Dilaprel, 10 mg capsules, 28 pcs.

Dilapril is an ACE inhibitor.

Ramipril inhibits angiotensin-converting enzyme (ACE), blocks the conversion of angiotensin I into angiotensin II, resulting in (regardless of plasma renin activity) hypotensive effect (in the patient “lying” and “standing”) without a compensatory increase in heart rate (HR). Reduces the production of aldosterone.

Decreases total peripheral vascular resistance (TPR) or post-load, pulmonary capillary pressure (preload), pulmonary vascular resistance; increases minute blood volume and exercise tolerance. With long-term use promotes inverse development of myocardial hypertrophy in patients with arterial hypertension. Reduces the frequency of myocardial reperfusion arrhythmias; improves blood supply to ischemic myocardium; prevents vascular endothelial changes caused by a high-cholesterol diet.

It enhances coronary and renal blood flow.

The onset of hypotensive action of Dilaprel is 1.5 hours after oral administration, the maximum effect is in 5-9 hours, the duration of action is 24 hours. There is no withdrawal syndrome.

. In patients with heart failure, which developed during first days of acute myocardial infarction (2-9 days), when taking ramipril from 3 to 10 days of acute myocardial infarction, the risk of death rate (by 27 %) and risk of sudden death (by 30 %) decrease, the risk of progression of chronic heart failure to severe (functional class III-IV according to NYHA classification)/resistant to therapy (by 27 %), the probability of subsequent hospitalization due to the development of heart failure (by 26 %).

In diabetic and nondiabetic nephropathy, administration of ramipril slows the rate of renal failure progresion and time to onset of end-stage renal failure and thereby reduces the need for hemodialysis or renal transplantation. In initial stages of diabetic or nondiabetic nephropathy, ramipril reduces the severity of albuminuria.

Indications

– arterial hypertension;
– chronic heart failure (as part of combined therapy, particularly in combination with diuretics);
– heart failure that developed during the first few days (from the 2nd to the 9th day) after an acute myocardial infarction;
– diabetic or nondiabetic nephropathy preclinical and clinically pronounced stages, including with significant proteinuria, especially when combined with arterial hypertension.

Active ingredient

Composition

1 capsule contains:

ramipril 10 mg

excipients:

lactose,

colloidal silicon dioxide (aerosil),

calcium stearate.

composition of hard gelatin capsules:

gelatin,

titanium dioxide,

iron oxide yellow dye.

How to take, the dosage

The capsules should be swallowed whole and drunk with enough (1/2 cup) water, regardless of meals (i.e., capsules can be taken before, during or after meals). The dose is adjusted according to the therapeutic effect and tolerability of the drug to the patient.

– Arterial hypertension
Orally, starting dose; 2.5 mg, once, in the morning. If BP does not normalize at this dose for 3 weeks or more, the dose may be increased to 5 mg of Dilaprel per day. If the 5 mg dose is not effective enough after 2-3 weeks, it may be doubled further to the maximum recommended daily dose; 10 mg per day. As an alternative to increasing the dose to 10 mg daily in case of insufficient antihypertensive effect of daily dose of 5 mg other antihypertensive agents, particularly diuretics or slow calcium channel blockers may be added to treatment.

– Chronic heart failure
Initial dose; 1.25 mg/day (other dosage form of ramipril is possible: 2.5 mg tablets with a rib). Depending on the patient’s response to the therapy, the dose may be increased. It is recommended to double it at intervals of 1-2 weeks. Doses of 2.5 mg or more should be taken once or divided into 2 doses. Maximum daily dose; 10 mg.

– In heart failure developed within the first few days (2nd to 9th day) after acute myocardial infarction
Initial dose; 5 mg divided into 2 doses, 2.5 mg morning and evening. If the patient cannot tolerate this initial dose (excessive decrease in BP is observed), it is recommended that 1.25 mg twice daily for two days (in this case, you can use ramipril in another dosage form: 2.5 mg tablets with a rib). Then, depending on the patient’s response, the dose may be increased. It is recommended that the dose be doubled at 1-3 day intervals when it is increased. Later, the total daily dose, which was initially divided into two doses, can be given once.

The maximum recommended dose is 10 mg.
Currently, there is insufficient experience in the treatment of patients with severe chronic heart failure (NYHA functional class III-IV) that occurred immediately after acute myocardial infarction.

If in such patients the decision is made to treat with Dilaprel, it is recommended that treatment should be started with the lowest possible dose; 1.25 mg once daily (in this case the drug ramipril in other dosage form can be used: tablets of 2.5 mg with a rib), and special care should be taken with each increase in the dose.

– In diabetic or nondiabetic nephropathy
The initial dose; 1.25 mg (Ramipril in other dosage form can be used: 2.5 mg tablets with a rib) once daily. The dose may be increased up to 5 mg once daily.
Maximum daily dose; 5 mg.

Patients with impaired renal function
If the CKR is 50 to 20 ml/min per 1.73 m2 of body surface area, the initial daily dose is usually 1.25 mg (in this case we can use ramipril in other dosage form: 2.5 mg tablets with a rib). Maximum daily dose; 5 mg.

– Patients with incompletely corrected fluid and electrolyte loss, patients with severe arterial hypertension, and patients for whom excessive BP reduction poses some risk (e.g., in severe atherosclerotic lesions of the coronary and cerebral arteries)

The initial dose is reduced to 1.25 mg/day (in this case, ramipril in other dosage form may be used: 2.5 mg tablets with a rice).

– Patients with prior therapy with diuretics

If possible, diuretics should be stopped 2-3 days (depending on the duration of action of diuretics) before starting treatment with Dilaprel® or at least the dose of diuretics taken should be reduced. Treatment of such patients should be started with the lowest dose equal to 1.25 mg of ramipril (in this case, ramipril in other dosage form can be used: 2.5 mg tablets with a slash), taken once a day, in the morning. After the first dose and whenever the dose of ramipril and/or loop diuretics is increased, patients must be under medical supervision for at least 8 hours to avoid uncontrolled hypotensive reactions.

– Elderly patients (older than 65 years)
The starting dose is reduced to 1.25 mg/day (in this case, ramipril can be used in another dosage form: 2.5 mg tablets with a rib).

Patients with hepatic impairment

The BP response to administration of Dilaprel may both increase (due to delayed excretion of ramipril) and decrease (due to delayed conversion of the inactive ramipril to the active ramipril). Therefore, close medical supervision is required at the beginning of treatment. Maximum tolerated daily dose; 2.5 mg.

Interaction

Contraindicated combinations
The use of certain high-flow membranes with a negative charged surface (e.g., polyacrylonitrile membranes) in hemodialysis or hemofiltration and the use of dextran sulfate in low-density lipoprotein apheresis increases the risk of severe anaphylactic reactions.

No recommended combinations
With potassium salts, potassium-saving diuretics (e.g., amiloride, triamterene, spironolactone) a more pronounced increase in serum potassium is possible (regular monitoring of serum potassium is required with simultaneous use).

Combinations to be used with caution
With antihypertensive agents (especially diuretics) and other drugs that reduce BP (nitrates, tricyclic antidepressants) potentiation of the antihypertensive effect is noted; in combination with diuretics the serum sodium content should be controlled.

With injectable gold preparations facial hyperemia, nausea, vomiting, hypotension are rarely possible.
With hypnotics, narcotic analgesics, agents for general anesthesia and analgesics may increase antihypertensive effect.

With vasopressor sympathomimetics (epinephrine) a decrease of antihypertensive effect of ramipril is noted, regular BP control is required.

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic glucocorticosteroids and other agents that may affect hematological parameters, the risk of leukopenia increases.

With lithium salts there is an increase in serum concentration of lithium and increased cardio- and neurotoxic effects of lithium.
With hypoglycemic agents for oral administration (sulfonylurea derivatives, biguanides), insulin due to the decrease of insulin resistance under the influence of ramipril increase of hypoglycemic effect of these drugs may occur, up to hypoglycemia development.

Combinations to consider
With nonsteroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid) the effect of ramipril may be weakened, the risk of renal dysfunction and increased serum potassium may increase.

With heparin may increase serum potassium.
With sodium chloride may weaken the antihypertensive effect of ramipril and less effective treatment of symptoms of chronic heart failure.

With ethanol there is an increase of vasodilation symptoms. Ramipril may increase the adverse effects of ethanol on the body.
With estrogens there is a weakening of the antihypertensive effect of ramipril (fluid retention).

Desensitizing therapy in hypersensitivity to insect venoms: ACE inhibitors, including ramipril, increase the likelihood of severe anaphylactic or anaphylactoid reactions to insect venoms.

When treated with ACE inhibitors, hypersensitivity reactions to insect venom (e.g., bees, wasps) develop more quickly and are more severe. If desensitization to insect venom is necessary, the ACE inhibitor should be temporarily replaced by the appropriate drug of another class.

Special Instructions

Treatment with Dilapril is usually prolonged and its duration is determined by the physician in each case. It also requires regular medical monitoring, in particular in patients with impaired liver and kidney function.

Hyponatremia and hypovolemia should be eliminated before initiating treatment with Dilaprel. If the patients used diuretics earlier it is necessary to cancel them or at least decrease their dosage 2-3 days before the beginning of the preparation administration of Dilaprel® (in this case the patients with chronic cardiac insufficiency should be carefully controlled due to the possibility of decompensation because of increase of circulating blood volume).

After the first dose of the drug, as well as when increasing its dose and/or doses of diuretics (especially loop diuretics) it is necessary to ensure close medical observation of the patient for at least 8 hours in order to take appropriate measures in case of excessive BP decrease.

If Dilaprel is used for the first time or in a high dose in patients with increased RAAS activity, their BP should be monitored carefully, especially at the beginning of treatment, since these patients have an increased risk of excessive BP reduction (see “Caution” section).

In malignant arterial hypertension and heart failure, especially in the acute stage of myocardial infarction, treatment with Dilaprel should be started only in a hospital setting.

In patients with chronic heart failure the use of the drug may lead to marked BP decrease which in some cases is accompanied with oliguria or azotemia and rarely; by development of acute renal failure.

Contraindications

– hypersensitivity to ramipril, other ACE inhibitors or to any of the components of the drug (see section “Composition”).
– history of angioedema (hereditary or idiopathic, as well as after taking ACE inhibitors);
– risk of rapid development of angioedema;
– hemodynamically significant stenosis of the renal arteries (bilateral or unilateral in case of a single kidney);
– hemodynamically significant stenosis of aortic or mitral valve or hypertrophic obstructive cardiomyopathy (HCMP);
– Severe renal insufficiency (creatinine clearance (CK) less than 20 ml/min on the body surface of 1.73 m2);
– hemodialysis;
– primary hyperaldosteronism;
– pregnancy, lactation;
– age under 18 years (safety and efficacy has not been studied);
– hyposensitizing therapy for hypersensitivity reactions to insect venoms, such as bees, wasps;
– arterial hypotension (systolic blood pressure (BP) less than 90 mm Hg) or conditions of unstable blood pressure.
– low-density lipoprotein apheresis with dextran sulfate (risk of hypersensitivity reactions);
– nephropathy treated with glucocorticosteroids, non-steroidal anti-inflammatory drugs, immunomodulators and/or other cytotoxic agents (see Section “Interaction with other cytotoxic agents”).
– chronic heart failure in decompensation stage (insufficient experience of clinical use);
– lactose intolerance; lactase deficiency; glucose-galactose malabsorption.

Additional contraindications for the use of the drug Dilaprel? In the acute phase of myocardial infarction
– severe chronic heart failure (functional class III-IV by classification NYHA);
– unstable angina;
– life-threatening ventricular arrhythmias;
– “pulmonary” heart.

With caution.
– conditions in which an excessive decrease in blood pressure is especially dangerous (in atherosclerotic lesions of the coronary and cerebral arteries);
– conditions accompanied by increased activity of renin-angiotensin-aldosterone system (RAAS), in which ACE inhibiting has the risk of a sharp decrease in BP with impaired renal function:
– severe arterial hypertension, especially malignant arterial hypertension;
– chronic heart failure, especially severe or for which other drugs with antihypertensive effect are taken;
– Haemodynamically significant unilateral stenosis of the renal artery (if both kidneys are present);
– Previous intake of diuretics;
– Water-electrolyte balance disorders as the result of insufficient fluid and table salt intake, diarrhea, vomiting, profuse sweating;
– Systemic connective tissue diseases, including, but not limited toч. Systemic lupus erythematosus, systemic scleroderma, concomitant therapy with myelotoxic agents that may cause changes in the peripheral blood (suppression of medullary hematopoiesis, neutropenia or agranulocytosis may occur);
– renal function disorders (CK more than 20 ml/min at 1.73 m2 body surface) due to the risk of hyperkalemia and leukopenia;
– elderly age (risk of increasing antihypertensive effect);
– liver function disorders (lack of experience of use: both strengthening and weakening of the effects of ramipril are possible; in the presence of patients with cirrhosis with ascites and edema, significant activation of the RAAS is possible, see above “conditions accompanied with increase of RAAS activity”);
– diabetes mellitus (risk of hyperkalemia);
– state after renal transplantation;
– hyperkalemia.

Side effects

Cardiovascular system:

often; excessive BP decrease, orthostatic hypotension, syncope, chest pain;
infrequently; Myocardial ischemia, including the development of an attack of angina or myocardial infarction, tachycardia, arrhythmias (occurrence or increase), palpitations, peripheral edema, “flushes” of blood to the face.

Urogenital system disorders:

infrequent; impaired renal function, including development of acute renal failure, increased urine excretion, increased existing proteinuria, increased blood urea and creatinine concentrations, transient impotence due to erectile dysfunction, decreased libido;
frequency unknown; gynecomastia.

From the central nervous system:

often; headache, feeling of “lightness” in the head, feeling of fatigue;
infrequent; dizziness, agueusia (loss of taste sensitivity), dysgeusia (impaired taste sensitivity), depressed mood, anxiety, increased excitability, motor anxiety, sleep disorders, including drowsiness;
rare; tremor, development or aggravation of circulatory disorders against stenotic vascular lesions, vasculitis, asthenia, impaired balance, confusion.
frequency unknown; Raynaud’s syndrome, cerebral ischemia, including ischemic stroke and transient cerebral circulation disorder, impaired psychomotor reactions, paresthesias (burning sensation), parosmia (smell perception disorders), attention disorders, depression.

Sense organs:

infrequent; visual disturbances, including blurred vision;
rare; conjunctivitis, hearing disturbances, tinnitus;

Muscular system disorders:
often; muscle cramps, myalgia;
infrequently; arthralgia.

Digestive system disorders:

often; inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting;

infrequently; pancreatitis, including lethal, increased plasma pancreatic enzyme activity, intestinal angioedema, abdominal pain, gastritis, constipation, dry oral mucosa, increased liver enzyme activity and concentration of conjugated bilirubin in blood plasma, anorexia, reduced appetite;
rarely; glossitis, cholestatic jaundice, hepatocellular lesions;

frequency unknown; aphthous stomatitis, acute liver failure, cholestatic or cytolytic hepatitis (lethal outcome observed very rarely).

Respiratory system:

often; dry cough (increased at night when lying down), sinusitis, bronchitis, dyspnea;
infrequently; bronchospasm, including worsening the course of bronchial asthma, nasal congestion.

Side of the skin:

often; skin rash, particularly maculopapular;
infrequent; angioedema, including fatal (laryngeal edema can cause fatal airway obstruction), skin itching, hyperhidrosis (increased sweating);

Rare; exfoliative dermatitis, urticaria, onycholysis;
very rare; photosensitization reactions;

frequency unknown; toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, worsening the course of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia, anaphylactic or anaphylactoid reactions (ACE inhibition increases anaphylactic or anaphylactoid reactions to insect venoms), increased concentration of antinuclear antibodies.

Hematopoietic organs:

infrequent; eosinophilia;
rare; leukopenia, including neutropenia and agranulocytosis, decreased peripheral blood erythrocyte count, decreased hemoglobin concentration, thrombocytopenia;

frequency unknown; suppression of medullary hematopoiesis, pancytopenia, hemolytic anemia.

Others:

infrequent; hyperthermia.

Laboratory findings:

often; increased blood potassium;
unknown frequency; decreased blood sodium. Cases of hypoglycemia have been reported in patients with diabetes mellitus who were taking insulin and oral hypoglycemic medications.

Overdose

Symptoms: excessive vasodilation with the development of marked reduction of blood pressure, shock; bradycardia, disruption of water-electrolyte balance, acute renal failure, stupor.

Treatment: in mild cases of overdose; gastric lavage, absorbents and sodium sulfate administration (preferably within 30 minutes after intake).

In case of marked decrease in blood pressure; replenishment of circulating blood volume, restoration of water-electrolyte blood balance, intravenous administration of catecholamines, angiotensin II; in bradycardia; administration of artificial pacemaker. In case of overdose, serum concentrations of creatinine and electrolytes should be monitored. Hemodialysis is ineffective.

Pregnancy use

The use of Dilaprel during pregnancy and breastfeeding

Dilaprel should not be used during pregnancy. Therefore, before starting treatment it is necessary to make sure that there is no pregnancy.

If a patient becomes pregnant during treatment, the drug therapy with Dilaprel should be replaced with another therapy as soon as possible.

There is a risk of fetal renal development disorders, decreased fetal and neonatal blood pressure, impaired renal function, hyperkalemia, skull bone hypoplasia, oligohydramnios, limb contractures, skull deformities, lung hypoplasia, especially in the first trimester of pregnancy.

If treatment with Dilaprel is necessary during lactation, breastfeeding should be discontinued.

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