Хартил® Amlo
the Trade name
of Hartil®
of Amlo Mezhdunarodnoye the unlicensed name
Is not present
the Dosage form
of the Capsule of 2.5 mg / 2.5 mg, 5 mg / 5 mg, 10 mg / 5 mg, 5 mg / 10 mg, 10 mg / 10 mg
Structure
One capsule of 2.5 mg / 2.5мг contains
active agents: a ramiprila of 2.5 mg
an amlodipina of 2.5 mg (3.475 mg of an amlodipin of the besilat are equivalent),
One capsule of 5 mg / 5мг contains
active agents: a ramiprila of 5 mg
an amlodipina of 5 mg (6.95 mg of an amlodipin of the besilat are equivalent),
One capsule of 5 mg / 10мг contains
active agents: a ramiprila of 5 mg
an amlodipina of 10 mg (13.9 mg of an amlodipin of the besilat are equivalent),
One capsule of 10 mg / 5мг contains
active agents: a ramiprila of 10 mg
an amlodipina of 5 mg (6.95 mg of an amlodipin of the besilat are equivalent),
One capsule of 10 mg / 10мг contains
active agents: ramiprila10mg
an amlodipina of 10 mg (13.9 mg of an amlodipin of the besilat are equivalent)
excipients: krospovidon, gipromelloza, cellulose microcrystalline, glitserola dibegenat.
Structure of a solid gelatin capsule (Coni-Snap 3):
gland (III) oxide red (E172), the titan dioxide (E 171), gelatin (for capsules of 2.5 mg / 2.5 mg),
diamond blue FCF+FD and C blue 1 (E 133), a pace red AC+FD and C red 40 (E 129), the titan dioxide (E 171), gelatin (for capsules of 5 mg / 5 mg),
Structure of a solid gelatin capsule (Coni-Snap 0):
the titan dioxide (E 171), gland (III) oxide red (E 172), an azoruby (karmoizin (E 122)), indigo carmine + FD and C blue 2 (E132), gelatin (for capsules of 5 mg / 10 mg),
the titan dioxide (E 171), gland (III) oxide red (E172), diamond blue FCF +FD and C blue 1 (E133), a pace red AC+FD and C red 40 (E 129), gelatin (for capsules of 10 mg / 5 mg),
an azoruby (karmoizin (E 122)), indigo carmine + FD and C blue 2 (E132), the titan dioxide (E 171), gelatin (for capsules of 10 mg / 10 mg).
The description
of the Capsule of 2.5 mg / 2.5 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 3 which, not marked, are self-closed with the opaque body of light pink color and an opaque cover of light pink color
of the Capsule of 5 mg / 5 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 3 which, not marked, are self-closed with the opaque body of light-burgundy color and an opaque cover of light-burgundy color.
Capsules of 5 mg / 10 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 0 which, not marked, are self-closed with the opaque body of light pink color and an opaque cover of dark burgundy color
of the Capsule of 10 mg / 5 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 0 which, not marked, are self-closed with the opaque body of light pink color and an opaque cover of light-burgundy color
of the Capsule of 10 mg / 10 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 0 which, not marked, are self-closed with the opaque body of dark burgundy color and an opaque cover of the dark burgundy
Contents of Capsules color - the mix of granules and powders which is not containing mechanical impurity, white or almost white color without or almost flavourless.
Pharmacotherapeutic group
the Drugs influencing a system renin-angiotensin. AKF inhibitors in a combination with blockers of slow calcium channels. Ramipril and amlodipin.
The ATX C09BB07 code
After intake ramiprit the Pharmacological Pharmacokinetics properties quickly is soaked up from digestive tract. The peak of concentration of a ramipril in plasma is reached within 1 hour. Taking into account urine removal, the level of absorption is, at least, 56% and does not depend on meal. The bioavailability of an active metabolite of the ramiprilat after intake of 2.5 mg and 5 mg of a ramipril is 45%.
The peak of plasma concentration of the ramiprilat, the only active metabolite of a ramipril, is reached in 2 - 4 hours after reception of a ramipril. The equilibrium condition of plasma concentration of the ramiprilat is reached, approximately, for the 4th day of reception of a ramipril in a therapeutic dose. Linking of a ramipril with serum proteins makes about 73%, and the ramiprilat - about 56%. Ramipril is almost completely metabolized in ramiprilat and in diketopiperazine ether, diketopiperazine acid and in glucuronides of a ramipril and the ramiprilat. Excretion of metabolites is carried out, generally through kidneys. Plasma concentration of the ramiprilat decrease in the polyphase mode. Thanks to the saturable linking with APF and weak dissociation with enzyme, ramiprilat shows a long final phase of elimination at very low concentration of drug in plasma. After multiple dose of a ramipril on one dose a day, effective elimination half-life of the ramiprilat made 13 - 17 hours (at a dosage of 5 - 10 mg), and after decrease in a dosage to 1.25 - 2.5 mg this period was extended. This distinction is connected with the saturating ability of enzyme which communicates with ramiprilaty.
After single dose of a dose of a ramipril of signs of maintenance of a ramipril and its metabolites in breast milk it was not established. However influence of a ramipril on breast milk at repeated introduction of doses of drug remains obscure.
Patients with a renal failure
the Renal excretion of the ramiprilat decreases at patients with renal failures, and renal clearance of the ramiprilat in proportion we depend on clearance of creatinine. It leads to increase in plasma concentration of the ramiprilat which decrease more slowly, than at patients with normal function of kidneys.
Patients with a liver failure
At patients with abnormal liver functions, metabolic transformation of a ramipril in ramiprilat slows down owing to decrease of the activity of hepatic esterases, and plasma levels of a ramipril at these patients increase. Peak values of concentration of the ramiprilat at these patients, however, do not differ from similar indicators at patients with normal function of a liver.
After intake amlodipin it is slowly absorbed from digestive tract. The maximum concentration in blood serum is observed in 6–12 hours the Meal does not affect bioavailability of an amlodipin. The absolute bioavailability is 64-80%. The volume of distribution is 21 l/kg (body weight). Equilibrium concentration in blood plasma (5–15 ng/ml) is reached in 7 – 8 days of daily administration of drug. The researches in vitro showed that 93–98% of the amlodipin circulating in a blood-groove contact proteins of blood plasma. Amlodipin is quickly metabolized (approximately for 90%) in a liver with formation of inactive metabolites. About 10% of initial connection and 60% of inactive metabolites are excreted with urine, 20-25% with a stake. Decrease in concentration in blood plasma has two-phase character. Final eliminative plasma elimination half-life of blood makes about 35 - 50 hours at reception of 1 times a day. The general clearance is equal to 7 ml/min. (weighing patient of 60 kg - 25 l/hour). At elderly patients this value is 19 l/hour.
The pharmacokinetics of an amlodipin does not undergo significant changes in a renal failure and with increase in age of patients.
Patients of advanced age
Time of achievement of peak concentration of an amlodipin in plasma at patients of advanced and young age matches. The clearance of an amlodipin, as a rule, decreases with increase in an indicator of AUC and elimination half-life at elderly patients. Patients with stagnant heart failure had the same increase in an indicator of AUC and elimination half-life, as at patients of advanced age.
Patients with renal failures
Amlodipin is extensively metabolized with education inactive metabolites. 10% of initial connection are removed in not changed view with urine. Changes of plasma concentration of an amlodipin are not connected with degree of a renal failure. Such patients can accept usual doses of an amlodipin. Dialysis of an amlodipin is inefficient.
Patients with abnormal liver functions
the Elimination half-life of an amlodipin at patients with abnormal liver functions is extended.
A pharmacodynamics
Hartil Amlo - the combined antihypertensive drug which part are a blocker of slow calcium channels (amlodipin) and APF inhibitor (ramiprit).
Ramiprilat, an active metabolite of a ramipril, competitively inhibits activity of the angiotensin-converting enzyme (ACE), reduces the speed of transformation of angiotensin I into angiotensin II. Reduction of concentration of angiotensin II is resulted by secondary increase in activity of renin of plasma due to elimination of negative feedback at release of renin and direct decrease in secretion of Aldosteronum. Reduces degradation of bradykinin and increases synthesis of prostaglandins. Reduction of formation of angiotensin II and increase in activity of bradykinin leads to vasodilatation and makes the contribution to cardioprotective and endotelioprotektivny action of a ramipril.
The average level of the response to monotherapy with prescribing of APF inhibitor was lower in population of black (Afro-Caribbean) patients with arterial hypertension (population of patients with hypertensia, and, as a rule, with the low content of renin), than at patients with other skin color.
Thanks to vasodilating action reduces the general peripheric vascular resistance (afterload), pressure in pulmonary capillaries (preloading) and resistance in pulmonary vessels. Usually does not cause significant changes in a renal blood-groove (in some cases it raises) and glomerular filtration rate. Drug causes antihypertensive effect both in position of the patient standing, and in a prone position without compensatory increase in heart rate.
The antihypertensive effect begins in 1-2 hours after intake of a single dose of drug, the maximum effect develops in 3-6 hours after reception and remains within 24 hours. At daily use the hypotensive activity gradually increases within 3-4 weeks and remains at long-term treatment. At short-term cancellation the significant increase in arterial blood pressure is not observed (there is no withdrawal).
Amlodipin inhibits transmembrane transition of calcium ions to myocardial and smooth vascular muscle cells (a blocker of slow calcium channels or the antagonist of calcium ions). The mechanism of antihypertensive action is connected with the direct relaxing effect on smooth muscles of vessels that leads to decrease in peripheric vascular resistance.
The exact mechanism by means of which stenocardia symptoms are facilitated completely is not installed, and can include:
1) expansion of peripheral arterioles, thus, reduction of the general peripheric resistance (afterload). As it does not lead to reflex tachycardia, energy expenses a myocardium and oxygen requirement decrease.
2) due to expansion of the main coronal arteries and arterioles as in normal, and ischemic areas, there is an oxygen supply improvement. At the expense of it supply of oxygen to a myocardium, even in case of a spasm of coronal arteries (alternative stenocardia or Printsmetal's stenocardia) increases.
At patients with arterial hypertension, single dose of drug for day provides clinically significant lowering of arterial pressure, as in a dorsal decubitus, and standing. Thanks to the slow beginning of action, sudden arterial hypotension is not characteristic.
At patients with stenocardia, at single dose in day the general time of tolerance to physical activities, time increases up to development of an attack of stenocardia and time to a significant depression of a segment of ST and also the frequency of attacks of stenocardia and quantity of the consumed glyceryl trinitrate tablets decreases. It was not connected with undesirable metabolic effects: drug did not affect the level of lipids in blood plasma, sugar level in blood and uric acid in blood serum, and was useful at patients with bronchial asthma.
Indications
- arterial hypertension, as drug of replacement therapy at which at patients simultaneous use of a ramipril and amlodipin in therapeutic doses, have adequate effect, as in a combination, and separately.
The route of administration and doses
use Drug strictly on doctor's orders!
Хартил® Amlo should be accepted at the same time day, every day throughout a course of treatment, both to meal, and after it. It is not necessary to crush or chew capsules.
The recommended daily dose - 1 capsule of a certain dosage.
The combined drug with a certain dosage is not suitable for the initial stage of therapy.
If there was a need for correction of a dosage, then the dose of the drug Hartil® Amlo can be changed or dosages of separate components at their free combination can be reconsidered.
Use of drug in group of adult patients
Is recommended to appoint drug with care to the patients accepting diuretics as these patients can have a disturbance of water and electrolytic balance. It is necessary to investigate renal function and to determine potassium level in blood serum.
Patients with abnormal liver functions
At patients with an abnormal liver function, treatment ramiprily has to be begun only under careful medical observation, at the same time the maximum daily dose makes 2.5 mg of a ramipril.
It is recommended to appoint Amlo's Hartil® only to those patients who were transferred to a dosage of 2.5 mg of a ramipril as an optimum maintenance dose at selection of dosing of a ramipril.
In case of a liver failure, the period of elimination of an amlodipin can increase. There are no exact recommendations about dosing concerning an amlodipin therefore drug at these patients has to be appointed with care.
Patients with renal failures
For definition of an optimum combination of an initial and maintenance dose at patients with renal failures, the dosage of drug is selected by individual definition of dosages of a ramipril and an amlodipin.
The daily dose of a ramipril at patients with a renal failure has to be established taking into account clearance of creatinine.
- with clearance of creatinine ≥ 60 ml/min., correction of an initial dose are not required from patients, the maximum daily dose - 10 mg,
- patients with clearance of creatinine
have no need for correction of a dosage of an amlodipin of patients with renal failures.
Amlodipin is not brought in the course of dialysis. The patients undergoing the procedure of dialysis amlodipin should appoint with extra care.
During the Hartil® drug treatment of Amlo the control of functional capacity of kidneys and content of potassium in blood serum is required. In case of deterioration in renal function the use of the drug Hartil® Amlo has to be stopped, and it is necessary to appoint his components in the doses modified properly.
Use for patients of advanced age
of the Initial ramipril of a dose has to be lower usual, and the subsequent correction of a dosage has to be softer, because of high risk of emergence of side effects. It is not recommended to appoint Amlo's Hartil® to very old and weak patients.
Elderly patients can accept usual doses of an amlodipin to raise, however, a dose of drug follows with care.
Use for patients of children's and teenage age
is not recommended to appoint Amlo's Hartil® to children and teenagers 18 years as safety and efficiency of use of drug in this group of patients is not established are younger.
Side effects
concerning a ramipril:
Often (from ≥ 1/100 to <>
- a headache, dizziness, fatigue
- a hyperpotassemia
- arterial hypotension, orthostatic hypotension, faints
- the dry irritating cough, bronchitis, sinusitis, short wind
- inflammation of digestive tract, digestion disturbance, discomfortable feelings in a stomach, dyspepsia, diarrhea, nausea, vomiting
- rash, makulopapulyozny dermatitis
- muscular spasms, myalgias
- a stethalgia
Infrequently (from ≥ 1/1000 to <>
- an eosinophilia
- suppressed mood, alarm, nervousness, concern, a sleep disorder, including drowsiness
- anorexia, a loss of appetite
- vertigo, paresthesias, loss of taste, a food faddism
- disorders of vision, including vagueness of sight
- myocardium ischemia, including stenocardias or a myocardial infarction, tachycardia, arrhythmia, heartbeat, peripheral swell
- rush of blood to the person
- a bronchospasm, including aggravation of a course of asthma, congestion of a nose
- pancreatitis (it was reported about very exceptional cases of a lethal outcome connected with use of APF inhibitors), increase in level of enzymes of a pancreas, an insignificant Quincke's disease of intestines, pain in an upper part of a stomach, including gastritis, constipations, dryness in a mouth
- increase in level of liver enzymes and/or bilirubin
- in exceptional cases, the Quincke's disease causing disturbance of passability of airways with the subsequent lethal outcome, an itching, perspiration
- an arthralgia
- a renal failure, including, an acute renal failure, urination increase, a severe form of a proteinuria, increase in level of urea in blood, increase in level of creatinine of blood
- decrease a libido, passing erectile impotence
- a hyperthermia
Seldom (from ≥ 1/10000 to <>
- a leukopenia (including, a neutropenia or an agranulocytosis), an erythropenia, decrease in level of hemoglobin, reduction of quantity of thrombocytes
- confusion of consciousness
- a tremor, balance disturbances
- conjunctivitis
- a hearing disorder, sonitus
- a glossitis
- a vascular stenosis, hypoperfusion, a vasculitis
- cholestatic jaundice, hepatocellular defeats
- exfoliative dermatitis, a small tortoiseshell, onikholizis
- an asthenia
Very seldom (
-reaction of photosensitivity
Does not know (on the basis of the available data assessment is impossible).
- damage of marrow, a pancytopenia, hemolytic anemia
- anaphylactic or anaphylactoid reactions, increase in quantity of anti-nuclear antibodies
- reduction of content of sodium in blood
- disturbance of ability to concentration of attention
- brain ischemia, including an ischemic stroke and tranzitorny ischemia, disturbance of psychomotor reactions, burning sensation, a parosmiya
- Reynaud's syndrome
- aphthous stomatitis
- an acute liver failure, cholestatic or cytolytic hepatitis (the lethal outcome was observed in exceptional cases)
- a gynecomastia
- a toxic epidermal necrolysis, Stephens-Johnson's syndrome, a multiformny erythema, a bladderwort, psoriasis in heavy degree, psoriazoformny dermatitis, a pemfigoidny or lichenoid dieback and an enantema, an alopecia
concerning an amlodipin:
Often (from ≥ 1/100 to <>
- a headache, dizziness, drowsiness (especially in an initiation of treatment), fatigue
- heartbeat
- rush of blood to the person
- nausea, an abdominal pain
- swell, puffiness of an ankle joint
Infrequently (from ≥ 1/1000 to <>
- a hyperglycemia
- change of mood (including alarm), insomnia, a depression
- a tremor, a food faddism, a syncope, a hypesthesia, paresthesias
- disorders of vision (including, a diplopia)
- a ring in ears
- arterial hypotension
- short wind, rhinitis
- vomiting, dyspepsia, change of motility of intestines (including diarrheas and constipations), feeling of dryness in a mouth
- an alopecia, a purpura, discoloration of skin, the increased perspiration, an itching, rash, a dieback
- arthralgias, myalgias, muscular spasms, dorsodynias
- urination disorder, a nocturia, increase in frequency of urination
- disturbance of potency, a gynecomastia
- a stethalgia, weakness, pain, an indisposition
- increase or decrease in body weight
Is rare (from ≥ 1/10000 to <>
- confusion of consciousness
Very seldom (
-a leukopenia, thrombocytopenia
- arterial hypertension, peripheral neuropathy
- a myocardial infarction, arrhythmias (including, bradycardia, ventricular tachycardia and fibrillation of auricles)
- a vasculitis
- cough
- pancreatitis, gastritis, a hyperplasia of gums
- jaundice *, hepatitis *
- a Quincke's disease, a multiformny erythema, a small tortoiseshell, exfoliative dermatitis, Stephens-Johnson's syndrome, a photosensitization
- increase in level of liver enzymes *
* In most cases with a cholestasia.
Contraindications
- hypersensitivity to a ramipril (or to APF inhibitors), to an amlodipin, dihydropyridine derivatives, and/or any of excipients
- existence in the anamnesis of a Quincke's disease (hereditary, idiopathic or arisen because of the previous Quincke's disease caused by use of APF inhibitors or antagonists of receptors of angiotensin II (APAT II)
- the extracorporal treatment which is followed by contact of blood with negatively charged surfaces
- the profound bilateral stenosis of renal arteries or a renal artery stenosis of the only operating kidney
- pregnancy and in the period of a lactation
- ramiprit it is not necessary to appoint to patients with hypotensive or hemodynamically unstable states
- a severe form of hypotension
- shock (including, cardiogenic shock)
- the vasoconstriction interfering outflow of blood from a left ventricle (for example, an aortal stenosis of heavy degree)
- hemodynamically unstable heart failure after the postponed acute myocardial infarction
Medicinal interactions
the Extracorporal procedures which are followed by contact of blood with negatively charged surfaces such as hemodialysis through high-permeability membranes (for example, membranes from polyacrylonitrile connections), haemo filtration or aferez lipoproteins of low density with dextran sulfate use, because of the increased danger of development of heavy anaphylactic or anaphylactoid reactions. If such treatment is necessary, then it is necessary to consider a question of use of other type of membranes for dialysis or antihypertensive drugs of other category.
At a concomitant use with the potassium drugs, kaliysberegayushchy diuretics and other active agents increasing plasma levels of potassium (including, with antagonists of receptors of angiotensin II, Trimethoprimum, takrolimusy, cyclosporine) development of a hyperpotassemia is possible therefore it is necessary to control attentively potassium level in blood serum.
At a concomitant use with antihypertensive drugs (for example, diuretics) and other substances which can reduce arterial blood pressure (for example, nitrates, tricyclic antidepressants, anesthetics, alcohol, Baclofenum, alfuzoziny, docsazoziny, Prazozinum, tamsuloziny, terazoziny) potentiation of risk of hypotension is possible.
At a concomitant use with angiotonic sympathomimetics and other drugs (for example, Isoproterenolum, Dobutaminum, a dopamine, adrenaline), decrease in antihypertensive effect of a ramipril is possible therefore carrying out monitoring of arterial blood pressure is recommended.
At a concomitant use with Allopyrinolum, immunodepressants, corticosteroids, procaineamide, cytostatics and other drugs which can change quantity of blood cells the likelihood of development of hematologic reactions raises.
At a concomitant use of APF inhibitors with drugs of lithium the reduction of its discharge and, respectively, increase in concentration of lithium in blood with the subsequent increase in its toxicity is possible. Regular control of level of lithium is necessary.
At a concomitant use with antidiabetic means (including, insulin) hypoglycemic reactions can develop. It is recommended to control strictly glucose level in blood.
At a concomitant use with non-steroidal anti-inflammatory drugs and acetylsalicylic acid the decrease in antihypertensive effect of a ramipril is possible. Besides, the combined use of APF and NPVS inhibitors can cause development of a hyperpotassemia and increase risk of a renal failure.
Drug is safely compatible to thiazide diuretics, β-blockers, nitrates of the prolonged action, sublingual dosage forms of nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics and oral hypoglycemic drugs.
At a concomitant use of drug with CYP3A4 inhibitor erythromycin at young patients and diltiazem at elderly patients, respectively, plasma concentration of an amlodipin increases by 22% and 50%, respectively. However, the clinical value of this circumstance remains obscure. It is impossible to exclude that powerful CYP3A4 inhibitors (for example, ketokonazol, itrakonazol, ritonavir) can increase plasma concentration of an amlodipin more than diltiazem. Amlodipin it is necessary to use with care at joint appointment with CYP3A4 inhibitors. However, messages about any side effects connected with similar interaction did not arrive.
Inductors CYP3A4: data on influence of the inductors CYP3A4 on amlodipin are absent. The combined use of drug with the inductors CYP3A4 (for example, the rifampicin or a St. John's wort which is made a hole) can lower plasma concentration of an amlodipin. Amlodipin it is necessary to use with care at joint appointment with the inductors CYP3A4.
During clinical trials of interaction with medicinal substances, simultaneous use of an amlodipin with grapefruit juice, Cimetidinum, aluminum/magnesium (antiacid drugs) and sildenafily did not influence pharmacokinetics of an amlodipin.
Simultaneous use of an amlodipin with other antihypertensive drugs enhances their therapeutic effectiveness.
During clinical trials of interaction with medicinal substances, amlodipin did not influence pharmacokinetics of an atorvastatin, digoxin, ethanol (alcohol), warfarin or cyclosporine.
Influence of an amlodipin on change of indicators of laboratory researches is not established.
Special instructions
Patients with the increased risk of developing of hypotension:
- Patients with the system which is hyper activated renin-angiotensin-aldosteronovoy are exposed to essential risk of acute falling of arterial blood pressure and deterioration in function of kidneys owing to APF inhibition, in particular, when APF inhibitors or the accompanying diuretics are appointed for the first time, or for the first time there is an increase in their dosage.
If hyper activation manifestation renin-angiotensin-aldosteronovoy of a system is obviously possible, then it is necessary to organize, if necessary, medical observation, including, monitoring of arterial blood pressure:
· at patients with heavy hypertensia,
· at patients with dekompensirovanny stagnant heart failure,
· at patients with hemodynamically significant inflow to a left ventricle or the complicated outflow from it (for example, a stenosis of an aorta or the mitral valve),
· at patients with a unilateral renal artery stenosis of the only operating kidney,
· at patients with existing (or possible) disturbances of water and electrolytic balance (including the patients accepting diuretics),
· at patients with cirrhosis and/or ascites,
· at the patients who underwent difficult surgery, or being exposed to anesthesia using the drugs causing hypotension
, in general, carrying out correction of conditions of dehydration, a hypovolemia or deficiency of salts prior to treatment (at patients with heart failure, however, all pluses and minuses of such actions, taking into account risk of a volume overload have to be carefully weighed) is recommended.
- at patients with tranzitorny (passing) or constant heart failure after the postponed myocardial infarction,
- at patients with risk of developing cardial or cerebral ischemia or in cases of acute hypotension.
At the initial stage of treatment the careful medical observation is required.
Safety and efficiency of an amlodipin in hypertensive crisis was not established.
It is necessary to appoint with care drug to patients with heart failure. During long placebo - a controlled research with participation of patients with heavy heart failure (III and IV class on NYHA) fluid lungs cases which frequency of emergence was higher in group with purpose of an amlodipin, in comparison with group of placebo were registered, but it was not followed by heavier heart failure.
At patients with abnormal liver functions the elimination half-life of an amlodipin is extended, recommendations about change of a dosage are absent. Patients of this group have to take amlodipin with caution.
Elderly patients have to take amlodipin with caution.
Patients with renal failures can accept amlodipin in usual doses. Changes of plasma concentration of an amlodipin of concentration do not correlate with degree of a renal failure. Amlodipin at dialysis is not brought.
It is recommended to stop, whenever possible, use of APF inhibitors, such as ramiprit, in one day prior to performing surgical intervention.
Renal function needs to be investigated prior to treatment and during it, and the dosage of drug is adjusted, in particular, in the first weeks of treatment. Patients with a renal failure require carrying out especially careful control. There is a risk of a renal failure, especially at patients with stagnant heart failure or after transplantation of a kidney.
It was in rare instances reported about developing of a Quincke's disease at the patients accepting APF inhibitors including, ramiprit.
When developing a Quincke's disease the use of a ramipril has to be stopped. In this case immediately use means and methods of emergency treatment. The patient has to be under observation, at least, for 12 - 24 hours, to full permission of symptoms. It was reported about developing of an intestinal Quincke's disease at the patients accepting APF inhibitors including, ramiprit. These patients complained of pains in a stomach (with symptoms of nausea or vomiting, or without those).
In rare instances at the patients taking the drug at the desensibilizing therapy for the purpose of prevention or treatment of allergic reaction to a sting of insects heavy, life-threatening anaphylactic reactions developed. Therefore before completion of desensitization it is necessary to consider a question of the temporary termination of reception of a ramipril.
At some patients accepting APF inhibitors and, including, ramiprit, the hyperpotassemia was observed. Patients with a renal failure, patients of advanced age (70 years are more senior), patients with uncontrollable diabetes, or the patients accepting the potassium salts, kaliysoderzhashchy diuretics and other active agents promoting increase in level of potassium in blood plasma and also patients at such states as dehydration, an acute heart failure or a metabolic acidosis enter into group of patients with the increased risk of development of a hyperpotassemia. If simultaneous use of above-mentioned medicines is recognized as reasonable, then carrying out regular control of level of potassium in blood serum is recommended.
There are rare messages about cases of a neutropenia/agranulocytosis, thrombocytopenia and anemia and also about a marrow depression. For perhaps earlier detection of a leukopenia it is recommended to control quantity of leukocytes. More frequent control at the initial stage of treatment and among patients with renal failures and also patients with the accompanying collagenoses (for example, a lupus erythematosus or a scleroderma), and at all patients accepting other medicines which could cause changes of a picture of blood is recommended.
At the patients of negroid race accepting APF inhibitors, the Quincke's disease develops more often than at other patients. As well as other APF inhibitors, ramiprit can render smaller hypotensive effect at patients of negroid race, in comparison with persons of other race, perhaps, owing to higher frequency of persons with the low level of renin in population of patients of negroid race with arterial hypertension.
Administration of drug can be followed by dry cough with continuous increase in a tussive reflex. Cough can stop after drug withdrawal. The cough caused by administration of drug should be considered differential diagnostic character.
Pregnancy and the period of a lactation
APF Inhibitors, such as ramiprit, or antagonists of receptors of angiotensin II (APAT II) are contraindicated during pregnancy. If there is a need of continuation of therapy using APF/ARAT II inhibitors, then the patients planning pregnancy have to change the therapeutic mode to alternative antihypertensive treatment which meets safety requirements at its appointment during pregnancy. At pregnancy confirmation the treatment using APF/ARAT II inhibitors has to be immediately stopped, and, if necessary, use of alternative therapy has to be begun.
The epidemiological data confirming risk of teratogenecity after influence of APF inhibitors during the I trimester of pregnancy are not rather convincing, however it is not necessary to exclude
the Trade name
of Hartil®
of Amlo Mezhdunarodnoye the unlicensed name
Is not present
the Dosage form
of the Capsule of 2.5 mg / 2.5 mg, 5 mg / 5 mg, 10 mg / 5 mg, 5 mg / 10 mg, 10 mg / 10 mg
Structure
One capsule of 2.5 mg / 2.5мг contains
active agents: a ramiprila of 2.5 mg
an amlodipina of 2.5 mg (3.475 mg of an amlodipin of the besilat are equivalent),
One capsule of 5 mg / 5мг contains
active agents: a ramiprila of 5 mg
an amlodipina of 5 mg (6.95 mg of an amlodipin of the besilat are equivalent),
One capsule of 5 mg / 10мг contains
active agents: a ramiprila of 5 mg
an amlodipina of 10 mg (13.9 mg of an amlodipin of the besilat are equivalent),
One capsule of 10 mg / 5мг contains
active agents: a ramiprila of 10 mg
an amlodipina of 5 mg (6.95 mg of an amlodipin of the besilat are equivalent),
One capsule of 10 mg / 10мг contains
active agents: ramiprila10mg
an amlodipina of 10 mg (13.9 mg of an amlodipin of the besilat are equivalent)
excipients: krospovidon, gipromelloza, cellulose microcrystalline, glitserola dibegenat.
Structure of a solid gelatin capsule (Coni-Snap 3):
gland (III) oxide red (E172), the titan dioxide (E 171), gelatin (for capsules of 2.5 mg / 2.5 mg),
diamond blue FCF+FD and C blue 1 (E 133), a pace red AC+FD and C red 40 (E 129), the titan dioxide (E 171), gelatin (for capsules of 5 mg / 5 mg),
Structure of a solid gelatin capsule (Coni-Snap 0):
the titan dioxide (E 171), gland (III) oxide red (E 172), an azoruby (karmoizin (E 122)), indigo carmine + FD and C blue 2 (E132), gelatin (for capsules of 5 mg / 10 mg),
the titan dioxide (E 171), gland (III) oxide red (E172), diamond blue FCF +FD and C blue 1 (E133), a pace red AC+FD and C red 40 (E 129), gelatin (for capsules of 10 mg / 5 mg),
an azoruby (karmoizin (E 122)), indigo carmine + FD and C blue 2 (E132), the titan dioxide (E 171), gelatin (for capsules of 10 mg / 10 mg).
The description
of the Capsule of 2.5 mg / 2.5 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 3 which, not marked, are self-closed with the opaque body of light pink color and an opaque cover of light pink color
of the Capsule of 5 mg / 5 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 3 which, not marked, are self-closed with the opaque body of light-burgundy color and an opaque cover of light-burgundy color.
Capsules of 5 mg / 10 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 0 which, not marked, are self-closed with the opaque body of light pink color and an opaque cover of dark burgundy color
of the Capsule of 10 mg / 5 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 0 which, not marked, are self-closed with the opaque body of light pink color and an opaque cover of light-burgundy color
of the Capsule of 10 mg / 10 mg (ramiprit / amlodipin): the solid gelatin capsules of CONI-SNAP 0 which, not marked, are self-closed with the opaque body of dark burgundy color and an opaque cover of the dark burgundy
Contents of Capsules color - the mix of granules and powders which is not containing mechanical impurity, white or almost white color without or almost flavourless.
Pharmacotherapeutic group
the Drugs influencing a system renin-angiotensin. AKF inhibitors in a combination with blockers of slow calcium channels. Ramipril and amlodipin.
The ATX C09BB07 code
After intake ramiprit the Pharmacological Pharmacokinetics properties quickly is soaked up from digestive tract. The peak of concentration of a ramipril in plasma is reached within 1 hour. Taking into account urine removal, the level of absorption is, at least, 56% and does not depend on meal. The bioavailability of an active metabolite of the ramiprilat after intake of 2.5 mg and 5 mg of a ramipril is 45%.
The peak of plasma concentration of the ramiprilat, the only active metabolite of a ramipril, is reached in 2 - 4 hours after reception of a ramipril. The equilibrium condition of plasma concentration of the ramiprilat is reached, approximately, for the 4th day of reception of a ramipril in a therapeutic dose. Linking of a ramipril with serum proteins makes about 73%, and the ramiprilat - about 56%. Ramipril is almost completely metabolized in ramiprilat and in diketopiperazine ether, diketopiperazine acid and in glucuronides of a ramipril and the ramiprilat. Excretion of metabolites is carried out, generally through kidneys. Plasma concentration of the ramiprilat decrease in the polyphase mode. Thanks to the saturable linking with APF and weak dissociation with enzyme, ramiprilat shows a long final phase of elimination at very low concentration of drug in plasma. After multiple dose of a ramipril on one dose a day, effective elimination half-life of the ramiprilat made 13 - 17 hours (at a dosage of 5 - 10 mg), and after decrease in a dosage to 1.25 - 2.5 mg this period was extended. This distinction is connected with the saturating ability of enzyme which communicates with ramiprilaty.
After single dose of a dose of a ramipril of signs of maintenance of a ramipril and its metabolites in breast milk it was not established. However influence of a ramipril on breast milk at repeated introduction of doses of drug remains obscure.
Patients with a renal failure
the Renal excretion of the ramiprilat decreases at patients with renal failures, and renal clearance of the ramiprilat in proportion we depend on clearance of creatinine. It leads to increase in plasma concentration of the ramiprilat which decrease more slowly, than at patients with normal function of kidneys.
Patients with a liver failure
At patients with abnormal liver functions, metabolic transformation of a ramipril in ramiprilat slows down owing to decrease of the activity of hepatic esterases, and plasma levels of a ramipril at these patients increase. Peak values of concentration of the ramiprilat at these patients, however, do not differ from similar indicators at patients with normal function of a liver.
After intake amlodipin it is slowly absorbed from digestive tract. The maximum concentration in blood serum is observed in 6–12 hours the Meal does not affect bioavailability of an amlodipin. The absolute bioavailability is 64-80%. The volume of distribution is 21 l/kg (body weight). Equilibrium concentration in blood plasma (5–15 ng/ml) is reached in 7 – 8 days of daily administration of drug. The researches in vitro showed that 93–98% of the amlodipin circulating in a blood-groove contact proteins of blood plasma. Amlodipin is quickly metabolized (approximately for 90%) in a liver with formation of inactive metabolites. About 10% of initial connection and 60% of inactive metabolites are excreted with urine, 20-25% with a stake. Decrease in concentration in blood plasma has two-phase character. Final eliminative plasma elimination half-life of blood makes about 35 - 50 hours at reception of 1 times a day. The general clearance is equal to 7 ml/min. (weighing patient of 60 kg - 25 l/hour). At elderly patients this value is 19 l/hour.
The pharmacokinetics of an amlodipin does not undergo significant changes in a renal failure and with increase in age of patients.
Patients of advanced age
Time of achievement of peak concentration of an amlodipin in plasma at patients of advanced and young age matches. The clearance of an amlodipin, as a rule, decreases with increase in an indicator of AUC and elimination half-life at elderly patients. Patients with stagnant heart failure had the same increase in an indicator of AUC and elimination half-life, as at patients of advanced age.
Patients with renal failures
Amlodipin is extensively metabolized with education inactive metabolites. 10% of initial connection are removed in not changed view with urine. Changes of plasma concentration of an amlodipin are not connected with degree of a renal failure. Such patients can accept usual doses of an amlodipin. Dialysis of an amlodipin is inefficient.
Patients with abnormal liver functions
the Elimination half-life of an amlodipin at patients with abnormal liver functions is extended.
A pharmacodynamics
Hartil Amlo - the combined antihypertensive drug which part are a blocker of slow calcium channels (amlodipin) and APF inhibitor (ramiprit).
Ramiprilat, an active metabolite of a ramipril, competitively inhibits activity of the angiotensin-converting enzyme (ACE), reduces the speed of transformation of angiotensin I into angiotensin II. Reduction of concentration of angiotensin II is resulted by secondary increase in activity of renin of plasma due to elimination of negative feedback at release of renin and direct decrease in secretion of Aldosteronum. Reduces degradation of bradykinin and increases synthesis of prostaglandins. Reduction of formation of angiotensin II and increase in activity of bradykinin leads to vasodilatation and makes the contribution to cardioprotective and endotelioprotektivny action of a ramipril.
The average level of the response to monotherapy with prescribing of APF inhibitor was lower in population of black (Afro-Caribbean) patients with arterial hypertension (population of patients with hypertensia, and, as a rule, with the low content of renin), than at patients with other skin color.
Thanks to vasodilating action reduces the general peripheric vascular resistance (afterload), pressure in pulmonary capillaries (preloading) and resistance in pulmonary vessels. Usually does not cause significant changes in a renal blood-groove (in some cases it raises) and glomerular filtration rate. Drug causes antihypertensive effect both in position of the patient standing, and in a prone position without compensatory increase in heart rate.
The antihypertensive effect begins in 1-2 hours after intake of a single dose of drug, the maximum effect develops in 3-6 hours after reception and remains within 24 hours. At daily use the hypotensive activity gradually increases within 3-4 weeks and remains at long-term treatment. At short-term cancellation the significant increase in arterial blood pressure is not observed (there is no withdrawal).
Amlodipin inhibits transmembrane transition of calcium ions to myocardial and smooth vascular muscle cells (a blocker of slow calcium channels or the antagonist of calcium ions). The mechanism of antihypertensive action is connected with the direct relaxing effect on smooth muscles of vessels that leads to decrease in peripheric vascular resistance.
The exact mechanism by means of which stenocardia symptoms are facilitated completely is not installed, and can include:
1) expansion of peripheral arterioles, thus, reduction of the general peripheric resistance (afterload). As it does not lead to reflex tachycardia, energy expenses a myocardium and oxygen requirement decrease.
2) due to expansion of the main coronal arteries and arterioles as in normal, and ischemic areas, there is an oxygen supply improvement. At the expense of it supply of oxygen to a myocardium, even in case of a spasm of coronal arteries (alternative stenocardia or Printsmetal's stenocardia) increases.
At patients with arterial hypertension, single dose of drug for day provides clinically significant lowering of arterial pressure, as in a dorsal decubitus, and standing. Thanks to the slow beginning of action, sudden arterial hypotension is not characteristic.
At patients with stenocardia, at single dose in day the general time of tolerance to physical activities, time increases up to development of an attack of stenocardia and time to a significant depression of a segment of ST and also the frequency of attacks of stenocardia and quantity of the consumed glyceryl trinitrate tablets decreases. It was not connected with undesirable metabolic effects: drug did not affect the level of lipids in blood plasma, sugar level in blood and uric acid in blood serum, and was useful at patients with bronchial asthma.
Indications
- arterial hypertension, as drug of replacement therapy at which at patients simultaneous use of a ramipril and amlodipin in therapeutic doses, have adequate effect, as in a combination, and separately.
The route of administration and doses
use Drug strictly on doctor's orders!
Хартил® Amlo should be accepted at the same time day, every day throughout a course of treatment, both to meal, and after it. It is not necessary to crush or chew capsules.
The recommended daily dose - 1 capsule of a certain dosage.
The combined drug with a certain dosage is not suitable for the initial stage of therapy.
If there was a need for correction of a dosage, then the dose of the drug Hartil® Amlo can be changed or dosages of separate components at their free combination can be reconsidered.
Use of drug in group of adult patients
Is recommended to appoint drug with care to the patients accepting diuretics as these patients can have a disturbance of water and electrolytic balance. It is necessary to investigate renal function and to determine potassium level in blood serum.
Patients with abnormal liver functions
At patients with an abnormal liver function, treatment ramiprily has to be begun only under careful medical observation, at the same time the maximum daily dose makes 2.5 mg of a ramipril.
It is recommended to appoint Amlo's Hartil® only to those patients who were transferred to a dosage of 2.5 mg of a ramipril as an optimum maintenance dose at selection of dosing of a ramipril.
In case of a liver failure, the period of elimination of an amlodipin can increase. There are no exact recommendations about dosing concerning an amlodipin therefore drug at these patients has to be appointed with care.
Patients with renal failures
For definition of an optimum combination of an initial and maintenance dose at patients with renal failures, the dosage of drug is selected by individual definition of dosages of a ramipril and an amlodipin.
The daily dose of a ramipril at patients with a renal failure has to be established taking into account clearance of creatinine.
- with clearance of creatinine ≥ 60 ml/min., correction of an initial dose are not required from patients, the maximum daily dose - 10 mg,
- patients with clearance of creatinine
have no need for correction of a dosage of an amlodipin of patients with renal failures.
Amlodipin is not brought in the course of dialysis. The patients undergoing the procedure of dialysis amlodipin should appoint with extra care.
During the Hartil® drug treatment of Amlo the control of functional capacity of kidneys and content of potassium in blood serum is required. In case of deterioration in renal function the use of the drug Hartil® Amlo has to be stopped, and it is necessary to appoint his components in the doses modified properly.
Use for patients of advanced age
of the Initial ramipril of a dose has to be lower usual, and the subsequent correction of a dosage has to be softer, because of high risk of emergence of side effects. It is not recommended to appoint Amlo's Hartil® to very old and weak patients.
Elderly patients can accept usual doses of an amlodipin to raise, however, a dose of drug follows with care.
Use for patients of children's and teenage age
is not recommended to appoint Amlo's Hartil® to children and teenagers 18 years as safety and efficiency of use of drug in this group of patients is not established are younger.
Side effects
concerning a ramipril:
Often (from ≥ 1/100 to <>
- a headache, dizziness, fatigue
- a hyperpotassemia
- arterial hypotension, orthostatic hypotension, faints
- the dry irritating cough, bronchitis, sinusitis, short wind
- inflammation of digestive tract, digestion disturbance, discomfortable feelings in a stomach, dyspepsia, diarrhea, nausea, vomiting
- rash, makulopapulyozny dermatitis
- muscular spasms, myalgias
- a stethalgia
Infrequently (from ≥ 1/1000 to <>
- an eosinophilia
- suppressed mood, alarm, nervousness, concern, a sleep disorder, including drowsiness
- anorexia, a loss of appetite
- vertigo, paresthesias, loss of taste, a food faddism
- disorders of vision, including vagueness of sight
- myocardium ischemia, including stenocardias or a myocardial infarction, tachycardia, arrhythmia, heartbeat, peripheral swell
- rush of blood to the person
- a bronchospasm, including aggravation of a course of asthma, congestion of a nose
- pancreatitis (it was reported about very exceptional cases of a lethal outcome connected with use of APF inhibitors), increase in level of enzymes of a pancreas, an insignificant Quincke's disease of intestines, pain in an upper part of a stomach, including gastritis, constipations, dryness in a mouth
- increase in level of liver enzymes and/or bilirubin
- in exceptional cases, the Quincke's disease causing disturbance of passability of airways with the subsequent lethal outcome, an itching, perspiration
- an arthralgia
- a renal failure, including, an acute renal failure, urination increase, a severe form of a proteinuria, increase in level of urea in blood, increase in level of creatinine of blood
- decrease a libido, passing erectile impotence
- a hyperthermia
Seldom (from ≥ 1/10000 to <>
- a leukopenia (including, a neutropenia or an agranulocytosis), an erythropenia, decrease in level of hemoglobin, reduction of quantity of thrombocytes
- confusion of consciousness
- a tremor, balance disturbances
- conjunctivitis
- a hearing disorder, sonitus
- a glossitis
- a vascular stenosis, hypoperfusion, a vasculitis
- cholestatic jaundice, hepatocellular defeats
- exfoliative dermatitis, a small tortoiseshell, onikholizis
- an asthenia
Very seldom (
-reaction of photosensitivity
Does not know (on the basis of the available data assessment is impossible).
- damage of marrow, a pancytopenia, hemolytic anemia
- anaphylactic or anaphylactoid reactions, increase in quantity of anti-nuclear antibodies
- reduction of content of sodium in blood
- disturbance of ability to concentration of attention
- brain ischemia, including an ischemic stroke and tranzitorny ischemia, disturbance of psychomotor reactions, burning sensation, a parosmiya
- Reynaud's syndrome
- aphthous stomatitis
- an acute liver failure, cholestatic or cytolytic hepatitis (the lethal outcome was observed in exceptional cases)
- a gynecomastia
- a toxic epidermal necrolysis, Stephens-Johnson's syndrome, a multiformny erythema, a bladderwort, psoriasis in heavy degree, psoriazoformny dermatitis, a pemfigoidny or lichenoid dieback and an enantema, an alopecia
concerning an amlodipin:
Often (from ≥ 1/100 to <>
- a headache, dizziness, drowsiness (especially in an initiation of treatment), fatigue
- heartbeat
- rush of blood to the person
- nausea, an abdominal pain
- swell, puffiness of an ankle joint
Infrequently (from ≥ 1/1000 to <>
- a hyperglycemia
- change of mood (including alarm), insomnia, a depression
- a tremor, a food faddism, a syncope, a hypesthesia, paresthesias
- disorders of vision (including, a diplopia)
- a ring in ears
- arterial hypotension
- short wind, rhinitis
- vomiting, dyspepsia, change of motility of intestines (including diarrheas and constipations), feeling of dryness in a mouth
- an alopecia, a purpura, discoloration of skin, the increased perspiration, an itching, rash, a dieback
- arthralgias, myalgias, muscular spasms, dorsodynias
- urination disorder, a nocturia, increase in frequency of urination
- disturbance of potency, a gynecomastia
- a stethalgia, weakness, pain, an indisposition
- increase or decrease in body weight
Is rare (from ≥ 1/10000 to <>
- confusion of consciousness
Very seldom (
-a leukopenia, thrombocytopenia
- arterial hypertension, peripheral neuropathy
- a myocardial infarction, arrhythmias (including, bradycardia, ventricular tachycardia and fibrillation of auricles)
- a vasculitis
- cough
- pancreatitis, gastritis, a hyperplasia of gums
- jaundice *, hepatitis *
- a Quincke's disease, a multiformny erythema, a small tortoiseshell, exfoliative dermatitis, Stephens-Johnson's syndrome, a photosensitization
- increase in level of liver enzymes *
* In most cases with a cholestasia.
Contraindications
- hypersensitivity to a ramipril (or to APF inhibitors), to an amlodipin, dihydropyridine derivatives, and/or any of excipients
- existence in the anamnesis of a Quincke's disease (hereditary, idiopathic or arisen because of the previous Quincke's disease caused by use of APF inhibitors or antagonists of receptors of angiotensin II (APAT II)
- the extracorporal treatment which is followed by contact of blood with negatively charged surfaces
- the profound bilateral stenosis of renal arteries or a renal artery stenosis of the only operating kidney
- pregnancy and in the period of a lactation
- ramiprit it is not necessary to appoint to patients with hypotensive or hemodynamically unstable states
- a severe form of hypotension
- shock (including, cardiogenic shock)
- the vasoconstriction interfering outflow of blood from a left ventricle (for example, an aortal stenosis of heavy degree)
- hemodynamically unstable heart failure after the postponed acute myocardial infarction
Medicinal interactions
the Extracorporal procedures which are followed by contact of blood with negatively charged surfaces such as hemodialysis through high-permeability membranes (for example, membranes from polyacrylonitrile connections), haemo filtration or aferez lipoproteins of low density with dextran sulfate use, because of the increased danger of development of heavy anaphylactic or anaphylactoid reactions. If such treatment is necessary, then it is necessary to consider a question of use of other type of membranes for dialysis or antihypertensive drugs of other category.
At a concomitant use with the potassium drugs, kaliysberegayushchy diuretics and other active agents increasing plasma levels of potassium (including, with antagonists of receptors of angiotensin II, Trimethoprimum, takrolimusy, cyclosporine) development of a hyperpotassemia is possible therefore it is necessary to control attentively potassium level in blood serum.
At a concomitant use with antihypertensive drugs (for example, diuretics) and other substances which can reduce arterial blood pressure (for example, nitrates, tricyclic antidepressants, anesthetics, alcohol, Baclofenum, alfuzoziny, docsazoziny, Prazozinum, tamsuloziny, terazoziny) potentiation of risk of hypotension is possible.
At a concomitant use with angiotonic sympathomimetics and other drugs (for example, Isoproterenolum, Dobutaminum, a dopamine, adrenaline), decrease in antihypertensive effect of a ramipril is possible therefore carrying out monitoring of arterial blood pressure is recommended.
At a concomitant use with Allopyrinolum, immunodepressants, corticosteroids, procaineamide, cytostatics and other drugs which can change quantity of blood cells the likelihood of development of hematologic reactions raises.
At a concomitant use of APF inhibitors with drugs of lithium the reduction of its discharge and, respectively, increase in concentration of lithium in blood with the subsequent increase in its toxicity is possible. Regular control of level of lithium is necessary.
At a concomitant use with antidiabetic means (including, insulin) hypoglycemic reactions can develop. It is recommended to control strictly glucose level in blood.
At a concomitant use with non-steroidal anti-inflammatory drugs and acetylsalicylic acid the decrease in antihypertensive effect of a ramipril is possible. Besides, the combined use of APF and NPVS inhibitors can cause development of a hyperpotassemia and increase risk of a renal failure.
Drug is safely compatible to thiazide diuretics, β-blockers, nitrates of the prolonged action, sublingual dosage forms of nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics and oral hypoglycemic drugs.
At a concomitant use of drug with CYP3A4 inhibitor erythromycin at young patients and diltiazem at elderly patients, respectively, plasma concentration of an amlodipin increases by 22% and 50%, respectively. However, the clinical value of this circumstance remains obscure. It is impossible to exclude that powerful CYP3A4 inhibitors (for example, ketokonazol, itrakonazol, ritonavir) can increase plasma concentration of an amlodipin more than diltiazem. Amlodipin it is necessary to use with care at joint appointment with CYP3A4 inhibitors. However, messages about any side effects connected with similar interaction did not arrive.
Inductors CYP3A4: data on influence of the inductors CYP3A4 on amlodipin are absent. The combined use of drug with the inductors CYP3A4 (for example, the rifampicin or a St. John's wort which is made a hole) can lower plasma concentration of an amlodipin. Amlodipin it is necessary to use with care at joint appointment with the inductors CYP3A4.
During clinical trials of interaction with medicinal substances, simultaneous use of an amlodipin with grapefruit juice, Cimetidinum, aluminum/magnesium (antiacid drugs) and sildenafily did not influence pharmacokinetics of an amlodipin.
Simultaneous use of an amlodipin with other antihypertensive drugs enhances their therapeutic effectiveness.
During clinical trials of interaction with medicinal substances, amlodipin did not influence pharmacokinetics of an atorvastatin, digoxin, ethanol (alcohol), warfarin or cyclosporine.
Influence of an amlodipin on change of indicators of laboratory researches is not established.
Special instructions
Patients with the increased risk of developing of hypotension:
- Patients with the system which is hyper activated renin-angiotensin-aldosteronovoy are exposed to essential risk of acute falling of arterial blood pressure and deterioration in function of kidneys owing to APF inhibition, in particular, when APF inhibitors or the accompanying diuretics are appointed for the first time, or for the first time there is an increase in their dosage.
If hyper activation manifestation renin-angiotensin-aldosteronovoy of a system is obviously possible, then it is necessary to organize, if necessary, medical observation, including, monitoring of arterial blood pressure:
· at patients with heavy hypertensia,
· at patients with dekompensirovanny stagnant heart failure,
· at patients with hemodynamically significant inflow to a left ventricle or the complicated outflow from it (for example, a stenosis of an aorta or the mitral valve),
· at patients with a unilateral renal artery stenosis of the only operating kidney,
· at patients with existing (or possible) disturbances of water and electrolytic balance (including the patients accepting diuretics),
· at patients with cirrhosis and/or ascites,
· at the patients who underwent difficult surgery, or being exposed to anesthesia using the drugs causing hypotension
, in general, carrying out correction of conditions of dehydration, a hypovolemia or deficiency of salts prior to treatment (at patients with heart failure, however, all pluses and minuses of such actions, taking into account risk of a volume overload have to be carefully weighed) is recommended.
- at patients with tranzitorny (passing) or constant heart failure after the postponed myocardial infarction,
- at patients with risk of developing cardial or cerebral ischemia or in cases of acute hypotension.
At the initial stage of treatment the careful medical observation is required.
Safety and efficiency of an amlodipin in hypertensive crisis was not established.
It is necessary to appoint with care drug to patients with heart failure. During long placebo - a controlled research with participation of patients with heavy heart failure (III and IV class on NYHA) fluid lungs cases which frequency of emergence was higher in group with purpose of an amlodipin, in comparison with group of placebo were registered, but it was not followed by heavier heart failure.
At patients with abnormal liver functions the elimination half-life of an amlodipin is extended, recommendations about change of a dosage are absent. Patients of this group have to take amlodipin with caution.
Elderly patients have to take amlodipin with caution.
Patients with renal failures can accept amlodipin in usual doses. Changes of plasma concentration of an amlodipin of concentration do not correlate with degree of a renal failure. Amlodipin at dialysis is not brought.
It is recommended to stop, whenever possible, use of APF inhibitors, such as ramiprit, in one day prior to performing surgical intervention.
Renal function needs to be investigated prior to treatment and during it, and the dosage of drug is adjusted, in particular, in the first weeks of treatment. Patients with a renal failure require carrying out especially careful control. There is a risk of a renal failure, especially at patients with stagnant heart failure or after transplantation of a kidney.
It was in rare instances reported about developing of a Quincke's disease at the patients accepting APF inhibitors including, ramiprit.
When developing a Quincke's disease the use of a ramipril has to be stopped. In this case immediately use means and methods of emergency treatment. The patient has to be under observation, at least, for 12 - 24 hours, to full permission of symptoms. It was reported about developing of an intestinal Quincke's disease at the patients accepting APF inhibitors including, ramiprit. These patients complained of pains in a stomach (with symptoms of nausea or vomiting, or without those).
In rare instances at the patients taking the drug at the desensibilizing therapy for the purpose of prevention or treatment of allergic reaction to a sting of insects heavy, life-threatening anaphylactic reactions developed. Therefore before completion of desensitization it is necessary to consider a question of the temporary termination of reception of a ramipril.
At some patients accepting APF inhibitors and, including, ramiprit, the hyperpotassemia was observed. Patients with a renal failure, patients of advanced age (70 years are more senior), patients with uncontrollable diabetes, or the patients accepting the potassium salts, kaliysoderzhashchy diuretics and other active agents promoting increase in level of potassium in blood plasma and also patients at such states as dehydration, an acute heart failure or a metabolic acidosis enter into group of patients with the increased risk of development of a hyperpotassemia. If simultaneous use of above-mentioned medicines is recognized as reasonable, then carrying out regular control of level of potassium in blood serum is recommended.
There are rare messages about cases of a neutropenia/agranulocytosis, thrombocytopenia and anemia and also about a marrow depression. For perhaps earlier detection of a leukopenia it is recommended to control quantity of leukocytes. More frequent control at the initial stage of treatment and among patients with renal failures and also patients with the accompanying collagenoses (for example, a lupus erythematosus or a scleroderma), and at all patients accepting other medicines which could cause changes of a picture of blood is recommended.
At the patients of negroid race accepting APF inhibitors, the Quincke's disease develops more often than at other patients. As well as other APF inhibitors, ramiprit can render smaller hypotensive effect at patients of negroid race, in comparison with persons of other race, perhaps, owing to higher frequency of persons with the low level of renin in population of patients of negroid race with arterial hypertension.
Administration of drug can be followed by dry cough with continuous increase in a tussive reflex. Cough can stop after drug withdrawal. The cough caused by administration of drug should be considered differential diagnostic character.
Pregnancy and the period of a lactation
APF Inhibitors, such as ramiprit, or antagonists of receptors of angiotensin II (APAT II) are contraindicated during pregnancy. If there is a need of continuation of therapy using APF/ARAT II inhibitors, then the patients planning pregnancy have to change the therapeutic mode to alternative antihypertensive treatment which meets safety requirements at its appointment during pregnancy. At pregnancy confirmation the treatment using APF/ARAT II inhibitors has to be immediately stopped, and, if necessary, use of alternative therapy has to be begun.
The epidemiological data confirming risk of teratogenecity after influence of APF inhibitors during the I trimester of pregnancy are not rather convincing, however it is not necessary to exclude
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