PRILENAP

Active material: Enalapril, Gidroxlorotiazid
When ATH: C09BA02
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.03
Manufacturer: HEMOFARM A.D. (Serbia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills round, lenticular, from white to almost white, with Valium on one side.

Excipients: lactose monohydrate, magnesium carbonate, gelatin, krospovydon, magnesium stearate.

10 PC. – blisters (2) – packs cardboard.

Pills round, lenticular, from white to almost white, with Valium on one side.

Excipients: lactose monohydrate, magnesium carbonate, gelatin, krospovydon, magnesium stearate.

10 PC. – blisters (2) – packs cardboard.

Pharmacological action

Antihypertensive drugs. Contains enalapril and hydrochlorothiazide.

Enalapril – ACE inhibitor. It is a prodrug: pharmacologically active metabolite has enalaprilat, which is formed by hydrolysis of enalapril.

Gidroxlorotiazid – tiazidnый diuretic. It acts at the level of the distal tubule, increasing the excretion of sodium and chloride ions.

At the beginning of drug treatment due to being a part of hydrochlorothiazide fluid volume in the vessels is reduced by increasing excretion of sodium and fluid, resulting in reduced blood pressure and reduced cardiac output. Due hyponatremia and reduce body fluid activated RAAS. Reactive increase in the concentration of angiotensin II partially restricts blood pressure reduction. With continued therapy, the hypotensive effect of hydrochlorothiazide is based on the decrease in systemic vascular resistance. The result of the activation of the RAAS are metabolic changes in the electrolyte balance of blood, uric acid, glucose and lipid, partially neutralize the effectiveness of antihypertensive treatment. In spite of the effective reduction of blood pressure, thiazide diuretics did not reduce the structural changes in the heart and blood vessels.

It enhances the antihypertensive effect of enalapril – ingibiruyet of California, ie. production of angiotensin II and its effects. In addition, it reduces the production of aldosterone, and enhances the action of bradykinin, and prostaglandins release. Unnecessarily. enalapril has its own diuretic effect, this can increase the effects of hydrochlorothiazide. Enalapril reduces sight- and afterload, reduces the load on the left ventricle, reduces myocardial hypertrophy and proliferation of collagen, It prevents damage to myocardial cells. As a result, the heart rate slows down and reduces the load on the heart (in chronic heart failure), improved coronary blood flow and oxygen consumption decreases cardiomyocytes. Thus, reduced sensitivity of cardiac ischemia.

It has a beneficial effect on cerebral blood flow in patients with hypertension and chronic heart disease. It prevents the development of glomerulosclerosis, support and improve kidney function and slow the course of chronic kidney disease, even in those patients, who have not yet developed hypertension.

Known, that the antihypertensive effect of ACE inhibitors in patients with higher hyponatremia, hypovolemia, and elevated levels of renin in the blood serum, whereas the effect of hydrochlorothiazide is not dependent on the level of renin in serum. Therefore, co-administration of enalapril and hydrochlorothiazide promotes additional antihypertensive effect. Besides, enalapril prevents or reduces the metabolic effects of diuretic therapy, and has a favorable effect on the structural changes in the heart and blood vessels.

Co-administration of an ACE inhibitor and hydrochlorothiazide when used, when each drug alone is insufficiently effective or monotherapy conducted using maximum doses, which increases the frequency of adverse effects.

Antigipertenznvny effect of the combination is usually reserved for 24 no.

Pharmacokinetics

Enalapril

Absorption and metabolism

Enalapril is rapidly absorbed from the gastrointestinal tract (60%). Eating does not affect the absorption of enalapril. C_max achieved through 1 no. In baked эnalapril gidrolizuetsya to aktivnogo metabolite – эnalaprilata. C_max enalaprilat serum levels achieved after 3-6 no.

Distribution

Enalaprilat penetrates into most tissues of the body, mainly in the lungs, kidney and blood vessels. The binding to plasma proteins – 50-60%. Enalaprilat does not undergo further metabolism.

Enalapril and enalaprilat cross the placental barrier and is excreted in breast milk.

Deduction

Enalapril is excreted in the urine (60%) and feces (33%) predominantly in the form of enalaprilate.

The renal clearance of enalapril and enalaprilat is 0.005 ml / s (18 l /) and 0.00225-0.00264 ml / s (8.1-9.5 l /), respectively. T_1/2 enalaprilat from serum is approximately 11 no.

Pharmacokinetics in special clinical situations

Enalaprilat is removed from the blood by hemodialysis or peritoneal dialysis. Hemodialysis clearance enalaprilate 0.63-1.03 ml / s (38-62 ml / min); serum concentrations of enalaprilat after a 4-hour hemodialysis reduced by 45-57%.

In patients with reduced kidney function is slowing down, that it requires changing the dosage according to the function of kidneys, especially in patients with severe renal insufficiency.

Patients with liver failure enalapril metabolism can be slowed down without changing its pharmacodynamic effect.

Patients with heart failure absorption and metabolism enalaprilat slowing, also reduced V_d. Unnecessarily. these patients may develop kidney failure, it can slow down the excretion of enalapril.

Pharmacokinetics of enalapril may also vary in older patients, mostly due to comorbidities.

Gidroxlorotiazid

Absorption

Absorbed, mainly, in the duodenum and proximal small intestine. Absorption sostavlyaet 70% and increased by 10% when taken with food. C_max achieved through 1.5-5 no.

Distribution

V_d – about 3 l / kg. The binding to plasma proteins – 40%. Drug accumulates in erythrocytes, cumulation mechanism is not known.

It penetrates through the placental barrier and accumulates in the amniotic fluid. Serum concentrations of hydrochlorothiazide in the blood of the umbilical vein is essentially the same, as in maternal blood. The concentration in the amniotic fluid exceeds that in serum of umbilical vein (in 19 time). The concentration of hydrochlorothiazide in breast milk is very low. Hydrochlorothiazide was not detected in the serum of infants, whose mothers have taken hydrochlorothiazide during breastfeeding.

Deduction

Do not metabolized in the liver, excreted mainly by the kidneys (95% – as unchanged and about 4% – in the form HYDROLYZED-2-amino-4-chloro-m-benzenedisulʹfonamida). Renal clearance of hydrochlorothiazide in healthy volunteers and patients with hypertension is approximately 5.58 ml / s (335 ml / min). Hydrochlorothiazide is a biphasic elimination profile. T_1/2 in the initial phase of 2 no, in the final phase (through 10-12 h after administration) – about 10 no.

Pharmacokinetics in special clinical situations

Elderly patients hydrochlorothiazide has no negative effect on the pharmacokinetics of enalapril, but the serum concentration of enalaprilat it increases.

In the appointment of hydrochlorothiazide in patients with heart failure found, that its absorption is reduced in proportion to the extent of the disease – on 20-70%. T_1/2 hydrochlorothiazide increases to 28.9 no; renal clearance is 0.17-3.12 ml / s (10-187 ml / min), averages 1.28 ml / s (77 ml / min).

Patients, undergoing surgery intestinal bypass surgery for obesity, absorption of hydrochlorothiazide may be reduced by 30%, and serum concentration – on 50% compared with healthy volunteers.

Simultaneous administration of enalapril and hydrochlorothiazide has no effect on the pharmacokinetics of each.

Testimony

- Treatment of hypertension, requiring the use of combination therapy.

Dosage regimen

The dose and duration of therapy is determined individually.

It is recommended to take the drug for 1 tab. / day (10 mg + 12.5 mg) or lack of therapeutic effect 10 mg + 25 mg.

The tablets should be taken during the whole or postprandial, drinking a small amount of liquid.

In the absence of a therapeutic effect it is recommended to add another drug or change therapy.

Patients, are on diuretic therapy, it is recommended to cancel or reduce the dose of diuretics at least 3 days before the start of treatment Prilenapom^® to prevent the development of symptomatic hypotension. Before treatment should be investigated renal function.

Patients with CC > 30 ml / min or serum creatinine < 265 mmol / l (3 mg / dL) It can be assigned to the usual dose Prilenapa^® (10 mg +12.5 mg).

Side effect

Cardio-vascular system: heartbeat, various heart rhythm disturbances, marked reduction in blood pressure, orthostatic hypotension, cardiac arrest, myocardial infarction, cerebrovascular stroke, angina, Raynaud's syndrome.

From the digestive system: dry mouth, glossitis, stomatitis, inflammation of the salivary glands, anorexia, nausea, vomiting, diarrhea, constipation, flatulence, epigastric pain, intestinal colic, ileus, pancreatitis, hepatic failure, hepatitis, jaundice, ground, increase in liver enzymes, giperʙiliruʙinemija.

The respiratory system: rhinitis, sinusitis, pharyngitis, hoarseness, bronchospasm, asthma, pneumonia, pulmonary infiltrates, eosinophilic pneumonia, pulmonary embolism, pulmonary infarction, pulmonary edema, respiratory distress, including pneumonitis and pulmonary edema, nonproductive cough.

With the genitourinary system: oligurija, gynecomastia, reduced potency, renal failure, impairment of renal function, interstitial nephritis.

From the senses: blurred vision, taste disturbance, violation of smell, noise in ears, conjunctivitis, dryness of the conjunctiva, lacrimation.

From the central and peripheral nervous system: depression, ataxia, drowsiness, insomnia, anxiety, nervousness, perifericheskaya neuropathy (paresthesia, dysesthesia), dizziness.

From the hematopoietic system: leukocytosis, eozinofilija, neutropenia, leukopenia, agranulocytosis, anemia, gipogemoglobinemiâ, pancytopenia, decrease in hematocrit.

Allergic reactions: hives, itch, angioedema, anaphylactic reactions.

Dermatological reactions: increased perspiration, rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, alopecia, photosensitivity.

Laboratory findings: kaliopenia, hyperkalemia, gipomagniemiya, hypercalcemia, giponatriemiya, hypochloraemic alkalosis, giperglikemiâ, glycosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia.

Other: shingles, lupus-like syndrome (fever, myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, a positive test for antinuclear antibodies), muscle cramps, gout, trombotsitopenicheskaya purpura, necrotizing vasculitis, fever.

Contraindications

- Anurija;

- Expressed by the human kidney (CC < 30 ml / min);

- A history of angioedema, associated with previous ACE inhibitor;

- Hereditary or idiopathic angioedema;

- Primary hyperaldosteronism;

- Addison's disease;

- Porphyria;

- Up to 18 years (efficacy and safety have not been established);

- Hypersensitivity to the drug or sulfonamides.

FROM caution should be prescribed with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, renal impairment (CC 30-75 ml / min), marked aortic stenosis or hypertrophic subaortic stenosis, idiopathic, CHD, cerebrovascular diseases (incl. cerebrovascular insufficiency), chronic heart failure, severe autoimmune systemic diseases of connective tissue (incl. systemic lupus erythematosus, scleroderma), suppression of bone marrow hematopoiesis, diabetes, hyperkalemia, condition after kidney transplantation, severe hepatic dysfunction and / or kidney, states, accompanied by a decrease in the bcc (as a result of diuretic therapy, while limiting intake of salt, diarrhea and vomiting), podagre, elderly patients.

Pregnancy and lactation

The drug is contraindicated in pregnancy. In the event of pregnancy, the drug should be discontinued immediately.

If necessary, the appointment during lactation should decide the issue of termination of breastfeeding.

Cautions

At the beginning of treatment may develop hypotension (in patients with severe heart failure, hyponatremia, severe renal insufficiency, hypertension or left ventricular dysfunction and, especially, in patients with hypovolemia as a result of diuretic therapy, salt-free diet, diarrhea, vomiting or hemodialysis). Hypotension after the first dose and its more serious consequences is a rare and passing phenomenon. It is possible to avoid the cancellation of diuretics, if possible, before treatment Prilenapom^®.

In the event of hypotension is necessary to lay the patient on his back with a low headboard and, if necessary, adjust the bcc infusion of saline. Transient hypotension is not a contraindication to further treatment. After normalization of blood pressure and volume replacement patients usually tolerate subsequent doses.

Precautions should be prescribed to patients with impaired renal function (CC 30-75 ml / min). Patients, taking hydrochlorothiazide, may develop azotemia. In patients with impaired renal function may show signs of accumulation of the drug. If necessary, you can use a combination of enalapril with a lower number of hydrochlorothiazide or a combination therapy with enalapril and hydrochlorothiazide should be abolished.

Should be avoided in Prilenapa^® patients with bilateral renal artery stenosis or renal artery stenosis sole kidney, tk. possible deterioration of renal function until the development of acute renal failure (the effect of enalapril). Therefore necessary to monitor renal function before and during treatment.

Precautions should be prescribed to patients with coronary artery disease, severe cerebrovascular disease, aortic stenosis or other stenosis, preventing the outflow of blood from the left ventricle, severe atherosclerosis, elderly patients because of the risk of hypotension and deterioration of cardiac perfusion, brain and kidney.

Requires regular monitoring of serum electrolytes during treatment Prilenapom^® to identify potential imbalances and timely adoption of the necessary measures. Determination of serum electrolytes is necessary for patients with prolonged diarrhea, vomiting and getting in / Infusion.

Patients, taking Prilenap^®, you need to identify signs of electrolyte imbalance, such as dry mouth, thirst, weakness, drowsiness, slackness, excitation, muscle pain or cramps (mainly calf muscle), decrease in blood pressure, tachycardia, oliguria and gastrointestinal disturbances (nausea, vomiting).

Prilenap^® should be used with caution in patients with liver failure or advanced liver disease, tk. hydrochlorothiazide may cause hepatic coma even at minimum electrolyte disturbances.

During treatment Prilenapom^® It can be observed and occasionally hypomagnesemia – hypercalcemia, resulting increase excretion of magnesium and slow urinary excretion of calcium under the influence of hydrochlorothiazide. A significant increase in serum calcium levels can be a sign of hidden hyperparathyroidism.

In some patients as a result of hydrochlorothiazide may experience worsening of hyperuricemia or gout. If there is an increase in uric acid concentration in blood serum, treatment should be discontinued. It may be resumed after the normalization of laboratory values ​​and subsequently held under their control.

Caution is required in all patients, treated with oral hypoglycemic agents or insulin, tk. Hydrochlorothiazide may attenuate, and enalapril – strengthen their action. Patients with diabetes should be supervised, if necessary, may require dosage adjustment of hypoglycemic agents.

If you experience angioedema face or neck is usually sufficient treatment discontinuation and administering to the patient antihistamines. In more severe cases, (swelling of the tongue, pharynx and larynx) Epinephrine should be appointed (adrenaline) and the need to maintain an open airway (intubation or thyroidotomy).

The antihypertensive effect Prilenapa^® can be amplified after sympathectomy.

Due to the increased risk of anaphylactic reactions should not be given Prilenap^® patients, hemodialysis with polyacrylonitrile membranes, undergoing apheresis with dextran sulfate and immediately before desensitization to wasp or bee venom.

During treatment Prilenapom^® may experience hypersensitivity reactions in patients without prior allergies or asthma.

It has been reported about the deterioration of the current systemic lupus erythematosus.

A few cases of acute liver failure with cholestatic jaundice, liver necrosis and death during treatment with an ACE inhibitor. The cause of these syndromes is not completely clear. If you have jaundice and elevated liver enzymes the treatment should be stopped immediately, and patients should be monitored.

Caution is also required in patients, receiving sulfonamides or oral hypoglycemic agents of the sulfonylureas group (possible cross-hypersensitivity).

Patients, taking antihypertensive drugs, after major surgery during general anesthesia, enalapril may block the formation of angiotensin II, secondary to compensatory renin release. If your doctor suggests this mechanism of arterial hypotension, treatment may be aimed at increasing the bcc.

During treatment requires periodic monitoring of white blood cell count, especially in patients with connective tissue disease or renal.

During treatment requires periodic monitoring of serum electrolytes, Glucose, urea, creatinine, liver enzymes, and urinary protein.

Treatment Prilenapom^® It should be discontinued before carrying out research function of the parathyroid glands.

Effects on ability to drive vehicles and management mechanisms

Prilenap^® It does not affect the ability to drive a car or operating machinery, However, some patients, mainly early in treatment may occur hypotension and dizziness, This can reduce the ability to control the vehicle and operate machinery. So at the beginning of treatment is recommended to avoid driving a car, working with machinery and other work, requiring concentration of attention, until, until the preferred treatment response.

Overdose

Symptoms: increased diuresis, marked reduction in blood pressure with bradycardia or other cardiac arrhythmias, convulsions, paresis, paralytic ileus, disturbance of consciousness (including who), renal failure, violation of AAR, blood electrolyte imbalance.

Treatment: the patient is transferred to a horizontal position with a low headboard. In mild cases, it shows a gastric lavage and ingestion of saline, in more severe cases, – measures to stabilize the blood pressure – in / in a saline solution, plasma expanders. It is necessary to control blood pressure, Heart Rate, respiratory rate, serum concentration of urea, creatinine, electrolytes and diuresis, if necessary – in / with the introduction of angiotensin II, hemodialysis (rate of excretion enalaprilate – 62 ml / min).

Drug Interactions

Simultaneous treatment with other antihypertensive agents, ʙarʙituratov, tricyclic antidepressants, phenothiazine, Opioid analgesics, Ethanol enhances the antihypertensive effect Prilenapa^®.

Analgesics and NSAIDs, a large amount of salt in the food, concomitant use of cholestyramine or colestipol reduce the effect Prilenapa^®.

Concomitant use Prilenapa^® drugs lithium and can lead to lithium intoxication, tk. enalapril and hydrochlorothiazide reduce the excretion of lithium. Necessary to control the concentration of lithium in blood serum and, if necessary, – dose adjustment. If possible, avoid simultaneous treatment Prilenapom^® and lithium preparations.

Concomitant use Prilenapa^® and NSAIDs and analgesics (due to inhibition of prostaglandin synthesis) Enalapril may reduce the effectiveness and increase the risk of worsening renal function and / or for heart failure. Some patients may also decrease the antihypertensive effect of enalapril, so if you must use this combination shows a control.

The simultaneous use of potassium-sparing diuretics (spironolactone, amilorid, triamterene) medications or potassium can lead to hyperkalemia.

Concomitant use with allopurinol, cytostatics, systemic corticosteroids or immunosuppressants can lead to leukopenia, anemia or pancytopenia, therefore, requires periodic monitoring of hemogram.

It reported the development of acute renal failure in two patients after renal transplantation, simultaneously receiving enalapril and cyclosporine. Expected, that acute renal failure was the result of decreased renal blood flow, cyclosporin induced, and reduction of glomerular filtration, caused by enalapril. Therefore, caution is necessary, while the application of enalapril and cyclosporine.

The simultaneous use of sulfonamides and oral hypoglycemic agents of the sulfonylureas may cause hypersensitivity reactions (possible cross-hypersensitivity).

Care should be taken while the application Prilenapa^® with cardiac glycosides. Possible hypovolemia, hypokalemia and hypomagnesemia may increase the toxicity of glycosides.

Concomitant use Prilenapa^® with corticosteroids increases the risk of hypokalemia.

In an application Prilenapa^® and theophylline enalapril may reduce T_1/2 teofillina.

In an application Prilenapa^® and cimetidine may increase T_1/2 Enalapril.

The risk of hypotension is increased during general anesthesia or the use of non-depolarizing muscle relaxants (eg, tuʙokurarina).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be protected from moisture, inaccessible to children at temperature from 15 ° to 25 ° C. Shelf life – 2 year.