Composition, form of production and packaging
Tablets are yellow, round, biconvex, with a corrugated edge, on the one hand engraving "MSD 718", on the other - risk.
1 tab.
enalapril maleate 20 mg
hydrochlorothiazide 12.5 mg
Excipients: sodium bicarbonate, water lactose, corn starch, corn pregelatinized starch, iron oxide oxide yellow, magnesium stearate.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
56 pcs. - polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2008.
PHARMACHOLOGIC EFFECT
Combined antihypertensive drug, which includes an ACE inhibitor (enalapril maleate) and a thiazide diuretic (hydrochlorothiazide). Has antihypertensive and diuretic effect.
Enalapril is an ACE inhibitor that catalyzes the conversion of angiotensin I into a pressor substance called angiotensin II. After absorption, enalapril is converted by hydrolysis to enalaprilate, which inhibits ACE. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which leads to an increase in renin plasma activity (due to elimination of reverse negative reaction to changes in renin production) and a decrease in aldosterone secretion.
The ACE is identical to the kinase II enzyme, so enalapril can also block the destruction of bradykinin, a peptide that has a vasodilating effect. The significance of this mechanism in the therapeutic action of enalapril requires refinement. Despite the fact that enalapril reduces blood pressure by suppressing the renin-angiotensin-aldosterone system, which plays an important role in the regulation of blood pressure, the drug reduces BP even in patients with low-renin hypertension.
Decrease in blood pressure is accompanied by a decrease in OPSS, a slight increase in cardiac output and no changes or slight changes in heart rate. As a result of enalapril, renal blood flow increases, the glomerular filtration rate remains unchanged. However, in patients with initially reduced glomerular filtration, its rate usually increases.
Antihypertensive therapy with enalapril leads to a significant regression of left ventricular hypertrophy and preservation of left ventricular systolic function.
Therapy with enalapril is accompanied by a favorable effect on the ratio of fractions of lipoproteins and the absence of influence or favorable effect on the content of total cholesterol.
The use of enalapril in patients with arterial hypertension leads to a decrease in blood pressure both standing and lying, without a significant increase in heart rate.
Symptomatic postural hypotension develops rarely. In some patients, achieving an optimal BP reduction may require several weeks of therapy. Interruption of enalapril therapy does not cause a sharp rise in blood pressure.
Effective inhibition of ACE activity usually develops 2-4 hours after a single dose enalapril intake. The onset of antihypertensive action occurs within 1 hour, the maximum decrease in blood pressure is observed 4-6 hours after taking the drug. The duration of action depends on the dose. However, when used in the recommended doses, the antihypertensive effect and hemodynamic effects persist for 24 hours.
Hydrochlorothiazide has a diuretic and antihypertensive effect, increases the activity of renin. Although enalapril itself has an antihypertensive effect even in patients with arterial hypertension amid a low renin concentration, the concomitant use of hydrochlorothiazide in such patients leads to a more pronounced decrease in blood pressure.
Enalapril reduces the loss of potassium ions caused by the use of hydrochlorothiazide. Enalapril and hydrochlorothiazide have a similar dosing regimen. Therefore, Co-renitek is a convenient dosage form for the co-administration of enalapril and hydrochlorothiazide.
The use of a combination of enalapril and hydrochlorothiazide leads to a more pronounced decrease in blood pressure than monotherapy with each drug alone and allows the anti-hypertensive effect of the Co-renitek drug to be maintained for at least 24 hours.
PHARMACOKINETICS
Enalapril
Suction
After ingestion of enalapril, the maleate is rapidly absorbed. C max enalapril in the serum is observed within 1 h after administration. After oral administration, the absorption is approximately 60%.
Eating does not affect the absorption of enalapril. The duration of absorption and hydrolysis of enalapril is similar for different recommended therapeutic doses.
After absorption, enalapril is rapidly hydrolyzed to form the active substance enalaprilata, a potent ACE inhibitor. C max enalaprilat in the blood serum is observed 3-4 hours after taking enalapril dose inside.
Excretion
Enalapril is excreted mainly by the kidneys. The main metabolites detected in urine are enalaprilat, which is approximately 40% of the dose, and unaltered enalapril.Data on other significant ways of metabolism of enalapril, with the exception of hydrolysis in enalaprilat, are not available. The concentration curve of enalaprilate in blood plasma has a long final phase, which is apparently due to its binding to the ACE. In individuals with normal renal function, a stable concentration of enalaprilat is achieved on the 4th day after the start of enalapril. T 1/2 of enalaprilat for a course of oral administration is 11 hours.
Hydrochlorothiazide
Metabolism and distribution
Not exposed to metabolism. Hydrochlorothiazide penetrates the placental barrier, but does not penetrate the BBB.
Excretion
T 1/2 hydrochlorothiazide from 5.6 to 14.8 hours. Quickly excreted by the kidneys. At least 61% of the dose taken orally is excreted unchanged for 24 hours.
The combination of enalaprilate maleate and hydrochlorothiazide
Regular intake of a combination of enalapril and hydrochlorothiazide does not affect or slightly affects the bioavailability of each component of the drug. The use of a combination tablet of the preparation of Co-renitek is bioequivalent to the simultaneous administration of its ingredients in separate dosage forms.
INDICATIONS
- treatment of arterial hypertension in patients who are shown combined therapy.
DOSING MODE
The drug is administered orally, regardless of food intake.
With arterial hypertension, the initial dose is 1 tab. 1 time / day. If necessary, the dose can be increased to 2 tablets. 1 time / day.
At the beginning of Co-renitek therapy, symptomatic arterial hypotension may develop, more often in patients with water-electrolyte balance disorders due to previous treatment with diuretics. Therapy with diuretics should be discontinued 2-3 days before the application of Co-Renitech.
In patients with impaired renal function, thiazides may not be effective enough, and with QC? 30 ml / min (ie, with moderate to severe renal failure) are ineffective.
With KK 80-30 ml / min Korenitek should be used only after the preliminary selection of the doses of each of the components.
With mild renal insufficiency, the recommended dose of enalapril maleate taken separately is 5 mg to 10 mg.
SIDE EFFECT
In clinical trials, the side effects were usually mild, transient, and in most cases did not require discontinuation of treatment.
From the cardiovascular system: 1-2% - orthostatic effects, including arterial hypotension; seldom - a syncope, an arterial hypotension irrespective of a position of a body, palpitation, a tachycardia, a pain in a breast.
From the side of the central nervous system and the peripheral nervous system: often - dizziness, increased fatigue (usually taken at a lower dose and rarely required the drug to be withdrawn); 1-2% - asthenia, headaches; rarely - insomnia, drowsiness, systemic dizziness, paresthesia, increased excitability.
On the part of the respiratory system: 1-2% - cough; rarely - shortness of breath.
From the digestive system: 1-2% - nausea; rarely - pancreatitis, diarrhea, vomiting, indigestion, abdominal pain, flatulence, constipation, dry mouth.
From the musculoskeletal system: 1-2% - muscle cramps; rarely - arthralgia.
Allergic reactions: rarely - angioedema, swelling of the face, extremities, lips, tongue, glottis and / or larynx. There are rare reports of the development of angioedema of the intestine due to the administration of ACE inhibitors, including enalapril.
Dermatological reactions: rarely - Stevens-Johnson syndrome, hyperhidrosis, skin rash, itching.
From the urinary system: rarely - a violation of kidney function, kidney failure.
On the part of the reproductive system: 1-2% - impotence; rarely - decreased libido.
On the part of laboratory indicators: hyperglycemia, hyperuricemia, hypo- or hyperkalemia, increased urea blood concentration, serum creatinine, increased activity of hepatic enzymes, and / or increased serum bilirubin (these parameters usually normalized after discontinuation of Co-renitek therapy); in some cases - a decrease in hemoglobin and hematocrit.
Other: rarely - tinnitus, gout. Described symptom complex, possible manifestations of which are fever, serositis, vasculitis, myalgia, myositis, arthralgia / arthritis, positive test for antinuclear antibodies, acceleration of ESR, eosinophilia and leukocytosis; possible the development of photosensitization.
CONTRAINDICATIONS
anuria;
- angioedema in history, associated with the appointment of ACE inhibitors, as well as hereditary or idiopathic angioedema;
- hypersensitivity to the components of the drug;
- hypersensitivity to other sulfonamide derivatives.
With caution should prescribe the drug for aortic stenosis, cerebrovascular diseases (including cerebral circulatory insufficiency), IHD, chronic heart failure, severe autoimmune systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma), oppression of bone marrow hematopoiesis , diabetes mellitus, hyperkalemia, bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney, condition after kidney transplantation, kidney and / or liver failure and, on the background with sodium diet restriction, for conditions involving reduction bcc (including diarrhea, vomiting), elderly patients.
PREGNANCY AND LACTATION
It is not recommended to use the drug Co-renitek during pregnancy. With established pregnancy, the drug should be discontinued immediately.
The appointment of ACE inhibitors in the II and III trimesters of pregnancy can cause the disease or death of the fetus or newborn. The negative effect of ACE inhibitors on the fetus and newborn is manifested by arterial hypotension, renal insufficiency, hyperkalemia and / or hypoplasia of the skull. Perhaps the development of oligohydramnion, apparently due to impaired renal function of the fetus. This complication can lead to limb contracture, deformation of the skull, including its facial part, to lung hypoplasia.
The use of diuretics in women during pregnancy is not recommended, since there is a risk of jaundice in the fetus and newborn, thrombocytopenia and, possibly, other side effects observed in adult patients.
If Co-renitek is prescribed during pregnancy, the patient should be warned about the potential risk to the fetus. In those rare cases where the prescription of the drug is considered necessary during pregnancy, periodic ultrasound examinations should be performed to assess the fetal condition, as well as the intra-amniotic space.
Newborns, whose mothers took Co-renitek, should be carefully monitored for the development of arterial hypotension, oliguria, and hyperkalemia. Enalapril, which penetrates the placental barrier, was removed from the bloodstream of the newborn by peritoneal dialysis with some favorable clinical effect, in theory it can be removed by exchange blood transfusion.
Enalapril and thiazides, incl. hydrochlorothiazide, excreted in breast milk. If you need to use the drug during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with impaired renal function, thiazides may not be effective enough, and with QC less than or equal to 30 ml / min (ie, with severe renal failure) are ineffective.
With KK 80-30 ml / min Korenitek should be used only after the preliminary selection of the doses of each of the components.
With moderate renal failure, the recommended dose of enalapril maleate taken separately is 5 mg to 10 mg.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should prescribe the drug for liver failure.
SPECIAL INSTRUCTIONS
During treatment with Co-renitek, as with any antihypertensive therapy, the development of symptomatic hypertension is possible. Patients should be examined for the purpose of identifying clinical signs of a disturbance of the water-electrolyte balance, i.e. dehydration of the body, hyponatremia, hypochloraemic alkalosis, hypomagnesemia or hypokalemia, which can occur as a result of episodes of diarrhea or vomiting. In such patients, during therapy, the electrolyte blood composition should be periodically determined at regular intervals.
With extreme caution, the drug should be given to patients with ischemic heart disease or cerebrovascular disease, an excessive decrease in blood pressure can lead to the development of myocardial infarction or stroke.
With the development of arterial hypotension, bed rest and, if necessary, intravenous injection of saline are indicated. Transient arterial hypotension in the appointment of Co-renitek is not a contraindication to its further use. After the normalization of blood pressure and bcc therapy can be resumed, either in slightly reduced doses, or each of the components of the drug can be used separately.
Corenitec should not be given to patients with renal insufficiency (CC <80 ml / min) until the selection of individual components of the drug shows that the necessary doses for this patient are present in this dosage form.
In some patients with no evidence of kidney disease prior to treatment with enalapril in combination with a diuretic, there was usually a slight and transient increase in urea levels in the blood and creatinine in the serum. In such cases, treatment with Co-renitek should be discontinued. In the future, it is possible to resume therapy in reduced doses or the administration of each component of the drug alone.
Like all drugs that have a vasodilating effect, ACE inhibitors should be administered with caution to patients who have difficulty in draining blood from the left ventricle of the heart.
In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney in the treatment with ACE inhibitors, there was an increase in urea in the blood and serum creatinine. These changes were reversible, as a rule, the indicators returned to normal after discontinuation of treatment.
Caution should be exercised with thiazide diuretics in patients with impaired hepatic function or with progressive liver disease, since even small changes in the water-electrolyte balance can lead to hepatic coma.
When performing large surgical operations or during general anesthesia using the means that cause arterial hypotension, enalaprilat blocks the formation of angiotensin II caused by compensatory release of renin. If the developed arterial hypotension, explained by a similar mechanism, develops, it can be corrected by an increase in BCC.
Thiazide diuretics may not be effective in patients with impaired renal function and are ineffective in CC? 30 ml / min (i.e., with moderate to severe renal failure).
Thiazide diuretics can cause impaired glucose tolerance. You may need to adjust the dosage of hypoglycemic drugs, including insulin.
Thiazide diuretics can reduce the excretion of calcium in the urine, and also cause a slight and transient increase in serum calcium. Expressed hypercalcemia may be a sign of latent hyperparathyroidism. Admission of thiazides should be discontinued before the study of the function of parathyroid glands.
The increase in cholesterol and TG levels may also be associated with thiazide diuretic therapy, however, with a dose of hydrochlorothiazide 12.5 mg contained in 1 Co-renitek tablet, similar effects were either not observed or were insignificant.
Thiazide therapy can lead to hyperuricemia and / or gout in some patients. However, enalapril may increase the urinary acid content in urine and thereby weaken the hyperuricemic effect of hydrochlorothiazide.
In the treatment of ACE inhibitors, including enalapril maleate, rare cases of angioedema of the face, extremities, lips, tongue, glottis and / or larynx have been described. These reactions can occur at any stage of therapy. In such cases, it is necessary to immediately stop taking enalapril maleate and establish careful monitoring of the patient's condition in order to control and correct clinical symptoms. Even in cases where there is only a swelling of the tongue edema without respiratory organs, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.
There are rare reports of deaths due to angioedema, accompanied by edema of the larynx or tongue edema. Swelling of the tongue, glottis or larynx may lead to airway obstruction, especially in patients who have undergone surgical intervention on the organs of respiration.
In those cases where localized swelling in the tongue, glottis or larynx, which can lead to airway obstruction, should immediately enter n / a 0.3-0.5 ml of 0.1% solution of epinephrine (adrenaline) and quickly ensure airway patency.
Patients blacks who took ACE inhibitors, angioneurotic edema was observed more frequently than in other patients.
When specifying a history of angioneurotic edema, not associated with ACE inhibitors increases significantly the risk of angioedema during treatment with ACE inhibitors.
Patients receiving thiazides, allergic reactions may occur regardless of whether a history of allergic conditions or asthma. Reported recurrence or worsening of the severity of SLE patients receiving thiazides.
In rare cases, patients receiving ACE inhibitors have developed life-threatening anaphylactoid reactions during desensitization of allergen Hymenoptera venom. Such reactions can be avoided if before the start of desensitization to temporarily stop taking the ACE inhibitor.
Appointment of Co-Renitec is contraindicated in patients with renal failure who are on hemodialysis. Anaphylactoid reactions were observed in patients undergoing dialysis, using the high throughput membranes (such as AN69) and simultaneously receiving treatment with ACE inhibitors. These patients need to use a different type of dialysis membrane or antihypertensives of other classes.
On background therapy of ACE cough cases are marked. Typically, the cough is dry, has a permanent character and disappears after the end of therapy. Cough associated with ACE inhibitors, should be considered in the differential diagnosis of cough.
Results from clinical studies the efficacy and tolerability of enalapril maleate and hydrochlorothiazide with concomitant administration was similar in elderly and younger patients.
Use in Pediatrics
Safety and efficacy of Co-Renitec in children have not been established, therefore use in pediatric patients is not recommended.
OVERDOSE
Symptoms: marked hypotension, starting after about 6 hours after ingestion, and stupor. Upon receiving Enalapril maleate at doses of 330 mg and 440 mg enalaprilat plasma concentrations exceeded respectively 100 and 200 times its concentration at therapeutic doses.
With an overdose of hydrochlorothiazide is most commonly observed symptoms caused by hypokalemia, chloropenia, hyponatremia and dehydration due to excessive diuresis. If therapy with digitalis previously held, possibly worsening the flow of arrhythmia due to hypokalemia.
Treatment:Co-renitek should be abolished; It requires careful medical supervision. It recommended gastric lavage if the drug was recently adopted; carrying out of symptomatic and supportive therapy for the correction of violations of water-electrolyte balance and hypotension. Information on the specific treatment of overdose is available.
In overdose enalapril maleate recommended / in infusion saline, effectively administering angiotensin II. Enalaprilat can be removed from the systemic circulation via hemodialysis.
DRUG INTERACTION
In the appointment of enalapril in combination with other antihypertensive drugs can summation effect.
Potassium loss, which cause thiazide diuretics number usually decreases under the influence of enalaprilat. Serum potassium concentration usually remains within normal limits.
The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt, especially in patients with renal failure may lead to a significant increase in serum potassium.
Diuretics and ACE inhibitors reduce the excretion of lithium by the kidneys and increase the risk of lithium toxicity. Lithium formulations are generally not administered simultaneously with diuretic or ACE inhibitors.
NSAIDs, including selective inhibitors of COX-2 may reduce the effectiveness of diuretics or other antihypertensives. Therefore possible to reduce the hypotensive effect of ACE inhibitors with concomitant administration of NSAIDs, including selective COX-2 inhibitors.
Patients with impaired renal function receiving NSAIDs, including selective inhibitors of COX-2, with concomitant ACE inhibitors may further deterioration of renal function. These changes are usually reversible.
Thiazide diuretics may increase the effect of tubocurarine.
The hypotensive effect of the drug is reduced NSAID, estrogen, ethanol.
Immunosuppressants, allopurinol, cytostatics increases the risk of gematotoksichnosti.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life for tablets in blister packs - 3 years for tablets in high density vials - 2 years.
