Universal reference book for medicines

Product name:
ZONIXEM NL (ZONIXEM NL)

Active substance: hydrochlorothiazide, lisinopril

Type: Antihypertensive drug

Manufacturer: KRKA-FARMA (Croatia)
Composition, form of production and packaging
Tablets
1 tab.

lisinopril 10 mg

hydrochlorothiazide 12.5 mg

10 pieces.
- blisters (2) - packs of cardboard.
10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (6) - packs of cardboard.
14 pcs.
- blisters (1) - packs of cardboard.
14 pcs.
- blisters (2) - packs of cardboard.
14 pcs.
- blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Zonixem NL is a combination of fixed doses of lisinopril (ACE inhibitor) and hydrochlorothiazide (thiazide diuretic), which have a complementary effect and complement each other's antihypertensive effect.

Lisinopril

The ACE inhibitor reduces the formation of angiotensin II from angiotensin I. Reducing angiotensin II leads to a direct decrease in the release of aldosterone.
Reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces the overall peripheral vascular resistance (OPSS), arterial pressure (BP), preload on the myocardium, pressure in the pulmonary capillaries, causes an increase in the minute volume of blood and increased tolerance to loads in patients with chronic heart failure (CHF) . Expands arteries more than veins. Some effects are explained by the effect on the renin-angiotensin-aldosterone system (RAAS). With prolonged use, the severity of myocardial hypertrophy and the walls of arteries of resistive type decreases. Improves the blood supply of the ischemic myocardium.
ACE inhibitors increase life expectancy in patients with CHF, slow the progression of left ventricular dysfunction in patients who underwent myocardial infarction without clinical manifestations of heart failure.
The antihypertensive effect begins in about 6 hours and persists for 24 hours. The duration of the effect also depends on the amount of the dose. The onset of action is after 1 hour. The maximum effect is 6-7 hours. With arterial hypertension, the effect is observed in the first days after the beginning of treatment, stable effect develops in 1-2 months.
With a sharp withdrawal of lisinopril, there is no pronounced increase in blood pressure.
In addition to reducing blood pressure, lisinopril reduces albuminuria. In patients with hyperglycemia contributes to the normalization of the function of the damaged glomerular endothelium.
Hydrochlorothiazide

A thiazide diuretic whose diuretic effect is associated with a disruption of the reabsorption of sodium, chlorine, potassium, magnesium, water in the distal nephron;delays the excretion of calcium ions, uric acid.
Has antihypertensive properties; the antihypertensive effect develops due to the expansion of argeriol. Virtually no effect on normal blood pressure.
The diuretic effect develops in 1-2 hours, reaches a maximum after 4 hours and persists for 6-12 hours. Antihypertensive effect occurs in 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect.

Lizinopril and hydrochlorothiazil, with simultaneous use, have an additive antihypertensive effect.

PHARMACOKINETICS

Simultaneous use of lisinopril and hydrochlorothiazide does not affect the bioavailability and pharmacokinetic of each of the active components of the drug.

Lisinopril

After taking lisinopril, C max in the blood serum is reached after 7 hours. It weakly binds to blood plasma proteins.
The average degree of absorption of lisinopril is about 25%, with a significant interindividual variability (6-60%). Food does not affect the absorption of lisinopril. Lizinopril is not metabolized and is excreted unchanged only by the kidneys. After repeated use of T 1/2, lisinopril is 12 hours. Impaired renal function slows the excretion of lisinopril, but this slowing becomes clinically significant only when the glomerular filtration rate decreases below 30 mL / min. In elderly patients there is an average of 2 times the Cis level of lisinopril in blood plasma and AUC (area under the concentration-time curve), compared with younger patients. Lizinopril is excreted from the body by hemodialysis. It penetrates to a small extent through the blood-brain barrier.
Hydrochlorothiazil

It is not metabolized, but is rapidly eliminated through the kidneys.
T 1/2 hydrochlorothiazide ranges from 5.6 to 14.8 hours. At least 61% of the ingested hydrochlorothiazide is excreted unchanged for 24 hours. Hydrochlorothiazil penetrates the placental barrier, but does not penetrate the blood-brain barrier.
INDICATIONS

- Arterial hypertension (in patients who are shown combined therapy)

DOSING MODE

Inside, 1 tablet Zoniksem NL once a day.

If necessary, the daily dose can be increased to 2 tablets (Zoniksem NL 20 or Zonixem ND may be used in other dosages).
Symptomatic arterial hypotension can occur after taking the initial dose of the drug. Such cases are more common in patients with reduced circulating blood volume (BCC) and reduced electrolyte content due to previous treatment with diuretics. Therefore, you should stop taking diuretics 2-3 days before the start of treatment with Zonix NL.
Renal impairment

The drug Zoniksem NL is contraindicated in the presence of severe renal dysfunction (QC 30 ml / min or less).

With QC 30-80 ml / min, the use of Zoniksem NL is possible only after selecting the dose of each of the active components of the drug separately.

Elderly patients : dose adjustment is not required.

SIDE EFFECT

Classification of the incidence of adverse events (WHO): very often> 1/10, often> 1/100 to <1/10, infrequently from> 1/1000 to <1/100, rarely> 1/10000 to <1 / 1000, very rarely from <1/10000, including individual messages.

In each group, undesirable effects are presented in order of decreasing severity.

On the part of the digestive system: rarely - dryness of the oral mucosa, nausea, vomiting, diarrhea, constipation, pancreatitis;
very rarely - intestinal edema of the intestine, abdominal pain, anorexia, gastritis, hepatitis, hepatic insufficiency, cholestatic jaundice.
From the side of the cardiovascular system: often - a marked decrease in blood pressure (including orthostatic hypotension), chest pain;
rarely - tachycardia, bradycardia, aggravation of symptoms of the course of chronic heart failure, violation of atrioventricular (AV) conduction, myocardial infarction or impaired cerebral circulation due to excessive arterial hypotension.
From the nervous system: often - dizziness, headache;
infrequent - lability of mood, impaired concentration, increased fatigue, drowsiness, sleep disturbance.convulsive twitching of the muscles of the limbs and lips; rarely - paresthesia, asthenic syndrome, confusion, depression.
From the respiratory system: often - dry cough;
rarely - bronchospasm. rhinitis, sinusitis, dyspnea, apnea, allergic alveolitis / eosinophilic pneumonia.
From the genitourinary system: rarely - decreased potency;
very rarely uremia, oliguria / anuria, glucosuria, renal dysfunction, acute renal failure, interstitial nephritis.
From the skin: rarely skin rash, photosensitivity, alopecia, itching, urticaria;
very rarely - increased sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, vasculitis, psoriasis.
From the immune system: very rarely - angioedema, swelling of the face, lips, tongue, throat and / or larynx, limbs, hypersensitivity reactions.

From the musculoskeletal system: rarely - muscle weakness, arthralgia / arthritis.

From the senses: very rarely - a transient disturbance of visual acuity, photophobia, xanthopsia.

From the hematopoietic organs: neutropenia / agranulocytosis, leukopenia, thrombocytopenia, oppression of bone marrow hematopoiesis.

Other: rarely - general weakness, asthenia, Raynaud's syndrome, gynecomastia, exacerbation of gout, impaired kidney fetal hypoglycemia;
very rarely - sialadenitis.
Laboratory indicators: rarely - hyperglycemia, hyperuricemia and gyerkalemia or hypokalemia, increased urea and creatinine concentrations decrease of hematocrit and hemoglobin, increased activity of hepatic enzymes and / or bilirubin, hypercholesterolemia, gynergriglyceridemia;
very rarely - hyponatremia, hypomagnesemia, hypochloraemia, hyiercalcemia, hemolytic anemia, aplastic anemia.
There are reports of a symptom complex, which may include fever, vasculitis, myalgia, arthralgia / arthritis, positive antinuclear antibodies, increased ESR, eosinophilia, leukocytosis.

CONTRAINDICATIONS

anuria;

- angioedema (including anamnesis from the use of ACE inhibitors);

- hemodialysis using high-flow membranes;

- hypercalcemia;

- porphyria;

- Prekoma;

- hepatic coma;

- expressed CRF (creatinine clearance (CK) less than 30 ml / min);

- exacerbation of gout;

- diabetes mellitus (severe forms);

- pregnancy, the period of breastfeeding;

- hereditary angioedema and idiopathic angioedema;

- age under 18 years (effectiveness and safety not established);

- Hypersensitivity to active substances or any other components of the drug (including other ACE inhibitors and derivatives of sulfonamides).

With caution: aortic and / or mitral stenosis, hypertrophic obstructive cardiomyopathy, bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney with progressive azotemia, condition after kidney transplantation, moderate chronic renal failure (QC more than 30 ml / min), primary hyperaldosteronism , arterial hypotension, bone marrow hypoplasia, hyponatremia (increased risk of arterial hypotension in patients on a low-salt or salt-free diet), conditions,
(including diarrhea, vomiting), connective tissue diseases (SLE, scleroderma), diabetes mellitus, gout, hyperuricemia, hyperkalemia, hepatic insufficiency, cerebrovascular insufficiency, severe chronic heart failure, advanced age, hemodialysis.
PREGNANCY AND LACTATION

Pregnancy

The use of Zoniksem NL during pregnancy is contraindicated.
ACE inhibitors in the II and III trimesters of pregnancy have an adverse effect on the fetus (marked decrease in blood pressure, renal failure, hyperkalemia, hypoplasia of the skull bones, fetal death). For newborns and infants who have undergone intrauterine exposure to ACE inhibitors, it is recommended to monitor for the timely detection of a marked decrease in blood pressure, oliguria, and hyperkalemia. The use of hydrochlorothiazide is contraindicated in the first trimester of pregnancy. In the case of planning or diagnosing a pregnancy, Zoniksem NL should be stopped immediately.
Breast-feeding

If you need Zoniksem NL during lactation, breastfeeding should be discontinued.

APPLICATION FOR FUNCTIONS OF THE LIVER

The drug Zoniksem NL is contraindicated in the presence of severe renal dysfunction (QC 30 ml / min or less).

With QC 30-80 ml / min, the use of Zoniksem NL is possible only after selecting the dose of each of the active components of the drug separately.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Thiazide diuretics should be used with caution in patients with impaired liver function or with progressive liver damage, since in such patients even minimal changes in electrolyte balance can trigger the development of hepatic coma.
The use of ACE inhibitors in patients with liver disease can lead to the development of fulminant liver necrosis.
APPLICATION FOR CHILDREN

Contraindicated in children under 18 years.

APPLICATION IN ELDERLY PATIENTS

Elderly patients : dose adjustment is not required.

SPECIAL INSTRUCTIONS

Symptomatic arterial hypotension

Most often, a marked decrease in blood pressure occurs with a decrease in bcc caused by diuretic therapy, a decrease in the amount of salt in the diet, dialysis, diarrhea, or vomiting.

With cirrhosis of the liver accompanied by edema and ascites, arterial hypotension, CHF, there may be a significant activation of RAAS, especially with pronounced hypovolemia and a decrease in the electrolyte content in the blood plasma (against a background of a salt-free diet or a long-term intake of diuretics).

The use of an ACE inhibitor causes blockade of the RAAS, in this connection, a sharp decrease in blood pressure and / or an increase in the plasma creatinine concentration, indicating the development of acute renal failure, is possible, which is more often possible with the initial application of Zoniksem NL or during the first two weeks of therapy.

Thus, in patients with a decrease in the volume of fluid on the background of diuretic therapy, diathesis, diarrhea, vomiting treatment should be started under the strict supervision of a doctor, with care to conduct a dose of the drug.

Renal impairment

Thiazide diuretics should not be used in patients with impaired renal function;
they are ineffective with QC 30 ml / min or less (ie, with moderate or severe renal impairment).
The drug Zoniksem NL can not be used in patients with renal insufficiency (CC less than 80 ml / min) until the doses of each of the components individually corresponding to the doses in the combined preparation are selected.

If patients with arterial hypertension without obvious signs of existing kidney diseases have an increase in the concentration of urea and creatinine in the blood serum on the background of Zoniksem HL, further use should be stopped.
Renewal of therapy is possible either by lower doses or by monotherapy of the active components of the drug.
In patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney that took PSA inhibitors, an increase in serum urea and serum creatinine levels, usually reversible after the withdrawal of therapy, is possible.

Dysfunction of the liver

Thiazide diuretics must be used with caution in patients with impaired liver function or with progressive liver damage, since in such patients even minimal changes in electrolyte balance can trigger the development of the hepatic coma.
The use of ACE inhibitors in patients with liver disease can lead to the development of fulminant liver necrosis.
Patients with diabetes mellitus and other endocrine pathologies

When using Zoniksem NL, patients with diabetes mellitus who receive hypoglycemic agents for ingestion or insulin during the first month of therapy should regularly monitor the concentration of glucose in the blood.
Thiazide diuretics can reduce the excretion of calcium by the kidneys and cause a temporary moderate increase in serum calcium. Expressed hypercalcemia may be a manifestation of undiagnosed hyperparathyroidism. Before the study of the function of parathyroid glands, thiazide diuretics should be discontinued.
Against the background of therapy with thiazide diuretics, the concentration of cholesterol and triglycerides can increase.

In some patients, therapy with thiazide diuretics can exacerbate hyperuricemia and / or aggravate the course of gout.
However, lisinopril enhances the excretion of uric acid by the kidneys, thereby counteracting the hyperuricemic effect of hydrochlorothiazide.
During the treatment period, regular monitoring of the calcium, potassium, glucose,

urea, lipids and creatinine in blood plasma.

Hypersensitivity / angioedema (angioedema)

With the use of ACE inhibitors, including lisinopril, in rare cases development of angioedema, lip, tongue, pharynx and / or larynx can be observed.
If these symptoms appear, the drug should be discontinued immediately, the patient should be observed until the signs of edema disappear completely.
If angioedema affects only the face and lips, then its manifestations usually go away alone or antihistamines may be used to treat its symptoms.
Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death.
If such symptoms appear, epinephrine (adrenaline) should be injected immediately (at a dilution of 1: 1000 (0.3 or 0.5 ml) and / or provide airway patency.

Patients with a history of Quincke edema not associated with the administration of ACE inhibitors may be at increased risk of developing with the use of drugs of this group.

In rare cases, against the background of therapy with ACE inhibitors, angioedema develops in the intestine.
In this case, patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without a previous angioedema and at a normal level of C-1-esterase. The diagnosis is established by means of computed tomography of the abdominal cavity, ultrasound examination or at the time of surgical intervention. Symptoms disappear after the cessation of the use of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the differential diagnosis should take into account the possibility of developing angioedema of the intestine.
Anaphylactoid reactions during desensitization procedures

There are separate reports on the development of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with the poison of Hymenoptera insects (bees, wasps).
ACE inhibitors should be used with caution in patients prone to reactions atlergicheskim undergoing desensitization procedure. Should be avoided ishibitora ACE patients receiving immunotherapy with Hymenoptera venom. Nevertheless, development of anaphylactoid reactions can be avoided by temporary discontinuation of ACE inhibitor at least 24 hours prior to the desensitization treatment.
Anaphylactoid reactions during apheresis lipoproteilov low density (LDL)
In rare cases, patients treated with ACE inhibitors, life-threatening anaphylactoid reactions may develop during LDL apheresis using a dextran sulfate. To prevent anaphylactoid reactions should discontinue therapy with an ACE inhibitor before every LDL apheresis procedure using vysokoirotochnyh membranes.
Hemodialysis
Patients receiving ACE inhibitors during hemodialysis using vysokoprotochnyh membranes (e.g., AN69 ® ) anafilaktodnye reactions were noted. It is therefore desirable to use a different type of membrane or apply other antihypertensive drug pharmacotherapeutic group.
Cough

Against the background of therapy with ACE inhibitors may cause coughing. By its nature, it is persistent, unproductive, which takes place after discontinuation of the drug. Cough caused by ACE inhibitors, should be considered in the differential diagnosis of cough.
Surgery / General anesthesia
Use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a marked decrease in blood pressure, particularly when using tools for general anesthesia providers antigiiergenzivnoe action.
It is recommended to discontinue the use of ACE inhibitors, including lisinopril, 12 hours before surgery, warning the surgeon / anesthetist on the use of ACE inhibitors.
Hyperkalemia

Perhaps the development of hyperkalemia. Risk factors for the development of hyperkalemia: renal failure, diabetes, use of potassium preparations or drugs that cause an increase in blood potassium concentration (including heparin), particularly in patients with impaired renal function.
In patients at risk for symptomatic hypotension lost fluids and salts before treatment must be compensated.
Elderly patients

Before the start of the drug Zoniksem NL should assess renal function and potassium content in the blood plasma. The initial dose is adjusted depending on stepenisnizheniya blood pressure, particularly when reducing the bcc and CHF (IV NYHA functional class classification). Such measures make it possible to avoid a sharp decrease in blood pressure.
Impact on the ability to drive vehicles and manage mechanisms

During drug treatment Zoniksem NL recommended to be careful when driving and classes of potentially hazardous activities that require high concentration and speed of psychomotor reactions, because In applying the drug may cause dizziness, especially early in the course of treatment.
OVERDOSE

In case of overdose combination lisinopril / hydrochlorothiazide, the following symptoms: marked decrease in blood pressure, collapse, tachycardia, palpitations dihanie, sensation sertsebienie, bradycardia, cough, dizziness, dryness of the oral mucosa, urinary retention, constipation, anxiety, disturbance of water-electrolyte balance, renal insufficiency.
Treatment:Gastric lavage and / or administration of activated charcoal, the recovery of water-electrolyte balance in a hospital environment. In marked decrease in blood pressure is necessary to transfer the patient to the "lying down" on the back with raised upside down; followed conduct activities aimed at increasing the bcc (addition of 0.9% sodium chloride solution i.v.). If necessary, the possible use of angiotensin II, bradycardia - atropine or formulation pacemaker. Necessary to monitor urine output, the concentration of urea, creatinine and electrolytes in the blood serum. Hemodialysis is effective.
DRUG INTERACTION

With simultaneous use of lisinopril and hydrochlorothiazide with the potassium-sparing diuretics (spironolactone. Triamterene, amiloride), potassium preparations kashysoderzhaschimi salt substitutes increases the risk of giierkaliemii, especially in patients with chronic renal insufficiency.
Hypoglycemic agents for oral use (sulfonylurea derivatives) and insulin: ACE inhibitors may enhance the hypoglycemic effect of hypoglycemic agents for oral and insulin in diabetic patients; at their simultaneous application may increase glucose tolerance which may require correction doses hypoglycemic agents for oral and insulin.
The simultaneous use of vasodilators, barbiturates, phenothiazines, tricyclic antidepressants increase the hypotensive effect.
Nonsteroidal anti-inflammatory drugs (indomethacin, etc.), Estrogens reduce antigipertenzivnos action of lisinopril.
The simultaneous use of lisinopril and hydrochlorothiazide with lithium therapy leads to slower elimination and increased lithium cardiotoxic and neurotoxic effects of lithium.
Antipsychotic agents (neuroleptics) may enhance the antihypertensive effect of lisinopril.
Concomitant use with antacids, colestyramine or colestipol resulting in decreased absorption of lisinopril and hydrochlorothiazide in the gastrointestinal tract.
Gold preparations: The use of ACE inhibitors, including lisinopril in patients receiving drugs gold (sodium aurothiomalate) / w, were marked nitratopodobnye reaction (nausea, vomiting, a marked reduction of blood pressure, skin hyperemia).
Allopurinol, cytostatics, immunosuppressants. glucocorticosteroids (for systemic use), and procainamide: the simultaneous use of these drugs with ACE inhibitors may increase the risk of leukopenia.
The simultaneous use of corticosteroids, adrenocorticotropin, carbenoxolone, amphotericin B may amplify the imbalance of electrolytes, especially potassium.
Concomitant use of lovastatin increases the risk of hyperkalemia.
Cyclosporin increases the risk of renal dysfunction and the development of hyperkalemia.
In an application with sotalol increased risk of arrhythmia.
Due to the risk of hypokalemia should be careful, while the use of hydrochlorothiazide and preparations causing tachycardia type "pirouette", eg some antipsychotics and other means.
General anesthetics: APF inhibitors may enhance the hypotensive effect of certain funds for general anesthesia.
Sympathomimetics may reduce antihypertensive effect of lisinopril.
Diuretics (thiazide and "loop"): the use of diuretics in high doses can lead to hypovolemia (due to reduction of blood volume), and adding to therapy lisinopril - a pronounced decrease in BP.
A combination of lisinopril and hydrochlorothiazide reduces the effect of hypoglycemic agents for oral administration, norepinephrine, epinephrine and protivopodagricakih means enhances the effects (including spin), cardiac glycosides, peripheral muscle relaxant effect, reduces the excretion of quinidine.
Lisinopril and gidrohlorotiazil reduces the effect of oral contraceptives.
Ethanol enhances the hypotensive effect of lisinopril and hydrochlorothiazide.
In an application with methyldopa increased risk of hemolysis.
TERMS OF RELEASE FROM PHARMACY

On prescription.

TERMS AND CONDITIONS OF STORAGE

At temperatures above 25 ° C, in the original package.
Keep out of the reach of children. Shelf life - 3 years.
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