Энап®-Р

General characteristics. Structure:

Active ingredient: 1,25 mg of enalaprilat.

Excipients: benzyl alcohol, sodium chloride, sodium hydroxide, water for injections.

Antihypertensive.

Pharmacological properties:

Pharmacodynamics. Enalaprilat is an enalapril metabolite  - APF inhibitor. Reduces formation of II angiotensin of angiotensin I, concentration of Aldosteronum in blood, increases release of a renin, stimulates release of prostaglandins and the endothelial running-down factor of veins, oppresses a sympathetic nervous system.

Reduces the general peripheric vascular resistance, the arterial pressure (AP), before - and an afterload on a myocardium, expands arteries more than veins. The hypotensive effect is more expressed at the high level of a renin of a blood plasma, than at normal or its reduced level. Decrease in the ABP in therapeutic limits does not exert impact on cerebral circulation. Improves blood supply of an ischemic myocardium. Time of approach of therapeutic effect after intravenous administration of 5-15 min., reaches a maximum in 1-4 h, about 6 h remain.

Pharmacokinetics. Enalaprilat is badly absorbed after oral administration and is almost inactive therefore it is entered only intravenously. The maximum concentration after intravenous administration (in/in) is reached in 15 min.

The period of semi-distribution makes 4 hours. Communication with proteins of a blood plasma of 50-60%. Circulates in blood in an invariable look. Badly gets through a blood-brain barrier. It is not metabolized.

It is brought out of an organism in not changed look, through kidneys (more than 90%) by glomerular filtering and canalicular secretion. Elimination half-life (T1/2) about 35 hours.

The Clearance of Creatinine (CC) at a hemodialysis – 38-62 ml/min., concentration of enalaprilat in blood serum after a 4-hour hemodialysis decreases by 45-75%.

Indications to use:

Hypertensive crisis, arterial hypertension in cases when reception of medicines is inside impossible, hypertensive encephalopathy.

Route of administration and doses:

Intravenously (in/in), within 5 minutes slowly or kapelno in cultivation in 20-50 ml of 5% of solution of a dextrose (glucose), 0,9% of solution of sodium of chloride on 1,25 mg (1 ml – 1 ampoule) each 6 hours.

The usual dose makes 1,25 mg (1 ml) of drug each 6 hours, including the patients accepting earlier the drug Enap® for intake (tablet).

At the patients accepting diuretics, the initial dose of drug decreases to 0,625 mg (0,5 ml – ½ ampoules). If in 1 hour after introduction therapeutic effect unsatisfactory, the same dose can be entered repeatedly, and after 6 hours treatment by drug in a dose of 1,25 mg is continued each 6 hours.

Dosage at a renal failure: At moderately expressed chronic renal failure (CRF) for patients with KK more than 0,5 ml / with (30 ml/min., creatinine in blood serum does not exceed 265 µmol/l) a dose make 1,25 mg (1 ml – 1 ampoule) drug each 6 hours, is not required to dose adjustment. If in 1 hour after introduction therapeutic effect unsatisfactory, the dose of 1,25 mg (1 ml – 1 ampoule) can be entered repeatedly, and after 6 hours treatment by drug in a dose of 1,25 mg (1 ampoule) is continued each 6 hours.

For patients with KK less than 0,5 ml / with (30 ml/min., creatinine in blood serum exceeds 265 µmol/l) an initial dose make 0,625 mg (0,5 ml), with the subsequent control of indicators of the ABP within 1 hour for identification of risk of excessive decrease in the ABP. In the absence of effect in 1 hour administration of drug in a dose of 0,625 mg (0,5 ml) is repeated, and treatment each 6 hours continue by drug in a dose 1,25 mg (1 ml-1 ampoule).

For the patients who are on a hemodialysis, the dose of the drug Enap® P makes 0,625 mg (0,5 ml) each 6 hours within 48 hours.

Upon transition to administration of drug inside: the recommended initial dose of enalapril makes 5 mg a day for patients to whom usual (1,25 mg/ml) drug Enap® doses were entered earlier. If necessary the dose can be increased. For patients whose treatment was carried out twice by a reduced initial dose of 0,625 mg (0,5 ml) of the drug Enap® P the recommended initial dose of enalapril upon transition to intake makes 2,5 mg a day.

Features of use:

Treatment is carried out only in the conditions of treatment and prevention facility or crews of emergency medical service.

Arterial hypotension  can  be observed  (in  several  hours  after  introduction  of the first  dose)  at  patients  with  the expressed HSN and  a hyponatremia,     and also at patients with the expressed renal failure and at patients with arterial hypertension, especially against the background of a hypovolemia as a result of treatment  by diuretics,  an electrolyte-deficient  diet,  diarrhea,  vomiting  or  a hemodialysis.   Treatment  of patients  with  the increased  risk  of development of arterial hypotension should  be begun   with  a half  of a dose  of the drug Enap® P  (0,625 mg – 0,5 ml).   At arterial hypotension  the patient  should  give  horizontal  position  with  a low  headboard   and    , if necessary,  to adjust    plasma volume   by means of  infusion  of 0,9%  of solution    of sodium chloride. Tranzitorny (passing)  arterial hypotension    is not  a contraindication to further treatment     by enalaprilat.  After  a correcting  of the ABP and    the volume of the circulating blood (VCB) patients    usually well  transfer  the following  doses  of drug.     In case of  symptomatic  arterial hypotension  it is necessary  to lower  a dose  of drug  or  to stop   treatment  by drug Enap ® River.

It is necessary to avoid treatment by drug Enap ® P at patients with a bilateral  stenosis  of renal  arteries  or  a stenosis of an artery   of the only  kidney  as  it  can  cause  arterial hypotension, deterioration  in function  of kidneys     and even      the acute renal failure (ARF)  which  usually  has  reversible  character. It is recommended to begin therapy with the minimum doses and in the conditions of careful medical observation; in the subsequent it is necessary to carry out – titration of a dose and regular control of function of kidneys.

At patients with a renal failure the dose is correlated depending on the KK level (see the section: "Route of administration and doses"). Control of creatinine and potassium concentration in blood is recommended.

As    during  treatment by the drug Enap® P  increase  in level  of content  of potassium  in  blood serum,  especially  at  patients from HSN suffering also from a diabetes mellitus,  co-administration  of drug and  kaliysberegayushchy  diuretics,  such  as  Spironolactonum,  amiloride  and  Triamterenum and other drugs capable to cause a hyperpotassemia is possible,    it is not recommended.

Development of the syndrome beginning with the cholestatic jaundice progressing to a fulminantny necrosis of a liver is in rare instances possible. The mechanism of development of this syndrome is unknown. At emergence of jaundice or increase in activity of "hepatic" enzymes it is necessary to stop administration of drug immediately.

Against the background of simultaneous therapy with hypoglycemic means (derivative sulphonylurea and insulin) control of level of glucose in blood is necessary within the first several months.

Before the beginning and during therapy by APF inhibitors, especially, thrombocytopenia and anemia or receiving high doses of APF inhibitors, and also at the first symptoms of an infection, control of total number of leukocytes and a leukocytic formula with frequency once a month in the first 3-6 months of treatment and with periodic intervals about one year is necessary for patients with the increased risk of a neutropenia/agranulocytosis (at a renal failure or general diseases of connecting fabric, against the background of therapy by Allopyrinolum and procaineamide). At confirmation of a neutropenia (the number of neutrophils are less 1000/mkl) therapy by APF inhibitors should be stopped.
To and during treatment by APF inhibitors control of the ABP, blood indicators (hemoglobin, potassium, creatinine, urea, activity of "hepatic" enzymes), a squirrel in urine is necessary. 

It is necessary to consider possible development of dry, unproductive cough which disappears after the therapy termination at behavior of the differential diagnosis.

In the presence in the anamnesis of a Quincke's disease (even not connected with reception of APF inhibitors), there is an increased risk of its repeated development against the background of treatment.

Before surgical interventions (including stomatology) it is necessary to warn the anesthesiologist about use of APF inhibitors (risk of development of arterial hypotension).

It is recommended to observe newborns or babies who were exposed to pre-natal influence of APF inhibitors for early detection of the expressed decrease in the ABP, an oliguria, a hyperpotassemia and neurologic disturbances, possible owing to reduction of a renal and brain blood-groove at decrease in the ABP called by APF inhibitors. At an oliguria maintenance of the ABP and renal perfusion by administration of the corresponding liquids and vasoconstrictors is necessary.

Drug contains less than 1 mmol (23 mg) of sodium in each dose (1,25 mg) therefore it is considered as "the drug which is not containing sodium".

At pregnancy drug is contraindicated. It is not necessary to apply in the I trimester of pregnancy. At pregnancy confirmation enalapril needs to be cancelled. Drug is contraindicated in the II-III trimesters of pregnancy. Use in the II-III trimesters of pregnancy can cause fetotoksichesky effects (depression of function of kidneys, an oligoamnios, delay of ossification of bones of a skull) and neonatal toxic effects (a renal failure, arterial hypotension, a hyperpotassemia). At use of drug in the II-III trimester of pregnancy it is recommended to conduct ultrasound examination of kidneys and bones of a skull of a fruit. Enalapril gets through a placenta and can be removed from a neonatal blood-groove by peritoneal dialysis.

Enalapril and enalaprilat is emitted in breast milk, but safety them is not studied. In need of use of drug in the period of a lactation to stop breastfeeding. 

There are no data on influence on speed of response and ability to manage atotransportny means.

Side effects:

Classification of frequency of development of side effects (World Health Organization (WHO)):
very often  > 1/10
often             from> 1/100, <1/10
infrequently         from> 1/1000, <1/100
seldom             from> 1/10000, <1/1000
very seldom  from <1/10000, including separate messages.
From cardiovascular system: often - a stethalgia, heartbeat, arrhythmias (atrial bradi-or tachycardia, atrial fibrillation), an acute left ventricular failure, an embolism of pulmonary arteries, excessive decrease in the ABP, an orthostatic collapse. Seldom – Reynaud's syndrome. At excessive decrease in the ABP, generally at patients with an ischemic heart disease and clinically significant vasoconstriction of a brain, myocardium ischemia (stenocardia or a myocardial infarction) or cerebrovascular disturbances can develop.

From central (TsNS) and a peripheral nervous system: very often – an adynamy; often - a headache, a depression, weakness; infrequently - dizziness, paresthesias, drowsiness, sleeplessness, the increased nervous irritability; seldom – "dreadful" dreams, sleep disorders.

From the alimentary system: very often – nausea; often – diarrhea, abdominal pains, changes of flavoring feelings; infrequently – a lock, vomiting, intestinal impassability, pancreatitis, dyspepsia, anorexia, dryness in a mouth, a round ulcer; seldom – stomatitis / aphthous ulcerations, a glossitis.

From respiratory system: very often - unproductive dry cough; often - an asthma, a rhinorrhea, pharyngitis, a dysphonia, a bronchospasm; seldom – pulmonary infiltrates, rhinitis, an allergic alveolitis / eosinophilic pneumonia.

From bodies of a hemopoiesis: infrequently – anemia (including aplastic and hemolitic), a hypoglycemia; seldom – a neutropenia, decrease in concentration of hemoglobin, decrease in a hematocrit, thrombocytopenia, an agranulocytosis, oppression of a marrowy hemopoiesis, a pancytopenia.

From an urinary system: infrequently - a renal failure, a proteinuria; seldom – an oligouriya.

Allergic reactions: often - skin rash, a Quincke's disease of the person, extremities, lips, language, a glottis and/or throat; infrequently – a skin itch, a small tortoiseshell; seldom - exfoliative dermatitis, a multiformny erythema, a malignant exudative erythema (Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease), a pemphigus (pempigus), an erythrosis; very seldom – a Quincke's disease of a mucous membrane of intestines, a photosensitization, a dieback.

Development of the symptom complex including is possible: fever, serositis, vasculitis, миалгию / miositis, arthralgia/arthritis, positive test of ANA (antinuclear antibodies), increase in SOE (blood sedimentation rate), eosinophilia and leukocytosis.

From an organ of sight: very often – visual acuity disturbances.

Laboratory indicators: often - a hyperpotassemia, tranzitorny increase in blood serum of concentration of creatinine; infrequently - increase in blood serum of concentration of urea, a hyponatremia; seldom – increase in activity of "hepatic" transaminases, bilirubin.

Others: infrequently – fever, an alopecia, perspiration, muscular spasms, feelings of "inflows" to face skin, noise in the head, impotence, decrease in a libido; seldom - a limfoadenopatiya, autoimmune diseases, a gynecomastia.

Interaction with other medicines:

Simultaneous use with diuretics, other antihypertensives, nitroglycerine, other nitrates and vazodilatator, tricyclic antidepressants, neuroleptics, opioid analgetika, means for the general anesthesia increases risk of developing of arterial hypotension.

The non-steroidal anti-inflammatory drugs (NPVP), estrogen, adrenostimulyator, medicines activating renin-angiotensin-aldosteronovuyu system, a salt diet ethanol weaken hypotensive effect of drug.

NPVP and APF inhibitors render reversible additive effect - increase in potassium in blood serum. In rare instances – the acute renal failure can develop (for example, at the elderly or dehydrated patients).

Potassium drugs, kaliysberegayushchy diuretics (Spironolactonum, amiloride, Triamterenum), cyclosporine increase risk of development of a hyperpotassemia.

Co-administration of enalaprilat and drugs of lithium can lead to reversible intoxication lithium. Simultaneous use with drugs of lithium is not recommended. At justified need of such combination it is necessary to control carefully contents of lithium in blood serum.

Enalaprilat strengthens hypoglycemic effect of derivatives of sulphonylurea, insulin (is more often at the beginning of a combination therapy or at a renal failure).

At simultaneous use with Allopyrinolum, cytostatic means, immunodepressants, procaineamide the risk of development of a neutropenia and/or agranulocytosis increases.

Энап® P it is possible to apply along with acetylsalicylic acid, trombolitika and beta adrenoblockers.

At simultaneous use with gold drug (ауротималат sodium) in an injection form strengthening of effect of APF inhibitors is noted ("inflows" of blood to face skin, nausea, vomiting, arterial hypotension).

Contraindications:

Hypersensitivity to enalapril, enalaprilat, other components of drug or other APF inhibitors (including and in the anamnesis); hereditary and idiopathic Quincke's disease; age up to 18 years (safety and efficiency are not proved); the patients who are on a hemodialysis with use of poliakrilnitrilny membranes (high-flux (high-flowing) membranes, for example AN 69); at an afereza of lipoproteids of the low density (LPNP) of a dextran sulfate; just before a desensitization course aspen or apitoxin.

With care: primary hyper aldosteronism, an aortal stenosis, a mitral stenosis, a hypertrophic subaortic stenosis (GKMP) a bilateral stenosis of renal arteries, a stenosis of an artery of the only kidney, a hyperpotassemia, a state after transplantation of a kidney, general diseases of connecting fabric, cerebrovascular diseases, a diabetes mellitus, the chronic heart failure (CHF), a miyelosupressiya (a leukopenia, thrombocytopenia), the coronary heart disease (CHD), a renal failure (KK less than 1,33 ml / with, a proteinuria more than 1 g/days), a hypovolemia (a hyponatremia, against the background of therapy by diuretics; the patients keeping to a diet with restriction of table salt or being on a hemodialysis; diarrhea, vomiting), advanced age (65 years are more senior), simultaneous use with lithium drugs.

Overdose:

Symptoms: excessive decrease in the ABP up to development of a collapse, a myocardial infarction, an acute disorder of cerebral circulation or tromboembolic episodes, spasms, a stupor.

Treatment: at the expressed decrease in the ABP – to give to the patient horizontal position with the raised legs; 0,9% chloride sodium solution (in/in). The hemodialysis is effective: removal speed – 38-62 ml/min. (serumal concentration of enalaprilat decrease by 45-57% after a 4-hour hemodialysis). Regular control is recommended: The ABP, functions of breath, potassium concentration in blood serum and a diuresis.

Storage conditions:

List B. To store at a temperature not higher than 25 degrees of S. Hranit in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous administration, 1,25 mg / 1 ml. On 1 ml of drug in an ampoule from transparent glass (type I, Ph.Eur.). On an ampoule the color point and two color quoted rings are put. On 5 ampoules place in a blister strip packaging (blister). 1 blister is packed into a pack cardboard together with the application instruction.