KOAPROVEL
Active material: Gidroxlorotiazid, Irbesartan
When ATH: C09DA04
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.05
Manufacturer: SANOFI WINTHROP INDUSTRY (France)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Pills Oval, lenticular, Peach (orange-pink) color with white inclusions, with an engraving in the shape of a heart on one side and “2775” – another.
| 1 tab. | |
| irbesartan | 150 mg |
| gidroxlorotiazid | 12.5 mg |
Excipients: microcrystalline cellulose, sodium croscarmellose, lactose monohydrate, magnesium stearate, silicon dioxide colloidal, hydrated, pregelatinized corn starch, iron oxide red, iron oxide yellow.
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
14 PC. – blisters (7) – packs cardboard.
Pills Oval, lenticular, Peach (orange-pink) color with white inclusions, with an engraving in the shape of a heart on one side and “2776” – another.
| 1 tab. | |
| irbesartan | 300 mg |
| gidroxlorotiazid | 12.5 mg |
Excipients: microcrystalline cellulose, sodium croscarmellose, lactose monohydrate, magnesium stearate, silicon dioxide colloidal, hydrated, pregelatinized corn starch, iron oxide red, iron oxide yellow.
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
14 PC. – blisters (7) – packs cardboard.
Pharmacological action
Combined antihypertensive drug, containing an Angiotensin II receptor antagonist irbesartan and hydrochlorothiazide diuretic tiazidnyj. The combination of these ingredients has additive hypotensive effect, reducing the HELL in greater, than each of them individually.
Selective antagonism of irbesartana against AT1-receptors manifested increasing of Renin and Angiotensin II and aldosterone content decrease in serum. The level of potassium in the blood serum of insignificant changes in the face of treatment irbesartanom when alone in the recommended doses
Irbesartan does not inhibit ACE (kininazu II), that contributes to the formation of angiotensin II, and it also turns bradikinin inactive metabolites. Irbesartan does not require metabolic activation for the manifestation of his actions.
Hydrochlorothiazide is a diuretic tiazidnam. Thiazide diuretics affect renal mechanisms of reabsorption of electrolytes, increasing the excretion of sodium and chloride in approximately equivalent quantities, inhibit reabsorbqiyu sodium. Hydrochlorothiazide reduces plasma volume, increasing the plasma Renin activity and aldosterone secretion, with the subsequent increase of the content of potassium in the urine and decreasing its serum. Presumably, by embargo Renin-angiotensin-aldosterone system activity using irbesartana leads to prevent loss of potassium in the blood serum, called by this diuretic.
When taking hydrochlorothiazide beginning diureza falls on the first 2 hours after the intake of, reaches a peak within 4 no, the remains of about 6-12 no.
Reducing ad appears after the first dose Koaprovelâ®, maximum effect is observed after 6-8 weeks of treatment. The effect persists for long term use (1 year). Increased blood pressure , Although not izučavšeesâ in the treatment of Koaprovelem®, There were no irbesartana when canceling or hydrochlorothiazide applied separately.
There is no difference in reactions to Koaprovel′® Depending on the age or gender.
Pharmacokinetics
Absorption
After intake of Koaprovelâ® the absolute bioavailability of irbesartana – 60- 80%, and hydrochlorothiazide – 50-80%. After oral administration, Cmax irbesartan in plasma achieved through 1.5-2 no, gidroxlorotiazida – 1-2.5 no.
Distribution
Irbesartana linking blood plasma proteins is approximately 96%. Vd irbesartana is 53-93 l.
Plasma protein binding of hydrochlorothiazide is 68%, Vd – 0.83-1.14 l / kg.
For pharmacokinetic characteristic of linear irbesartana indicators of the dose in the range of doses from 10 to 600 mg. Slacker, than proportional, the increase in intake were observed when administered in doses more 600 mg.
Hydrochlorothiazide crosses the placental barrier, excreted in breast milk, It does not penetrate the BBB.
Metabolism
Irbesartan is metabolized in the liver by conjugation with glukuronova acid and oxidation. The major circulating metabolite glucuronide is irbesartana (about 6%). In vitro studies suggest that, What is irbesartan metabolised by oxidation with the participation of CYP2C9.
Hydrochlorothiazide is not metabolized.
Deduction
General and kidney klirens is 157-176 ml / min 3.0-3.5 ml / min, respectively. T1/2 irbesartana – 11-15 no. Serum concentrations of sustainable value within reach 3 days after the start of therapy. Repeated receptions on the scheme 1 times per day there has been a limited accumulation of irbesartana in plasma (< 20%).
After oral admission 14C irbesartan 80-85% circulating radioactive blood plasma media constitute an unmodified irbesartan. Irbesartan and its metabolites are excreted in the bile and urine. Once inside, or on / in the 14C irbesartan 20% radioactivity detected in the urine and traces – Calais. Less, than 2% unmodified irbesartana excreted in the urine.
T1/2 hydrochlorothiazide varies from 5 to 15 no. Hydrochlorothiazide quickly displayed kidneys. At least 61% adopted inside dose excreted unchanged to within 24 no.
Pharmacokinetics in special clinical situations
Slightly higher concentration in the blood serum of irbesartana were detected in women with elevated AD, than men. However, there were differences of values T1/2 and accumulation of irbesartana. Hence, no need for dose adjustment in women irbesartana. Значения AUC и Cmax were higher in elderly (> 65 years), than younger people (18-40 years). However, T1/2 was not significantly changed. Therefore, dose adjustment in elderly patients is not required.
In patients with renal insufficiency or in gemodialise, Pharmacokinetic parameters irbesartana vary slightly. Irbesartan is not removed by hemodialysis. It has been reported, that patients with QC < 20 mL/min increased T1/2 to 21 no.
In patients with mild and moderate degree of liver irbesartana slightly altered pharmacokinetic parameters. In patients with severe hepatic insufficiency research has not been done.
Testimony
- Arterial hypertension.
Dosage regimen
Koaprovel′® It may be used 1 time/day before or at the time of delivery in patients, HELL insufficiently controlled irbesartanom or hydrochlorothiazide separately.
Koaprovel′® 150/12.5 MG patients, who the HELL is insufficiently controlled hydrochlorothiazide or irbesartanom (150 mg / day) monotherapy.
Koaprovel′® 300/12.5 MG patients, who the HELL is not sufficiently controlled by irbesartanom (300 mg) or Koaprovelem® (150/12.5 mg).
Use of the drug in doses more than 300 irbesartana mg/25 mg hydrochlorothiazide 1 times/day are not recommended.
Since Koaprovelâ® includes hydrochlorothiazide, the drug is contraindicated patients with severe renal insufficiency (CC <30 ml / min). In these cases, the application of “loop” Diuretics is preferable, use tiazidov. Is not required correction doses in Patients with renal insufficiency with CC>30 ml / min.
Before applying Koaprovelâ® You must adjust the lower BCC and/or sodium content. If this fails, It is necessary to consider the possibility of accepting a lower initial dose.
Koaprovel′® contraindicated patients with severe hepatic insufficiency. In patients with compromised liver function thiazides should be used with caution, but patients with liver failure mild and moderate dose adjustment is not required.
No need for dose adjustment Koaprovelâ® in elderly patients.
Side effect
Determination of the frequency of adverse reactions: Often (> 10%); often (> 1%, < 10%); sometimes (> 0.1%, < 1%); rarely (> 0.01% , < 0.1%); rarely (0.01%), including isolated reports.
Koaprovel′® in placebo-controlled studies in patients with arterial hypertension
The overall frequency of adverse events in groups irbesartana/hydrochlorothiazide versus placebo varied not. Cessation of therapy due to any clinical or laboratory side phenomenon was less frequent in patients, taking a combination of irbesartana and hydrochlorothiazide, than placebo. The frequency of adverse events is not dependent on sex, age, race or dose. Patients with arterial hypertension (n = 898) received a combination of irbesartan/hydrochlorothiazide in doses of 37.5 mg/6.25 mg to 300 mg /25 mg.
CNS: often - dizziness; sometimes – orthostatic dizziness.
Cardio-vascular system: sometimes – hypotension, swelling, syncope, tachycardia, tides.
From the digestive system: often- nausea, vomiting; sometimes diarrhea.
From the urinary system: often the violation of urination.
On the part of the reproductive system: sometimes – change in sexual desire, sexual dysfunction.
Other: often fatigue; sometimes – swelling of the upper and lower extremities.
From the laboratory parameters: often – increased urea nitrogen, creatinine and plasma CPK; sometimes – lower levels of potassium and sodium in serum. These changes of laboratory parameters rarely reached the threshold of clinical relevance.
Adverse Reactions, observed when applying Koaprovelâ® in general clinical practice
Allergic reactions: rarely – rash, hives, angioedema.
Metabolism: rarely – hyperkalemia.
CNS: rarely – headache.
From the senses: rarely – tinnitus.
The respiratory system: sometimes cough.
From the digestive system: rarely – change in taste, dyspepsia, abnormal liver function, hepatitis.
On the part of the musculoskeletal system: rarely – myalgia, arthralgia.
From the urinary system: rarely – impairment of renal function, incl. isolated cases of kidney failure in patients with high-risk groups.
Adverse Reactions, reported previously in the application irbesartana
Other: chest pain.
Adverse Reactions, reported previously when applying hydrochlorothiazide
From the hematopoietic system: aplasticheskaya anemia, bone marrow depression, gemoliticheskaya anemia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia.
From the central and peripheral nervous system: depression, sleep disorders, dizziness, paresthesia, anxiety.
On the part of the organ of vision: passing the vagueness of view, Xanthopsia.
Cardio-vascular system: Arrhythmia, postural hypotension.
The respiratory system: acute respiratory distress syndrome (including Pneumonitis and Lung edema).
From the digestive system: jaundice (Cholestatic jaundice vnutripečenočnaâ).
Allergic reactions: anaphylactic reactions, toxic epidermal necrosis, skin reaction type of Lupus Erythematosus, nekrotizirovannyj angiit (vasculitis, kozhnыy vasculitis), photosensitivity reaction, rash, the exacerbation of the skin manifestations of Lupus Erythematosus, hives.
On the part of the musculoskeletal system: muscle spasms, weakness.
From the urinary system: interstitial nephritis, renal dysfunction.
Other: fever.
From the laboratory parameters: electrolyte imbalance (incl. hypokalemia and hyponatremia), glycosuria, giperglikemiâ, hyperuricemia, increased cholesterol and TG.
Contraindications
— II and III trimenon of pregnancy;
- Hypersensitivity to the drug;
-hypersensitivity to other drugs, sulfonamide derivatives.
For the application of hydrochlorothiazide:
- Severe renal insufficiency (CC < 30 ml / min);
- Refractory hypokalaemia, hypercalcemia;
is a severe form of liver failure;
-biliary cirrhosis;
- Cholestasis.
Pregnancy and lactation
Koaprovel′® contraindicated in groups II and III trimestrah pregnancy. If the pregnancy is diagnosed, the Koaprovel′® should be abolished as soon as possible. Skull and kidney function should be monitored using echography if, negligence, therapy lasted for a long time.
Koaprovel′® contraindications throughout the lactation period.
Cautions
Koaprovel′® rarely causes symptomatic hypotension in patients with elevated AD. Symptomatic hypotension could conceivably occur in patients with reduced BCC or low sodium due to diuretic therapy, When the diet with salt restriction, If you have diarrhea or vomiting. Such conditions should be adjusted to the start of therapy Koaprovelem®.
The risk of severe arterial hypotension and renal insufficiency increases in patients with bilateral renal artery stenosis or stenosis of the artery only functioning kidneys in the application of ACE inhibitors or Angiotensin II receptor Blocker. Although when applying Koaprovelâ® such communications are not available, This effect must be taken into account.
When applying Koaprovelâ® in patients with impaired renal function, It is recommended that periodic monitoring of the levels of potassium, creatinine and uric acid in blood serum.
In patients after a recent kidney transplant experience of applying Koaprovelâ® missing. Koaprovel′® It should not be used in patients with severe renal insufficiency (CC < 30 ml / min). In patients with impaired kidney therapy tiazidnami dioretikami may develop азотемии.
With the utmost caution should appoint Koaprovel′® patients with stenosis aortic stenosis and estuary of the mitral valve, in obstructive hypertrophic cardiomyopathy.
We do not recommend the use of Koaprovelâ® primary al′dosteronizme.
While therapy tiazidnami dioretikami may decrease glucose tolerance. In patients with diabetes mellitus may require correction doses of insulin or gipoglikemicakih oral drugs. Tiazidami therapy may cause manifestation of latent diabetes mellitus.
Therapy at a dose of hydrochlorthiazide 12.5 mg, contained in Koaprovele®, virtually no effect on cholesterol and TG.
Tiazidami therapy in some patients may experience worsening gout or hyperuricemia.
Tiazidы, including hydrochlorothiazide, may cause violation of water and electrolyte balance (hypokalemia, giponatriemia and gipohloremicski alkaloz). Although the use of a thiazide diuretic may develop hypokalemia, parallel irbesartanom therapy can reduce gipokaliemia, caused by the diuretic. The risk gipokaliemii patients increases, who receive the GCS or ACTH. Conversely, Thanks to irbesartanu, component Koaprovelâ®, hyperkalemia is possible, especially if you have kidney failure and/or congestive heart failure, or diabetes mellitus. It is recommended that an adequate monitoring of the level of potassium in the blood serum of patients risk groups.
Potassium-sparing diuretics, potassium supplements or substitutes, containing potassium, should be cautious appoint simultaneously with Koaprovelem®.
No confirmation, What is irbesartan may reduce or prevent giponatriemia, caused by diuretics. Chloride deficiency is usually insignificant and does not require treatment.
Thiazides may reduce calcium excretion through the kidneys and cause a slight increase in the level of calcium in blood serum, assuming no violations in the exchange of calcium. Marked hypercalcemia may be a sign of latent hyperparathyroidism. Reception tiazidov should be discontinued before investigation functions of the parathyroid gland.
Tiazida increase excretion of magnesium in the urine, that can lead to gipomagniemii.
Not recommended to appoint Koaprovel′® in combination with the drug lithium.
Hydrochlorothiazide can cause a positive result in a doping test.
Patients, whose vascular tone and kidney function depends, primarily, of the Renin-angiotensin-aldosterone system activity (eg, in patients with chronic heart failure or kidney disease, including renal artery stenosis), therapy receptors angiotenzina II antagonists may cause a severe arterial hypotension, azotemiû, oliguria or, rarely, acute kidney failure. Excessive lowering ad in patients with ischemic heart disease or other cardiovascular diseases can lead to myocardial infarction or a brain stroke.
The development of allergic reactions to hydrochlorothiazide are more likely in patients, have similar reactions occurred in history.
When applying a thiazide diuretic mentioned aggravation of Systemic Lupus Erythematosus.
In the first trimester of pregnancy the use Koaprovelâ® not recommended.
Use in Pediatrics
The safety and efficacy of Koaprovelâ® in children and adolescents under the age of 18 years not set.
Effects on ability to drive vehicles and management mechanisms
Impact Koaprovelâ® the ability to drive vehicles and mechanisms was not investigated, but based on its pharmacodynamic properties is unlikely, that Koaprovel′® affects this ability. While driving or mechanisms must take into account, that in rare cases, you may experience dizziness and fatigue during therapy high HELL.
Overdose
There is no specific information on overdose Koaprovelâ®.
Symptoms: overdose irbesartana most probable arterial gipotenzia, tachycardia; bradycardia; overdose of hydrochlorothiazide – kaliopenia, giponatriemiya, dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose – nausea and drowsiness. Hypokalemia may lead to convulsions and/or strengthening of arrhythmias in case of concomitant use of glycosides naperstanki and complications.
Treatment: recommended action depending on the time, Since taking the drug, and the severity of symptoms – provoke vomiting and/or gastric lavage, activated carbon, careful monitoring of the patient's condition, the holding of symptomatic and supportive therapy. Should conduct frequent monitoring of electrolytes and creatinine in the serum. In the case of arterial hypotension patient needs to lay on the back with uplifted upper limbs and as quickly as possible to conduct compensation salts and fluids.
Irbesartan is not displayed during hemodialysis. The extent of breeding gidrohlorotiazida in gemodialise not installed.
Drug Interactions
Perhaps increased activity antigipertenzivnogo Koaprovelâ® together with the use of other antihypertensive medicines. Combination of irbesartan/hydrochlorothiazide doses 300 mg/25 mg should be used with caution in conjunction with other antigipertenzivei means, including calcium channel blockers and beta-adrenoblokatora. Preliminary therapy dioretikami high doses can lead to hypovolemia and risk of arterial hypotension.
Reversible increased concentrations of lithium in serum and toxic effects were observed with concomitant use of lithium with ACE inhibitors. With respect to irbesartan, similar effects were hitherto extremely rare. Besides, Kidney klirens lithium reduces tiazidami, Therefore, in the case of use of Koaprovelâ® the risk of toxic effects of lithium may be increased. So the combination of lithium and Koaprovelâ® not recommended. If the combination is necessary, We recommend careful monitoring of serum lithium levels.
Gipokaliemičeskij effect of hydrochlorothiazide weakened kalijsberegaûŝim effect irbesartana. However, this effect of hydrochlorothiazide can be strengthened by other drugs, causing loss of potassium and hypokaliemia (eg, Diuretics, laxatives, amphotericin, carbenaksolonom, sodium salt of penicillin G, derivatives of salicylic acid). Conversely, based on the experience of other drugs, that reduce the activity of the Renin-angiotensin system, the attendant application kalisberegath dioretikov, biologically active additives, Salt substitutes, containing potassium, or other drugs, able to increase the levels of potassium in the blood serum (eg, sodium salt of heparin), could increase the amount of potassium in the blood serum. Patients with high-risk groups recommended for adequate control of the level of potassium in serum.
It is recommended that periodic monitoring of the levels of potassium in the blood serum in the case of a joint application Koaprovelâ® and drugs, affected by the violation potassium balance in the serum (eg, Digitalis glycosides, antiarrhythmics).
With simultaneous use of angiotensin II antagonists and NSAIDs (eg, selective COX-2 inhibitors, acetylsalicylic acid >3 g / day and non-selective NSAIDs) can weakening gipotenzivnogo effect.
As in the case of ACE inhibitors, joint application of angiotensin II antagonists, and NSAIDS may increase the risk of kidney function, including the likelihood of acute renal failure, and lead to increased content of potassium in the blood serum, especially in patients with already compromised renal function. This combination should be used with caution, especially in elderly patients. Patients should not be dehydrated. Monitoring of kidney function should be implemented after initiation of combination therapy and periodically thereafter.
Pharmacokinetics irbesartana is not exposed to in a joint application with hydrochlorothiazide. Irbesartan is mainly metabolized by CYP2C9 and to a lesser extent – by glucuronidation. There were no significant pharmacokinetic and farmakodinamičeskogo interaction, When irbesartan is used together with warfarin, drug, subjected to metabolism involving CYP2C9. Influence of CYP2C9, such as rifampicin, the farmakokinetiku irbesartana not estimated. Pharmacokinetics of Digoxin was not changed when coupled with the use of irbesartanom.
If you are applying with tiazidnami dioretikami ethanol, barbiturates or means to narcosis may experience increased orthostatic hypotension.
When applying hydrochlorothiazide may require dose adjustment hypoglycemic means.
Absorption of hydrochlorothiazide is reduced in the presence of anion exchange resins.
Together with the use of CORTICOSTEROIDS or ACTH hydrochlorothiazide and perhaps more expressed violation of elektrolitnogo balance, in particular, strengthening of hypokalemia.
Gipokaliemia and gipomagniemia, caused by tiazidnam diuretic, contributed to arrhythmias, caused by Digitalis.
The use of NSAIDS can reduce the effects of thiazide diuretic in some patients.
May reduce the effectiveness of Catecholamines (eg, norepinephrine) under the influence of hydrochlorothiazide.
Effect nedepoliarizuth miorelaksantov hydrochlorothiazide can be strengthened.
May require correction doses protivopodagricakih funds, tk. hydrochlorothiazide can increase levels of uric acid in the serum. You may need to increase doses probenecida or sulfinpirazon. Joint application with tiazidnami dioretikami may increase the frequency of allergic reactions to allopurinol.
Thiazide diuretics may increase the level of calcium in blood serum due to reduced excretion. If must be assigned to calcium supplements or medications, influencing the level of calcium (eg, therapy with vitamin D), that needed to be monitored with serum calcium and appropriate correction dosage of calcium.
Giperglikemičeskij effect of beta-adrenoblokatorov and diazoxide can be strengthened tiazidami.
Anticholinergic agents (eg, atropyn) may increase the bioavailability of thiazide diuretic because of lower GASTROINTESTINAL motility.
Thiazides may increase the risk of side effects, caused by amantadine.
Thiazides may decrease urine excretion of cytotoxic medicines (eg, цiklofosfamida, methotrexate) and strengthen their mielosupressivnye effects.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 3 year.
