APROVEL
Active material: Irbesartan
When ATH: C09CA04
CCF: Angiotensin II receptor antagonists
ICD-10 codes (testimony): I10, N08.3
When CSF: 01.04.02
Manufacturer: SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC (France)
Pharmaceutical form, composition and packaging
Pills Oval, lenticular, white or nearly white, engraved as a heart on one side and the number of “2772” – another.
| 1 tab. | |
| irbesartan | 150 mg |
Excipients: lactose monohydrate, pregelatinized corn starch, sodium croscarmellose, poloxamer 188, aqueous colloidal silica, microcrystalline cellulose, magnesium stearate.
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
Pills Oval, lenticular, white or nearly white, engraved as a heart on one side and the number of “2773” – another.
| 1 tab. | |
| irbesartan | 300 mg |
Excipients: lactose monohydrate, pregelatinized corn starch, sodium croscarmellose, poloxamer 188, aqueous colloidal silica, microcrystalline cellulose, magnesium stearate.
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
Pharmacological action
Antihypertensive drugs, specific angiotensin II receptor antagonist (AT type1). Eliminates the vasoconstrictive action of angiotensin II and aldosterone reduces the concentration in the blood plasma.
Blocks all physiologically significant effects of angiotensin II, realized through receptor AT type1, regardless of the source or route of synthesis of angiotensin II. The specific antagonistic action against angiotensin II receptor (AT1) It leads to increased concentrations of renin and angiotensin II in plasma and to reduce the concentration of aldosterone in blood plasma. When using the recommended doses of a preparation of the potassium ion concentration in blood serum does not change significantly.
Irbesartan does not inhibit kininazu II, by which the formation of angiotensin II and destruction of bradykinin to inactive metabolites. For the manifestation of its effects Irbesartan does not require metabolic activation.
Irbesartan lowers blood pressure with minimal change in heart rate. When taken at doses up to 300 mg 1 time / day reduction in blood pressure is dose-dependent, However, with further increase in the dose of irbesartan increase of the hypotensive effect is negligible.
The maximum reduction in blood pressure is achieved through 3-6 hours after oral administration, and hypotensive effect persists at least for 24 no. Through 24 h after administration of the recommended doses of blood pressure reduction 50-70% compared with a maximum reduction of systolic and diastolic blood pressure in response to use of the drug. At reception 1 times / day dose 150-300 mg of the degree of reduction in blood pressure (systolic / diastolic) at the end of dosing interval (ie. through 24 h after dosing) with the patient lying or sitting on average 8-13/5-8 mmHg. (respectively) as compared to placebo.
The drug at a dose of 150 mg 1 time / day causes a hypotensive response (decrease in blood pressure before taking the next dose and mean blood pressure reduction of 24 no) as the same dose, razdelennoy of 2 admission.
The hypotensive effect of the drug Aprovel® develops within 1-2 weeks, and maximum therapeutic effect is obtained for 4-6 weeks after the start of treatment. The antihypertensive effect is maintained in long-term treatment. After stopping the treatment of blood pressure gradually returns to the initial value, withdrawal was not observed.
Irbesartan has no effect on the level of uric acid in the serum or on the excretion of uric acid in urine.
Pharmacokinetics in special clinical situations
The efficacy does not depend on age and sex.
Patients blacks less responsive to monotherapy Aprovelem® (as all other drugs, vliyayushtie renin-angiotensin-alydosteronovuyu sistemu).
Pharmacokinetics
Absorption
After ingestion well absorbed from the gastrointestinal tract. Cmax irbesartan in plasma achieved through 1.5-2 hours after ingestion. The absolute bioavailability of 60-80%. Simultaneous food intake did not significantly affect the bioavailability of the drug.
Irbesartan has a linear and proportional to the dose pharmacokinetics in a dosage range of from 10 to 600 mg; at doses greater than 600 mg (in 2 times higher than the recommended maximum dose) irbesartan becomes non-linear kinetics (decrease absorption).
Distribution
Plasma protein binding is approximately 96%. The binding to cellular blood components slightly. Vd – 53-93 l. Css reached within 3 days after initiation of drug administration 1 time / day. Repeated receptions 1 time / day indicated a limited accumulation of irbesartan in plasma (less 20%).
Metabolism
Once inside, or on / in the 14C irbesartan 80-85% radioactivity in the circulating blood falls onto the unmodified irbesartan.
Irbesartan is biotransformed in the liver by oxidation and conjugation with glucuronic acid. Irbesartan okislyaetsya, mainly, with the help of CYP2C9 isoenzymes, isozymes CYP3A4 has negligible effect. The major metabolite – irbesartan glucuronide (about 6%).
Deduction
The total clearance and renal clearance up 157-176 ml / min 3-3.5 ml / min, respectively. T1/2 for the terminal phase of 11-15 no. Irbesartan and its metabolites are excreted in the bile and urine. Once inside, or on / in the 14C irbesartan about 20% radioactivity found in urine, the rest of the – Calais. Less 2% of the administered dose excreted in the urine as unchanged irbesartan.
Pharmacokinetics in special clinical situations
Somewhat higher concentrations of irbesartan in plasma was observed in women (compared to men). However, differences in the quantity T1/2 and accumulation of irbesartan are not revealed. Correction doses of irbesartan in women is not required. Значения AUC и Cmax irbesartan were slightly higher in the elderly (senior 65 years), than in younger patients (18-40 years), T1/2 did not differ significantly. Correction dose of irbesartan in elderly patients is not required.
In patients with impaired renal function or patients, It is undergoing hemodialysis, pharmacokinetics irbesartan substantially unchanged. Irbesatan not removed from the body during hemodialysis.
In patients with liver cirrhosis mild to moderate pharmacokinetic parameters of the drug did not significantly change. A pharmacokinetic study in patients with severe hepatic impairment have not been conducted.
Testimony
- Arterial hypertension;
- Treatment of renal disease in patients with hypertension and diabetes mellitus type 2 (as part of combination antihypertensive therapy).
Dosage regimen
The drug is taken orally, Swallow whole tablets, drinking water.
The initial and maintenance dose is 150 mg 1 times / day, regardless of the meal. Use of the drug in a dose provides a more optimal 24-hour blood pressure control, than dose 75 mg / day. However, some patients, especially in patients, hemodialysis, or in patients over the age of 75 years, initial dose should be 75 mg (possible to use Aprovelya® v tab. by 75 mg).
In case of insufficient therapeutic effect when applied Aprovelya® dose 150 mg 1 time / day, the dose can be increased to 300 mg, or should appoint other agents. In particular it has been shown, that the appointment of a diuretic, such as hydrochlorothiazide, Enhances the action Aprovelya®.
In patients with hypertension and diabetes mellitus type 2 Treatment should start with a dose 150 mg 1 time / day and gradually increase to 300 mg – dose, It is preferred maintenance dose for the treatment of nephropathy.
Evidence of the beneficial effects of Aprovelya® on the kidney in patients with hypertension and diabetes mellitus type 2 prepared research, in which it was used in combination with other antihypertensives, necessary to achieve the target blood pressure.
Prior to the reception Aprovelya® BCC to restore and / or eliminate hyponatremia.
In patients with impaired renal function correction dosing regime is not required. Patient, hemodialysis, initial dose should be 75 mg / day (possible use of the drug Aprovel® v tab. by 75 mg).
In patients with impaired hepatic function or mild to moderate severity It does not require correction dosing regimen. Clinical experience with the drug in patients with severe hepatic impairment is not.
Although the recommended treatment patients aged 75 years start with a dose 75 mg (possible use of the drug Aprovel® v tab. by 75 mg), usually elderly patients correction dosing regime is not required.
Side effect
In describing the side effects of the following criteria frequency of occurrence: Often (>10%), often (>1%, <10%); sometimes (>0.1%,<1%); rarely (>0.01%, <0.1%); rarely (<0.01%; including isolated reports). The frequency of side effects were dose-dependent (the recommended dose range), gender, age, the race of the patient or of the duration of therapy.
Arterial hypertension
IN placebo-controlled studies (1965 patients received irbesartan) We noted the following adverse reactions.
CNS: often - dizziness.
Cardio-vascular system: sometimes - tachycardia, flushing of the skin.
The respiratory system: sometimes – cough.
From the digestive system: often – nausea, vomiting; sometimes – diarrhea, dyspepsia, heartburn.
On the part of the reproductive system: sometimes – sexual dysfunction.
From the body as a whole: often - fatigue; sometimes – chest pain.
From the laboratory parameters: often – a significant increase in CK (1.7%), not accompanied by clinical symptoms of the musculoskeletal system.
Arterial hypertension and diabetes mellitus type 2 with microalbuminuria without renal dysfunction
In addition to the above adverse reactions were observed when taking irbesartan:
Cardio-vascular system: sometimes – orthostatic dizziness, orthostatic hypotension in 0.5% patients (compared to the frequency of occurrence of these adverse events in the placebo).
From the laboratory parameters: Often – hyperkalemia (>5.5% mmol / l) when receiving 300 mg of irbesartan was observed in 29.4% patients, in the placebo group – in 22% patients.
Arterial hypertension and diabetes mellitus type 2 with severe proteinuria and chronic renal insufficiency
The following adverse reactions were observed more, than 2% patients (compared to the frequency of their occurrence in the placebo).
CNS: often – orthostatic dizziness, orthostatic hypotension.
On the part of the musculoskeletal system: often – pain in the muscles and bones.
From the laboratory parameters: Often – hyperkalemia (>5.5% mmol / l) while taking irbesartan have met 46.3% patients, in the placebo group – in 26.3% patients; often – a clinically significant decrease in hemoglobin concentration 1.7% patients with high blood pressure and diabetic nephropathy.
Since the introduction of irbesartan on the market were also identified the following adverse reactions:
CNS: rarely – headache.
From the digestive system: rarely – disgevziya, abnormal liver function, hepatitis.
On the part of the musculoskeletal system: rarely – myalgia, arthralgia (sometimes in conjunction with increased levels of creatine kinase), convulsions.
From the urinary system: rarely – impairment of renal function (incl. isolated cases of renal failure in patients at risk).
From the senses: rarely – tinnitus.
From the laboratory parameters: rarely – hyperkalemia.
Allergic reactions: rarely – rash, hives, angioedema.
Contraindications
- Hereditary galactose intolerance, lactase deficiency or malabsorption of glucose and galactose;
- Pregnancy;
- Lactation;
- Childhood and adolescence up 18 years (efficacy and safety have not been established);
- Hypersensitivity to the drug.
FROM caution use in patients with stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy, degidratacii, giponatriemii, diarrhea, rvote, a diet with limited intake of salt, diuretic therapy, bilateral renal artery stenosis, unilateral renal artery stenosis only, chronic heart failure III-IV functional class NYHA classification, Coronary artery disease and / or atherosclerotic vascular lesions of the brain, hyperkalemia, renal failure, gemodialize, a recent kidney transplant (lack of clinical experience with), severe hepatic insufficiency (lack of clinical experience with).
Pregnancy and lactation
Aprovel® contraindicated during pregnancy. If pregnancy occurs during treatment with the drug should be lifted immediately.
Switching to the appropriate alternative therapy should be carried out before planning pregnancy.
If necessary, the appointment during lactation should decide the issue of termination of breastfeeding, tk. it is not known whether irbesartan is allocated with breast milk.
Cautions
Disorders of water and electrolyte balance
When dehydration and / or deficiency of sodium ions (as a result of intensive treatment with diuretics, diarrhea or vomiting, restricting the salt intake), and in patients, hemodialysis, can develop clinically significant hypotension, particularly after the first dose. These pathological conditions need to be adjusted before the start of the drug Aprovel®.
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, taking other drugs, vliyayushtie sistemu of the renin-angiotensin-alydosteron, are at increased risk for developing severe hypotension and renal insufficiency. Although the development of such complications to drug Aprovel® not disclosed, similar effect can be expected when using angiotensin II receptor antagonists.
Renal impairment and kidney transplantation
In applying Aprovelya® in patients with renal insufficiency is recommended periodic monitoring of potassium and creatinine serum. No clinical data on the use of Aprovelya® patients, Kidney transplant.
Arterial hypertension and diabetes mellitus type 2
Marked at Aprovelya® a beneficial effect in slowing the progression of renal attitude and cardiovascular lesions had varying degrees of severity in different groups of patients: was less pronounced among women and people, does not apply to the European race.
Hyperkalemia
Perhaps the development of hyperkalemia in the application Aprovelya® (As with other means, vliyayushtih sistemu of the renin-angiotensin-alydosteron), especially in patients with renal failure and / or heart disease. For patients at risk is recommended adequate control potassium levels in the blood serum.
Stenosis of the aortic or mitral valve, obstruktivnaya gipertroficheskaya cardiomyopathy
It is necessary to take special precautions for use in patients with aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism
Patients with primary aldosteronism not normally responsive to antihypertensives, ingibiruyushtie sistemu renin-angiotensin. Therefore, the use Aprovelya® in such cases, it is not recommended.
In the group of patients, whose vascular tone and renal function in predominantly depend on the activity of the renin-angiotensin-aldosterone (eg, in patients with chronic heart failure III and IV functional class NYHA classification and with the respective kidney disease, including renal artery stenosis), Drug treatment, affecting the system, It has been associated with acute hypotension, azotemia, oliguria, and in rare cases – with acute renal failure. As with other antihypertensives, reducing high blood pressure in patients with ischemic heart disease could result in a myocardial infarction or cause angina attack. Treatment should be under the control of blood pressure.
Use in Pediatrics
The safety and efficacy of the drug Aprovel® patients were children or adolescents have not been established.
Effects on ability to drive vehicles and management mechanisms
Influence Aprovelya® the ability to engage in activities, require attention, It has not been studied, However, based on its pharmacodynamic properties, the drug should not affect this ability. When driving vehicles should take into account, during treatment of hypertension is sometimes possible dizziness, and increased fatigue.
Overdose
In applying the drug in adult patients at a dose of 900 mg / day for 8 weeks did not reveal any toxicity.
Symptoms: most likely marked reduction of blood pressure, tachycardia, bradycardia.
Treatment: Accidental taking the drug at high doses seem artificial vomiting and / or gastric lavage, Activated carbon, the holding of symptomatic and supportive therapy. Hemodialysis nyeeffyektivyen.
Drug Interactions
Diuretics and other antihypertensives
With simultaneous use of irbesartan with other antihypertensive agents may increase the hypotensive action. Irbesartan was used in combination with other antihypertensive drugs, such as beta-blockers, Calcium channel blockers slow and long-acting thiazide diuretics.
Hypotensive effects of irbesartan and thiazide diuretics are additive in nature.
In patients with uncontrolled blood pressure irbesartan monotherapy, the appointment of small doses of hydrochlorothiazide (12.5 mg / day) It leads to a further reduction (compared to placebo) RT on 7-10/3-6 mm Hg. Article. (systolic / diastolic blood pressure at the end of the period mezhdozovogo).
In the application of irbesartan with small doses of hydrochlorothiazide (12.5 mg / day) hypotensive effect of this combination in patients blacks closer to that of patients European race.
Previous treatment with diuretics in high doses can lead to dehydration and increase the risk of hypotension at the beginning of treatment with Aprovel®.
Preparations of potassium and potassium-sparing diuretics, Heparin
Based on experience, obtained by use of other drugs, vliyayushtih renin-angiotensin-alydosteronovuyu sistemu, while using drugs potassium, electrolyte solutions containing potassium, or other potassium-sparing diuretics, can increase the level of potassium in the blood, preparations (Heparin), may increase the level of potassium in blood serum.
Lithium
Reversible increasing concentrations of lithium in blood serum and its toxicity was observed, while the application of lithium with ACE inhibitors. To date the application of irbesartan similar effects were observed rarely. If there is a need in this combination, then during treatment should be carefully monitored the concentration of lithium in blood serum.
NSAIDs
With simultaneous use of angiotensin II antagonists and NSAIDs (incl. selective COX-2 inhibitors, acetylsalicylic acid (>3 g / day) and non-selective NSAIDs) may weaken hypotensive effect.
As with the simultaneous use of ACE inhibitors and NSAIDs, the joint application of angiotensin II antagonists and NSAIDs may increase the risk of renal dysfunction, including the possibility of acute renal failure, and an increase in serum potassium levels, especially in patients with already compromised renal function. It should be used with caution in this combination, especially in elderly patients. Patients need to recover the BCC and throughout the combination therapy and periodically after its closure to monitor renal function.
Additional information on the interaction of irbesartan
In an application with irbesartan hydrochlorothiazide pharmacokinetics of irbesartan is not changed. Irbesartan is mainly metabolized by CYP2C9 and is less subject to glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions with the combination of irbesartan and warfarin, drug, metabolized via CYP2C9. Studies of the impact of the activity of CYP2C9 inducers (incl. rifampicin), on the pharmacokinetics of irbesartan are not carried out. Irbesartan does not alter the pharmacokinetics of digoxin.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
List B. The drug should be stored out of reach of children, dry place at temperatures below 30 ° C. Shelf life – 3 year.
