2010/09/17

Accuzide




Composition, structure and packing

Coated tablets pink, oval, biconvex, with risks on both sides and marked "PD 222" on one side.

1 tab. hinapril (in the form of hydrochloride) 10 mg 12.5 mg Hydrochlorothiazide.

Excipients: magnesium carbonate, lactose monohydrate, povidone K25, krospovidon, magnesium stearate. The composition of the shell membrane: Opadry Pink OY-S-6937 (includes hydroxypropylmethylcellulose, titanium dioxide (E171), gidroksipropiltsellyulozu, polyethylene glycol 400 and iron oxide (E172)), wax candle.

Coated tablets pink, triangular, biconvex, scored and marked with "PD 220" on one side.

1 tab. hinapril (in the form of hydrochloride) 20 mg hydrochlorothiazide 12.5 mg.

Excipients: magnesium carbonate, lactose monohydrate, povidone K25, krospovidon, magnesium stearate. The composition of the shell membrane: Opadry Pink OY-S-6937 (includes hydroxypropylmethylcellulose, titanium dioxide (E171), gidroksipropiltsellyulozu, polyethylene glycol 400 and iron oxide (E172)), wax candle.

Coated tablets pink, round, biconvex, labeled "PD 223" on one side.

1 tab. hinapril (in the form of hydrochloride) 20 mg hydrochlorothiazide 25 mg.

Excipients: magnesium carbonate, lactose monohydrate, povidone K25, krospovidon, magnesium stearate. The composition of the shell membrane: Opadry Pink OY-S-6937 (includes hydroxypropylmethylcellulose, titanium dioxide (E171), gidroksipropiltsellyulozu, polyethylene glycol 400 and iron oxide (E172)), wax candle.

Clinico-pharmacological group: antihypertensive drugs.

Pharmacological action

Combined antihypertensive medication, consisting of an ACE inhibitor hinapril and thiazide diuretic hydrochlorothiazide in three different ratios. Hinapril - ACE inhibitor. ACE catalyzes the formation of angiotensin II, which has a vasoconstrictor effect and controls vascular tone, including due to the stimulation of secretion of aldosterone, the adrenal cortex. Hinapril inhibit circulating and tissue ACE and causes a decrease in pressor activity and the secretion of aldosterone. Removal of the negative effects of angiotensin II on renin secretion by the mechanism of feedback leads to an increase in renin activity of blood plasma. This lowering of BP accompanied by a decrease TPVR and resistance of renal vessels, whereas changes in heart rate, cardiac output, renal blood flow, glomerular filtration rate and filtration fraction were negligible or absent. In addition, hinapril somewhat reduces the potassium loss caused by hydrochlorothiazide, which through its diuretic action also increases the renin activity of blood plasma, aldosterone secretion, decreases serum potassium levels and increases its excretion in the urine.

Hydrochlorothiazide - diuretic, has a direct effect on the kidneys, increasing the excretion of sodium, chloride, water, and potassium and bicarbonate ions, and reducing the excretion of calcium ions. Although the mechanism of antihypertensive action of diuretics is not fully understood, with their long-term use have declined TPVR, probably associated with changes in the exchange of sodium ions. Thus, the use of a combination of hydrochlorothiazide and hinaprila leads to greater BP decrease than treatment with each preparation separately.

Antihypertensive effects hinaprila develops within 1 h after oral administration and reaches a maximum after 2-4 h. In the application of recommended doses of antihypertensive effect lasts for 24 hours and stored in long-term treatment. In some cases, to achieve the maximum effect of antihypertensive therapy requires at least 2 weeks.

Hydrochlorothiazide diuretic effect begins within 2 h, reaches a maximum after about 4 hours and lasts for about 6-12 hours

Pharmacokinetics

Hinapril and hydrochlorothiazide have no effect on the pharmacokinetics of each other.

Hinapril

Absorption and distribution

Once inside hinaprila Cmax achieved within 1 h. Hinapril rapidly metabolized to hinaprilata, which is a potent inhibitor of ACE. The degree of suction hinaprila approximately 60%. Hinaprilata Cmax plasma levels achieved approximately 2 hours after ingestion hinaprila. About 38% of the applied dose hinaprila circulates in the form of hinaprilata. Approximately 97% hinaprila hinaprilata and circulate in the blood plasma in protein-bound form. Hinapril and its metabolites do not penetrate the BBB.

Metabolism and excretion

Hinapril metabolized to hinaprilata by removal of air group (the main metabolite - diacid hinaprila).

T1 / 2 hinaprila from blood plasma is about 1 hour Hinaprilat derived mainly by renal excretion, and its T1 / 2 is about 3 hours

Pharmacokinetics in special clinical situations

In patients with renal insufficiency T1 / 2 hinaprilata increases with decreasing spacecraft. Putting hinaprilata also decreases in older people (over 65) and correlates closely with indicators of kidney function, but in general differences in the effectiveness and safety in patients older and younger age were not revealed.

Hydrochlorothiazide

Absorption and distribution

Hydrochlorothiazide is absorbed more slowly, Cmax is achieved through 1-2.5 hours

The degree of absorption of 50-80%. Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk, but does not cross the BBB. Metabolism and excretion of hydrochlorothiazide is not metabolized in the liver and excreted in the urine in unchanged form. T1 / 2 from 4 to 15 h. About 61% of the accepted oral dose excreted unchanged in within 24 hours

Statement
arterial hypertension (in patients who have shown combination therapy hinaprilom and diuretic).

Dosage regimen

For patients not receiving diuretics (whether as monotherapy hinaprilom or not), the recommended starting dose is 10 mg Akkuzida + 12.5 mg 1 time / day. In the future, if necessary, the dose may be increased to 20 mg + 12.5 mg or up to the maximum recommended daily dose of 20 mg + 25 mg. The preparation usually provides effective control of blood pressure at doses of 10 mg + 12.5 mg to 20 mg + 12.5 mg.

The range of doses Akkuzida allows an adequate selection of doses of its individual components. For example, patients receiving diuretic, the recommended starting dose is 5 mg hinaprila (to minimize the risk of excessive BP reduction). In the future, gradually increase the dose to achieve the required antihypertensive effect. If the choice were installed doses similar doses of the components of the combined drug, you can assign Akkuzid.

In patients with renal insufficiency moderately (CC 30-60 ml / min), treatment begins with a reception hinaprila a dose of 5 mg, if necessary, enlarging it. Patients who have shown combination therapy with a diuretic, you can assign Akkuzid in the initial dose of 10 mg + 12.5 mg. For maintenance therapy can be taken Akkuzid in standard doses.

Side effect

Adverse effects did not differ from those applying hinaprila and hydrochlorothiazide separately. The most frequent side effects (> 1%) when taking any combination of hinaprila and hydrochlorothiazide were headache (6.7%), dizziness (4.8%), cough (3.2%), which was usually nonproductive, persistent, and took place after cessation of therapy, fatigue (2.9%). In general, side effects were poorly marked and transient, not dependent on age, sex, race and duration of therapy.

Adverse events are encountered in 0.5-1.0% of patients receiving hinapril in combination with hydrochlorothiazide, are given below.
The part of the hemopoietic system: hemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis.
On the part of the immune system: anaphylactic reaction.
From the central nervous system and peripheral nervous system: irritability, asthenia, paresthesia.
Since the cardiovascular system: palpitations, tachycardia, marked hypotension, postural hypotension, syncope, rarely, cardiac arrhythmias -, myocardial infarction, ischemic stroke.
On the part of the respiratory system: dyspnoea, sinusitis.
On the part of the digestive system: dry mouth or throat, nausea, constipation or diarrhea, flatulence, pancreatitis, hepatitis.

Allergic reactions: skin rash, itching, angioedema (at about 0.1% of patients receiving hinapril); rarely - photosensitivity, erythema multiforme exudative, exfoliative dermatitis, pemphigus, Stevens-Johnson syndrome (associated with the presence of hydrochlorothiazide).
From the urinary system: urinary tract infections, renal failure.
From the laboratory parameters: an increase (more than 1.25 times compared to FHG), serum creatinine and blood urea nitrogen, respectively, in 3% and 4% of patients receiving hinapril and hydrochlorothiazide.
On the part of the organ of vision: visual impairment.
On the part of the reproductive system: reduction of potency.

Other: peripheral edema, arthralgia, alopecia.

Contraindications
angioedema in history as a result of previous therapy with ACE inhibitors;
childhood and adolescence to 18 years (efficacy and safety of the drug not established);
anuria;
Hypersensitivity to the drug's components;
sensitivity to sulfanilamide derivatives.

Precautions should be prescribed the drug in the presence of a history of angioedema unrelated to ACE inhibitors, symptomatic hypotension in patients previously taking diuretics and diet with restricted salt intake or who are on hemodialysis with severe heart failure patients with or without accompanying renal failure, with conditions involving reduced BCC (including vomiting and diarrhea), with hyperkalemia, depression of bone marrow hematopoiesis, aortic stenosis, cerebrovascular disease (a sharp decline in blood pressure during therapy with ACE inhibitors may worsen during these diseases), and severe renal failure (CC less than 30 ml / min), conditions after kidney transplantation, bilateral renal artery stenosis or stenosis of the artery of a sole kidney, severe systemic autoimmune connective tissue disease (including SLE), disturbance of function or progressive liver disease, diabetes , extensive surgery and general anesthesia, while receiving other antihypertensive agents, in violation of electrolyte balance.

Pregnancy and lactation

You should not use the drug Akkuzid pregnancy. ACE inhibitors can cause the development of disease and death of the fetus and newborn. In the application of ACE inhibitors in phase II and III trimester of pregnancy was observed cases of hypotension, renal insufficiency, hypoplasia of cranial bones in infants and / or death. Also described cases of oligohydramnios, which probably reflects a decline in renal function in the fetus, and this condition was combined with contractures of the limbs, facial deformity of the skull, hypoplasia of the lungs and intrauterine growth retardation. When using ACE inhibitors only in the I trimester of pregnancy, such adverse effects did not develop, however, women who received drugs in this group in the I trimester should be informed about these adverse reactions. If pregnancy occurs during treatment Akkuzidom, the drug should be as soon as possible to cancel. If necessary, therapy with ACE inhibitors in phase II and III trimester of pregnancy should be assessed against potential damage to the fetus, the purpose of diagnosing oligohydramnios (which can be detected only after irreversible damage to the fetus) should have regular ultrasonography. If there is a state, the drug should be abolished except in cases where its application is vital for the mother.

Other possible undesirable effects of ACE inhibitors on the fetus and newborn are intrauterine growth, prematurity and nezaraschenie ductus arteriosus; described the deaths of the fetus. It remains unclear whether these adverse events with the use of ACE inhibitors or maternal disease.

It is also unknown whether providing an undesirable effect on the fetus therapy, which was carried out only in the I trimester of pregnancy.

Infants who were exposed to ACE inhibitors in utero should be observed in order to identify arterial hypotension, oliguria and hyperkalemia. When oliguria should maintain blood pressure and perfusion of the kidneys.

Thiazides cross the placenta and are found in umbilical cord blood. Nonteratogenic effects of these drugs include jaundice and thrombocytopenia in the fetus or the newborn, also allows the possibility of other manifestations of adverse reactions observed in adults.

ACE inhibitors, including hinapril, to a limited extent allocated to breast milk. Thiazide diuretics are excreted in breast milk. Because of the possibility of serious adverse reactions in infants, should not be used Akkuzid during lactation, and if necessary, its use should stop breastfeeding.

Application for violations of liver function

Be wary if the violation function or progressive liver disease application for violations of renal function with caution in severe renal insufficiency (CC less than 30 ml / min).

Cautions

In the treatment with ACE inhibitors are described cases of angioedema of the head and neck, including at 0.1% of patients receiving hinapril. When the whistle or laryngeal angioedema face, tongue, or glottis Akkuzid should be lifted immediately. The patient must assign adequate treatment and watch it until the disappearance of edema. Edema of face and lips usually passes without treatment. To reduce the symptoms can be used antihistamines. Angioedema with lesions of the larynx can lead to death. If swelling of the tongue, glottis or larynx threatens the development of airway obstruction, requires an adequate emergency treatment, which includes the s / c the introduction of the solution of epinephrine (adrenaline) 1:1000 (0.3-0.5 ml). In the treatment with ACE inhibitors are also described cases of angioedema of the intestine.

The patients noted abdominal pain (with or without nausea and vomiting) in some cases without prior angioedema of face and a normal level of C-1 esterase. The diagnosis is established by computed tomography abdomen, ultrasound, or at the time of surgical intervention. The symptoms disappeared after discontinuation of ACE inhibitors. Therefore, patients with pain in the abdomen, taking ACE inhibitors during the differential diagnosis must take into account the possibility of angioedema of the intestine.

Patients who have experienced angioedema unrelated to ACE inhibitor, the risk of its development can be promoted in the treatment of drugs of this group. Patients receiving ACE inhibitors during desensitizing treatment of Hymenoptera venom may develop persistent anaphylactoid reactions, life-threatening. If you suspend the reception of ACE inhibitors of these reactions were avoided, but they arose again at random receiving these drugs. Anaphylactoid reactions may also develop in the appointment of ACE inhibitors patients who underwent LDL apheresis absorption of dextran sulfate, or patients undergoing hemodialysis with vysokoprotochnyh membranes such as polyacrylonitrile. Therefore, such a combination should be avoided, either by using other antihypertensive drugs or alternative membranes for dialysis.

Akkuzid may cause symptomatic hypotension, but no more frequently than with monotherapy both components of the drug. Symptomatic hypotension is rare in the treatment of hinaprilom patients with uncomplicated hypertension, but it may develop as a result of ACE inhibitor therapy in patients with lower BCC, for example, after treatment with diuretics, with a diet with restricted sodium intake or during hemodialysis. In the event of symptomatic hypotension, patients should give a horizontal position and if necessary, to hold it in / infusion with 0.9% sodium chloride solution. Transient hypotension is not a contraindication to further use of the drug, but in such cases it is advisable to reduce the dose. In patients with chronic heart failure in combination with or without renal insufficiency, ACE inhibitor therapy with arterial hypertension can lead to excessive blood pressure decrease, which may be accompanied by oliguria, azotemia and, rarely, acute renal failure and even death. Treatment of such patients Akkuzidom should start under close medical supervision and monitoring during the first 2 weeks and with increasing dose. In rare cases, therapy with ACE inhibitors may be associated with the development of agranulocytosis and suppression of bone marrow hematopoiesis in patients with uncomplicated hypertension, but more often in patients with impaired renal function, particularly with connective tissue diseases. In these cases, should control the number of leukocytes in the blood.

Thiazide diuretics are sometimes exacerbate SLE. Akkuzid should be used with caution in patients with severe kidney disease, because thiazide diuretics may cause azotemia in such patients, and their repeated use can lead to a cumulative effect.

In susceptible patients suppression of the renin-angiotensin-aldosterone system can lead to changes in renal function. In patients with severe heart failure, renal function may depend on the renin-angiotensin-aldosterone system, so treatment with ACE inhibitors, including hinapril may lead to oliguria and / or progressive azotemia and, in rare cases - to acute renal failure and / or lethal outcome.

T1 / 2 hinaprilata increases with decreasing spacecraft. When QA least 60 ml / min hinapril should be appointed at a lower initial dose. In these patients the drug dose should be improved in the light of clinical effect, with constant monitoring of renal function, although in clinical studies, there has been a further deterioration of renal function in the treatment of drug.

Some patients with hypertension without obvious signs of initial vascular lesions of the kidneys in the appointment hinaprila, especially in combination with a diuretic, noted increased levels of urea nitrogen in blood and serum creatinine, which were usually poorly marked and transient. Such changes are most likely in patients with initial renal dysfunction.

In such cases, you may need to lower the doses of the drug. All hypertensive patients should monitor renal function. In clinical studies in patients with hypertension with bilateral or unilateral renal artery stenosis for treatment with ACE inhibitors in some cases saw an increase in the level of blood urea nitrogen and serum creatinine. These changes are almost always reversible and disappeared after discontinuation of ACE inhibitor and / or diuretic. In such cases during the first few weeks of treatment should monitor renal function. Akkuzid should be used with caution in patients with impaired function or progressive liver disease, because small changes in water and electrolyte balance may cause the development of hepatic coma. Metabolism hinaprila to hinaprilata normally occurs under the action of liver enzymes. Concentrations hinaprilata reduced in patients with alcoholic cirrhosis due to violations deesterifikatsii hinaprila. In order to detect possible violations of electrolyte balance should regularly monitor the serum levels of electrolytes. Patients receiving monotherapy hinaprilom, like other ACE inhibitors may increase serum potassium levels. Hyperkalaemia (> 5.8 mmol / l) noted in approximately 2% of patients taking hinapril, but in most cases, this deviation was isolated and passed in the course of treatment. Risk factors for development of hyperkalemia include renal insufficiency, diabetes mellitus and simultaneous reception of potassium-sparing diuretics, potassium preparations and / or salt substitutes containing potassium. Simultaneous reception from Akkuzidom Potassium-sparing diuretics, which includes the thiazide diuretics is not recommended.

Treatment of thiazide diuretics, conversely, is accompanied by hypokalemia, hyponatremia and gipohloremicheskim alkalosis. Those violations sometimes occur with symptoms such as dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle weakness, muscle pain or cramps, reduced blood pressure, oliguria, tachycardia, nausea, confusion, seizures and vomiting. Hypokalemia may also increase the toxic effect of cardiac glycosides. The risk of hypokalemia is especially high in liver cirrhosis, forced diuresis, inadequate intake of electrolytes inside, concomitant therapy of GCS or ACTH. Opposing effects of components Akkuzida to the level of potassium in the serum lead to the fact that many patients its value does not change.

In some cases, the effect of one component may predominate over the other. Prior to and during treatment should be periodically determine the serum levels of electrolytes to detect possible violations of the electrolyte metabolism. Deficiency of chloride associated with thiazide diuretic therapy, usually poorly expressed and only in exceptional cases require special treatment (for example, in diseases of the liver or kidneys).

In hot weather, in patients with peripheral edema may develop hyponatremia breeding. Such patients show rather limiting fluid intake, and not the imposition of salt, except in rare cases where life threatening hyponatremia. When the actual loss of salt is needed adequate replacement therapy. Thiazide diuretics decrease the excretion of calcium. In rare cases, patients receiving long-term thiazide therapy, developed pathological changes parathyroid glands, accompanied by hypercalcaemia and hypophosphataemia. More serious complications of hyperparathyroidism (nephrolithiasis, bone resorption, and peptic ulcer) were not described. Prior to the study of the function of parathyroid glands with thiazide diuretics should be abolished. Thiazide diuretics increase the excretion of magnesium in the urine and can cause gipomagniemiyu. Thiazide diuretics may reduce glucose tolerance and raise serum levels of cholesterol, triglycerides and uric acid. These effects are usually mild, but in susceptible patients thiazide diuretics may provoke the development of gout or diabetes. ACE inhibitor therapy may be accompanied by the development of hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic funds. When treating patients with diabetes may need more careful monitoring. In the treatment with ACE inhibitors, including hinapril, noted the development of cough.

In a typical case, it is counter-productive, persistent and goes after the cessation of therapy. In the differential diagnosis of cough should take into account its possible relationship with ACE inhibitors. Patients who receive surgery or general anesthesia, ACE inhibitors should be used with caution, because they block the formation of angiotensin II, due to compensatory secretion of renin. This may lead to arterial hypotension, which is eliminated by the introduction of the liquid. Patients should be warned that inadequate fluid intake, increased sweating or dehydration can lead to excessive blood pressure decrease by reducing the BCC. Other causes of dehydration, such as vomiting or diarrhea may also lead to a drop in blood pressure. In such cases, consult a doctor. If you have any symptoms of infection (eg, sore throat, fever), the patient should also consult a doctor immediately, because These symptoms may be a manifestation of neutropenia.

Use in Pediatrics

Efficacy and safety of children and adolescents under the age of 18 is not installed. Effects on ability to drive vehicles and management mechanisms should use extreme caution when driving or carrying out other work that requires increased attention, especially in the beginning of treatment.

Overdose

No data are available about overdose Akkuzida and specific data about its treatment is required.

Symptoms: overdose hinaprila - clinical manifestations of BP decrease;
overdose hydrochlorothiazide - a violation of water-electrolyte balance (hypokalemia, chloropenia, hyponatremia) and dehydration on the background of pronounced diuresis.

In the application of cardiac glycosides hypokalemia increases the risk of cardiac arrhythmias.

Treatment: perform a standard symptomatic and supportive therapy, with marked reduction in blood pressure was shown in / at the introduction of 0.9% sodium chloride solution. Hemodialysis and peritoneal dialysis have little effect on excretion hinaprila and hinaprilata.

Drug Interactions

Tetracycline and other drugs that interact with magnesium

With simultaneous application of Akkuzida absorption of tetracycline is reduced by about 28-37% due to the presence of the drug magnesium carbonate as a filler.

Lithium preparations

Lithium preparations should not normally be given in combination with diuretics, as the latter reduce the renal clearance of lithium and increase the risk of intoxication. In patients receiving the drug lithium and ACE inhibitors, noted increased serum levels of lithium and symptoms of lithium intoxication. These changes are associated with loss of sodium under the influence of ACE inhibitors. In appointing Akkuzida risk of intoxication with lithium may be elevated. At the same time to use these drugs should be cautious.

Recommended frequent monitoring of lithium levels in blood serum.

Warfarin

Anticoagulant effect of one dose of warfarin (assessed by prothrombin time) did not change significantly, while use hinaprila 2 times / day.

Barbiturates, means for anesthesia, opioid analgesics, alcohol

Perhaps increased orthostatic hypotension with simultaneous application of ethanol, barbiturates, funds for general anesthesia or opioid analgesics with Akkuzidom because of the presence in its composition of hydrochlorothiazide.

Hypoglycemic drugs

When applied simultaneously with oral hypoglycemic Akkuzida drugs and insulin may need dosage adjustment of hypoglycemic.

Other antihypertensives

Thiazide diuretics, which is part Akkuzida can increase the effect of other antihypertensive agents, especially the ganglion blocking agents or blockers. Antihypertensive effect of thiazide diuretic, in turn, could worsen after sympathectomy.

Corticosteroids, ACTH

At simultaneous application with Akkuzidom is an increased loss of electrolytes, particularly potassium.

Pressor amines

When applied simultaneously with the possible reduction of Akkuzidom sympathomimetics (eg, norepinephrine), but this effect is negligible.

Nondepolarizing muscle relaxants

Perhaps reinforcing the nondepolarizing muscle relaxants while applying to Akkuzidom.

NSAID

NSAIDs can cause weakening of the diuretic, natriuretic, and antihypertensive effect "of loop, potassium-sparing and thiazide diuretics. In this regard, with their simultaneous application with Akkuzidom should monitor the effectiveness of therapy.

Tools that increase the amount of potassium in the blood

With simultaneous application Akkuzida with drugs and potassium salt substitutes containing potassium may increase serum potassium.

Ion Exchange Resins

Absorption of hydrochlorothiazide is deteriorating in the presence of kolestiramina and colestipol. For a single application of these drugs bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract at 85 and 43% respectively.

Other drugs

In applying hinaprila with propranolol, hydrochlorothiazide, digoxin, and cimetidine clinically significant pharmacokinetic interactions were observed.

Terms and Conditions of storage

List B. The drug should be stored away from children at or above 25 ° C.

Shelf life - 3 years.