be monitored.
Special patient groups.
Patients with hepatic impairment
In patients with impaired liver function, treatment with ramipril should only be initiated under close medical supervision.
The maximum daily dose should be 2.5 mg of ramipril.
Doses of the drug for use in patients with mild to moderate hepatic insufficiency have not been established, therefore dose selection should be carried out with caution and use should be started at the lowest dose.
Patients with renal impairment
The optimal initial and maintenance dose for patients with renal insufficiency should be adjusted individually by separate titration of ramipril and amlodipine.
The daily dose of ramipril for patients with renal insufficiency should be calculated based on creatinine clearance:
if creatinine clearance is ≥ 60 ml/min, there is no need to adjust the initial dose; the maximum daily dose is 10 mg;
if creatinine clearance is 30-60 ml/min, there is no need to adjust the initial dose (2.5 mg per day), and the maximum daily dose is 5 mg;
if creatinine clearance is 10-30 ml/min, the initial daily dose is 1.25 mg per day, and the maximum daily dose is 5 mg;
For patients with hypertension undergoing hemodialysis: ramipril is only slightly removed by hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the drug should be taken a few hours after the hemodialysis session.
No dose adjustment of amlodipine is required in patients with renal insufficiency.
Amlodipine is not dialyzable. Amlodipine should be administered with extreme caution to patients undergoing dialysis.
During treatment Har
