Enap®R (Enap®R)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEnalaprilatEnalaprilat
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  • Enap®R
    solution in / in 
    KRKA, dd, Novo mesto, AO    
    • Dosage form: & nbspsolution for intravenous administration
    Composition:

    1 ampoule contains (mg / ml):

    Active substance:

    Enalaprilate 1.25 mg

    Excipients:

    gasoline alcohol 9.00 mg, sodium chloride 6.20 mg, sodium hydroxide q.s. up to pH 7.0 ± 0.2, water for injection q.s. up to 1.00 ml

    Description:A clear, colorless solution
    Pharmacotherapeutic group:Angiotensin-converting enzyme (ACE) inhibitor.
    ATX: & nbsp

    C.09.A.A   ACE Inhibitors

    Pharmacodynamics:

    Enalaprilat is a metabolite of enalaryl ACE inhibitor. Reduces the formation of angiotensin II from angiotensin I, the concentration of aldosterone in the blood, increases the release of renin, stimulates the release of prostaglandins and endothelial relaxing factor of veins, depresses the sympathetic nervous system. Reduces the overall peripheral vascular resistance, arterial pressure (BP), pre - and postnagruzku on the myocardium, dilates the arteries to a greater extent than the veins. The hypotensive effect is more pronounced with a high level of renin of the blood plasma than at its normal or reduced level. Reduction of blood pressure within therapeutic limits does not affect cerebral circulation. Improves the blood supply of the ischemic myocardium.The time of the therapeutic effect after intravenous administration of 5-15 minutes, reaches a maximum after 1-4 hours, it lasts about 6 hours.

    Pharmacokinetics:

    Enalaprilat is poorly absorbed after oral administration and is practically inactive, therefore it is administered only intravenously. The maximum concentration after intravenous administration (IV) is achieved after 15 minutes.

    The half-distribution period is 4 hours. Relationship with plasma proteins 50-60%. Circulates in the blood in an unchanged form. Poorly penetrates the blood-brain barrier. It is not metabolized.

    It is excreted from the body in an unchanged form, through the kidneys (more than 90%) by glomerular filtration and tubular secretion. The half-life (T1 / 2) is about 35 hours.

    Creatinine clearance (CC) in hemodialysis is 38-62 ml / min, enalaprilat concentration in serum after 4-hour hemodialysis is reduced by 45-75%.

    Indications:

    Hypertensive crisis, arterial hypertension in cases when the intake of drugs inside is not possible, hypertensive encephalopathy.

    Contraindications:Hypersensitivity to enalapril, enalaprilat, other components of the drug or other ACE inhibitors (incl.and in the anamnesis); hereditary and idiopathic angioedema; age under 18 years (safety and efficacy not proven); patients on hemodialysis using polyacrylonitrile membranes (high-flux (high-flow) membranes, for example AN 69); in the apheresis of low-density lipoprotein (LDL) dextran sulfate; immediately before the course of desensitization with aspen or bee venom
    Carefully:

    Primary hyperaldosteronism, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy (HCMP), bilateral stenosis of the renal arteries, stenosis of the single kidney artery, hyperkalemia, condition after kidney transplantation, systemic connective tissue diseases, cerebrovascular diseases, diabetes mellitus, chronic heart failure (CHF), myelosuppression (leukopenia, thrombocytopenia), ischemic heart disease (CHD), renal failure (QC less than 1.33 ml / s, proteinuria more than 1 g / day), gi povolemia (hyponatremia, diuretic therapy, patients who are on a diet with restriction of sodium chloride or who are on hemodialysis, diarrhea, vomiting) * elderly age (over 65),simultaneous use with lithium preparations.

    Pregnancy and lactation:

    In pregnancy, the drug is contraindicated. Do not use in the first trimester of pregnancy. When pregnancy is confirmed enalapril necessary cancel. The drug is contraindicated in the II - III trimesters of pregnancy. Application in the II - III trimesters of pregnancy can cause fetotoxic effects (decreased kidney function, low blood pressure, slowing ossification of the skull bones) and neonatal

    toxic effects (renal failure, arterial hypotension, hyperkalemia). When applying the drug in the II - III trimester of pregnancy, it is recommended to perform ultrasound examination of the kidneys and bones of the fetal skull. Enalapril penetrates the placenta and can be removed from the neonatal blood flow by peritoneal dialysis.

    Enalapril and enalaprilate is excreted in breast milk, but their safety has not been studied. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

    Dosing and Administration:

    Intravenous (IV), for 5 minutes slowly or dropwise in a dilution of 20-50 ml of 5% dextrose (glucose) solution, 0.9% sodium chloride solution at 1.25 mg (1 ml - 1 ampoule) every 6 hours.

    The usual dose is 1.25 mg (1 ml) of the drug every 6 hours, including patients who had previously taken Enap® for oral administration (tablets).

    In patients taking diuretics, the initial dose of the drug is reduced to 0.625 mg (0.5 ml - ½ ampoules). If, after 1 hour after the administration, the therapeutic effect is unsatisfactory, the same dose can be reintroduced, and after 6 hours the drug is continued at a dose of 1.25 mg every 6 hours.

    Dosage for renal failure:

    With moderately severe chronic renal failure (CRF) for patients with CC greater than 0.5 ml / s (30 ml / min, creatinine in the serum does not exceed 265 μmol / l), the dose is 1.25 mg (1 ml - 1 ampoule ) of the drug every 6 hours, dose adjustment is not required. If, after 1 hour after the administration, the therapeutic effect is unsatisfactory, a dose of 1.25 mg (1 ml-1 ampoule) can be reintroduced, and after 6 hours the drug is continued at a dose of 1.25 mg (1 ampoule) every 6 hours.

    For patients with SC less than 0.5 ml / s (30 ml / min, creatinine in the blood serum is 265 μmol / L), the initial dose is 0.625 mg (0.5 ml), followed by monitoring the blood pressure for 1 hour for the risk of excessive BP reduction.In the absence of effect after 1 hour, the administration of the drug at a dose of 0.625 mg (0.5 ml) is repeated, and the drug is continued at a dose of 1.25 mg (1 ml-1 ampoule) every 6 hours.

    For patients on hemodialysis, the dose of Enap® P is 0.625 mg (0.5 ml) every 6 hours for 48 hours.

    When switching to taking the drug inside: the recommended initial dose of enalapril is 5 mg per day for patients who were previously given the usual dose (1.25 mg / ml) of Enap®. If necessary, the dose may be increased. For patients whose treatment was twice reduced by an initial dose of 0.625 mg (0.5 ml) of Enap® R, the recommended initial dose of enalapril for switching to ingestion is 2.5 mg per day.-
    Side effects:

    Classification of incidence of adverse events (World Health Organization (WHO)):

    very often> 1/10

    often from> 1/100, <1/10

    infrequently from> 1/1000, <1/100

    rarely from> 1/10000, <1/1000

    very rarely from <1/10000, including individual messages.

    From the cardiovascular system: often - chest pain, palpitations, arrhythmias (atrial brady or tachycardia, atrial fibrillation), acute left ventricular failure, pulmonary artery embolism, excessive blood pressure lowering, orthostatic collapse

    Rarely is a syndrome. With excessive decrease in blood pressure, mainly in patients with IHD and clinically significant narrowing of cerebral vessels, myocardial ischemia (angina pectoris or myocardial infarction) or cerebrovascular disorders may develop.

    From the central (CNS) and peripheral nervous system: very often - asthenia; often - headache, depression, weakness; infrequently - dizziness, paresthesia, drowsiness, insomnia, increased nervous excitability; rarely - "nightmarish" dreams, sleep disturbances.

    From the side of the digestive system, very often - nausea; often - diarrhea, abdominal pain, changes in taste; infrequent - constipation, vomiting, intestinal obstruction, pancreatitis, dyspepsia, anorexia, dry mouth, peptic ulcer; rarely - stomatitis / aphthous ulceration, glossitis.

    From the respiratory system: very often - an unproductive dry cough; often - shortness of breath, rhinorrhea, pharyngitis, dysphonia, bronchospasm; rarely - pulmonary infiltrates, rhinitis, allergic alveolitis / eosinophilic pneumonia.

    On the part of the organs of hematopoiesis: infrequently anemia (including aplastic and hemolytic), hypoglycemia; rarely - neutropenia,decrease in hemoglobin concentration, decrease in hematocrit, thrombocytopenia, agranulocytosis, oppression of bone marrow hematopoiesis, pancytopenia.

    From the urinary system: infrequently - a violation of kidney function, proteinuria; rarely - oliguria.

    Allergic reactions: often - skin rash, angioedema, swelling of the face, limbs, lips, tongue, glottis and / or larynx; infrequently - itchy skin, hives; rarely - exfoliative dermatitis, erythema multiforme, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus (pemphigus), erythroderma; very rarely - angioedema, swelling of the intestinal mucosa, photosensitivity, exanthema.

    It is possible to develop a symptom complex including: fever, serositis, vasculitis, myalgia / myositis, arthralgia / arthritis, positive ANA test (antinuclear antibodies), increased ESR (speed of erythrocyte sedimentation), eosinophilia and leukocytosis.

    From the side of the organ of vision: very often - a violation of visual acuity.

    Laboratory indicators: often - gitserkalemiya,transient Increased serum creatinine concentrations; infrequent - increase in serum blood urea concentration, hyponatremia; rarely - increased activity of "liver" transaminases, bilirubin.

    Other: infrequent - fever, alopecia, sweating, muscle cramps, sensations of "hot flashes" to the skin of the face, noise in the head, impotence, decreased libido; rarely - lymphadenopathy, autoimmune diseases, gynecomastia.

    Overdose:

    Symptoms: excessive decrease in blood pressure up to the development of collapse, myocardial infarction, acute disturbance of cerebral circulation or thromboembolic complications, convulsions, stupor.

    Treatment: with a pronounced decrease in blood pressure - give the patient a horizontal position with raised legs; 0.9% solution of sodium chloride (iv). Hemodialysis is effective: the rate of excretion is 38-62 ml / min (serum concentrations of enalaprilat decrease by 45-57% after 4 hours of hemodialysis). Regular monitoring is recommended: blood pressure, respiratory function, serum potassium concentrations and diuresis.

    Interaction:

    Simultaneous use with diuretics, other antihypertensive drugs, nitroglycerin, other nitrates and vasodilators,tricyclic antidepressants, neuroleptics, opioid analgesics, means for general anesthesia increases the risk of arterial hypotension. Non-steroidal anti-inflammatory drugs (NSAIDs), estrogens, adrenostimulators, drugs that activate the renin-angiotensin-aldosterone system, salt diet, ethanol weaken the hypotensive effect of the drug.

    NSAIDs and ACE inhibitors have a reversible additive effect - an increase in potassium in the serum. In rare cases, acute renal failure may develop (for example, in elderly or dehydrated patients).

    Potassium preparations, potassium-sparing diuretics (spironolactone, amiloride, triamterene), ciclosporin increase the risk of hyperkalemia.

    Simultaneous administration of enalaprilat and lithium preparations may lead to reversible intoxication with lithium. Simultaneous use with lithium preparations is not recommended. If this combination is justified, it is necessary to carefully monitor the lithium content in the blood serum.

    Enalaprilat enhances the hypoglycemic effect of derivatives of sulfonylureas, insulin (more often at the beginning of combination therapy or in violation of kidney function).

    When used simultaneously with allopurinol, cytostatic agents, immunosuppressants, procainamide, the risk of developing neutropenia and / or agranulocytosis increases.

    Enap ® P can be used simultaneously with acetylsalicylic acid, thrombolytic agents and beta-blockers.

    With the simultaneous application of gold (sodium arotomalate) to the preparation in injection form, the effect of ACE inhibitors ("hot flushes" of the blood to the skin of the face, nausea, vomiting, arterial hypotension) was noted.

    Special instructions:

    The treatment is carried out only in the conditions of the treatment-and-prophylactic institution or ambulance brigades.

    Arterial hypotension may be observed (within a few hours after the first dose) in patients with severe CHF and hyponatremia, as well as in patients with severe renal failure and in patients with hypertension, especially against the background of hypovolemia as a result of diuretic treatment, salt-free diet, diarrhea, vomiting or hemodialysis. Treatment of patients with an increased risk of developing arterial hypotension should begin with a half dose of Enap ® P (0.625 mg - 0.5 ml).With arterial hypotension, the patient should be given a horizontal position with a low head and, if necessary, adjust the volume of plasma by infusing 0.9% sodium chloride solution. Transient (transient) arterial hypotension is not a contraindication to further treatment with enalaprilat. After correcting blood pressure and circulating blood volume (BCC), patients usually tolerate the following doses of the drug well. In case of symptomatic arterial hypotension, the dose of the drug should be reduced or discontinued with Enap ® R

    Avoid treatment with Enap ® R in patients with bilateral renal artery stenosis or arterial stenosis with a single lice, as this can cause arterial hypotension, impaired renal function, and even acute renal failure (ARF), which is usually reversible. It is recommended to begin therapy with minimal doses and in conditions of careful medical supervision; in the subsequent it is necessary to carry out - a titration of a dose and the regular control of function of kidneys.

    In patients with renal insufficiency, the dose is correlated depending on the level of CC (see Fig.section: "Method of administration and dose"). It is recommended to monitor creatinine and the concentration of potassium in the blood.

    Since during the period of treatment with Enap® P the potassium level in the serum can be raised, especially in patients with CHF suffering from diabetes mellitus, simultaneous administration of the drug and potassium-sparing diuretics such as spironolactone, amiloride and triamterene, and other drugs that can cause hyperkalemia, is not recommended.

    In rare cases, it is possible to develop a syndrome that begins with cholestatic jaundice, progressing to fulminant liver necrosis. The mechanism of development of this syndrome is unknown. When jaundice or increased activity of "liver" enzymes should immediately stop the drug.

    Against the background of simultaneous therapy with hypoglycemic agents (derivatives of sulfonylureas and insulin), blood glucose control is necessary during the first few months.

    Before and during therapy with ACE inhibitors, especially in patients with an increased risk of neutropenia / agranulocytosis (with impaired renal function or systemic connective tissue diseases,on the background of therapy with allopurinol and procainamide), thrombocytopenia and anemia or receiving high doses of ACE inhibitors, as well as at the first signs of infection, it is necessary to control the total number of leukocytes and the leukocyte formula at a frequency of once a month in the first 3-6 months of treatment and at periodic intervals up to a year. When neutropenia is confirmed (the number of neutrophils is less than 1000 / μL) therapy with ACE inhibitors should be discontinued.

    Before and during treatment with ACE inhibitors, control of blood pressure, blood counts (hemoglobin, potassium, creatinine, urea, activity of "liver" enzymes) and protein in the urine is necessary.

    It is necessary to take into account in the behavior of a differential diagnosis the possible development of a dry, unproductive cough that disappears after discontinuation of therapy.

    If there is an angioedema in the anamnesis (even if not associated with the intake of ACE inhibitors), there is an increased risk of its re-development against the background of treatment.

    Before surgical interventions (including dentistry), an anesthesiologist should be warned about the use of ACE inhibitors (risk of developing arterial hypotension).

    For newborns or infants who have been exposed to the intrauterine effect of ACE inhibitors, it is recommended to monitor for a timely detection of a marked decrease in blood pressure, oliguria, hyperkalemia and neurological disorders, possibly due to a decrease in renal and cerebral blood flow with a decrease in blood pressure caused by ACE inhibitors. In oliguria it is necessary to maintain BP and renal perfusion by introducing appropriate fluids and vasoconstrictors.

    The drug contains less than 1 mmol (23 mg) of sodium in each dose (1.25 mg), therefore it is considered as a "sodium-free drug".

    Form release / dosage:

    Solution for intravenous administration, 1.25 mg / ml.

    Packaging:

    1 ml of the drug in a vial of clear glass (type I). The ampoule has a colored dot and two color coding rings. 5 ampoules are placed in a contour mesh package (blister) from PVC film and aluminum foil. 1 blister packs in a pack of cardboard along with instructions for use.

    Storage conditions:

    When temperature not higher than 25 ° С.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use the drug after the expiration date.

    Terms of leave from pharmacies:For hospitals
    Registration number:П N015813 / 01
    Date of registration:25.06.2009
    The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO
    Manufacturer: & nbsp
    Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO
    Information update date: & nbsp23.10.2015
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