Aprovel^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Winthrop Industrie (France)

Contact Information

SANOFI

ATC Code

C09CA04 (Irbesartan)

Active Substance

Irbesartan (Rec.INN registered by WHO)

Dosage Forms

	Aprovel®	Film-coated tablets, 150 mg: 14, 28 or 56 pcs.
		Film-coated tablets, 300 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oval, biconvex, with an engraving of a heart on one side and the number “2872” on the other.

Excipients : lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, silicon dioxide.

Film coating composition white dye*, carnauba wax.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
28 pcs. – blisters (1) – cardboard packs.

Film-coated tablets white or almost white, oval, biconvex, with an engraving of a heart on one side and the number “2873” on the other.

Excipients : lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, silicon dioxide.

Film coating composition white dye*, carnauba wax.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

* white dye contains lactose monohydrate, hypromellose, macrogol 3000, titanium dioxide (E171). Opadry^® II 32F38977 or a similar dye may be used.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Angiotensin II receptor antagonist

Pharmacological Action

Selective angiotensin II receptor antagonist (type AT₁). Irbesartan does not require metabolic activation to acquire pharmacological activity.

Angiotensin II is an important component of the RAAS and is involved in the pathogenesis of arterial hypertension, as well as sodium homeostasis. Irbesartan blocks all physiologically significant effects of angiotensin II, regardless of its source or synthesis pathway, including the pronounced vasoconstrictor effect and increased aldosterone secretion, mediated through AT₁ receptors located on the surface of vascular smooth muscle cells and in the adrenal cortex. Irbesartan has no agonistic activity towards AT₁ receptors and has a much greater affinity (more than 8500 times) for AT₁ receptors than for AT₂ receptors (receptors not associated with the regulation of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE) and does not affect receptors of other hormones or ion channels involved in the regulation of blood pressure and sodium homeostasis. Blockade of AT₁ receptors by irbesartan interrupts the feedback loop in the renin-angiotensin system, leading to increased plasma concentrations of renin and angiotensin II. After taking irbesartan at recommended doses, the plasma concentration of aldosterone decreases, without significantly affecting serum potassium levels (the average increase is <0.1 mEq/L).

Irbesartan does not have a significant effect on serum concentrations of triglycerides, cholesterol, and glucose. Irbesartan does not affect serum uric acid concentration or the rate of uric acid excretion by the kidneys.

The antihypertensive effect of irbesartan appears after the first dose and becomes significant within 1-2 weeks of administration, with its maximum antihypertensive effect achieved by 4-6 weeks of treatment. In long-term clinical studies, the antihypertensive effect of irbesartan was maintained for more than one year.

The antihypertensive effect with a single daily oral dose of irbesartan in doses up to 900 mg is dose-dependent. Irbesartan at a single daily dose of 150-300 mg reduces blood pressure, measured in the supine or sitting position at the end of the dosing interval (24 hours after taking the dose of irbesartan, i.e., before taking the next dose of irbesartan), on average by 8-13/5-8 mm Hg (systolic/diastolic blood pressure) compared to placebo. The antihypertensive effect of irbesartan before the next dose is 60-70% of the maximum values of diastolic and systolic blood pressure reduction. Optimal blood pressure reduction over 24 hours is achieved with once-daily irbesartan administration.

Irbesartan reduces blood pressure approximately equally in the standing and supine positions. Orthostatic effects are rare; however, as with ACE inhibitors, excessive blood pressure reduction with clinical manifestations is possible in patients with hyponatremia and/or hypovolemia.

The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients with insufficient blood pressure reduction with irbesartan monotherapy, the addition of low-dose hydrochlorothiazide (12.5 mg) once daily leads to an additional reduction in blood pressure of 7-10/3-6 mm Hg (systolic/diastolic) compared to the addition of placebo.

The efficacy of irbesartan does not depend on age or sex. As with other drugs that affect the RAAS, the antihypertensive effect of irbesartan in Black patients is noticeably less pronounced; however, when irbesartan is used concomitantly with low-dose hydrochlorothiazide (e.g., 12.5 mg/day), the antihypertensive response in Black patients approaches that in Caucasian patients.

After discontinuation of irbesartan, blood pressure returns to baseline gradually. No “withdrawal” syndrome is observed.

In patients with arterial hypertension and type 2 diabetes mellitus taking Irbesartan at a dose of 300 mg, there was a 20% reduction (compared to placebo) and a 23% reduction (compared to amlodipine at a dose of 10 mg) in the relative risk of the first occurrence of any of the following conditions: doubling of serum creatinine concentration, development of end-stage renal failure, or death from any cause (with comparable blood pressure reduction achieved with irbesartan and amlodipine).

Pharmacokinetics

Absorption

After oral administration, Irbesartan is rapidly and completely absorbed. C_max of irbesartan in plasma is reached 1.5-2 hours after oral administration. The absolute bioavailability is 60-80%. Concurrent food intake does not significantly affect the bioavailability of the drug.

Distribution

Plasma protein binding is approximately 96%. Binding to blood cellular components is negligible. V_d is 53-93 L.

With daily once-daily administration of irbesartan, C_ss is reached in 3 days, with limited accumulation in plasma (less than +20%).

Metabolism

After oral or IV administration of ¹⁴C-irbesartan, 80-85% of the radioactivity in circulating plasma is due to unchanged Irbesartan.

Irbesartan is metabolized in the liver by oxidation and conjugation with glucuronic acid. The oxidation of irbesartan occurs mainly with the participation of the CYP2C9 isoenzyme; the participation of the CYP3A4 isoenzyme in the metabolism of irbesartan is insignificant. The main metabolite in the systemic circulation is irbesartan glucuronide (about 6%).

Irbesartan is not metabolized by most of the isoenzymes that are usually involved in drug metabolism (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1 isoenzymes) and does not cause their inhibition or induction. Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.

Excretion

Irbesartan and its metabolites are eliminated from the body both through the intestines and the kidneys. Less than 2% of the administered dose is excreted by the kidneys as unchanged irbesartan. The terminal T_1/2 is 11-15 hours. The total clearance of IV administered irbesartan is 157-176 ml/min, and its renal clearance is 3-3.5 ml/min.

Pharmacokinetics in special clinical situations

Gender. Women (compared to men) had slightly higher plasma concentrations of irbesartan. However, no gender-related differences in T_1/2 and accumulation of irbesartan were identified. Dose adjustment of irbesartan in women is not required. No gender-related differences in the effects of irbesartan were observed.

Elderly patients. The AUC and C_max values of irbesartan in elderly patients (65-80 years) with clinically normal renal and hepatic function were approximately 20-50% higher than in younger patients (18-40 years). The terminal T_1/2 values were comparable. No age-related differences in the effects of irbesartan were observed.

Impaired hepatic function. In patients with mild (Child-Pugh class A or 5-6 points) and moderate (Child-Pugh class B or 7-9 points) hepatic insufficiency due to liver cirrhosis, the pharmacokinetic parameters of irbesartan do not change significantly.

Impaired renal function. In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetic parameters of irbesartan do not change significantly. Irbesartan is not removed from the body by hemodialysis.

Race. In Black individuals without arterial hypertension, the AUC and T_1/2 of irbesartan are approximately 20-25% higher than in Caucasian individuals; the C_max of irbesartan in them was almost similar to that in Caucasian individuals.

Indications

• Arterial hypertension (as monotherapy and in combination with other antihypertensive drugs, for example, thiazide diuretics, beta-blockers, long-acting calcium channel blockers);
• Nephropathy in arterial hypertension and type 2 diabetes mellitus (as part of combined antihypertensive therapy).

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals. The tablet should be swallowed whole with water.

The initial dose is 150 mg once daily.

In patients who require additional blood pressure reduction to achieve target values, the dose may be increased to 300 mg once daily.

In case of insufficient blood pressure reduction with irbesartan monotherapy, diuretics (e.g., hydrochlorothiazide 12.5 mg/day) or other antihypertensive agents (e.g., beta-blockers, long-acting calcium channel blockers) may be added to the treatment.

In patients with nephropathy in arterial hypertension and type 2 diabetes mellitus, the preferred maintenance dose is 300 mg once daily.

The maximum daily dose is 300 mg/day.

Use of the drug in children and adolescents under 18 years of age is contraindicated (insufficient clinical data on the safety and efficacy of the drug).

Elderly patients (over 65 years): dose adjustment is not required.

Patients with impaired renal function: dose adjustment is not required.

Patients with impaired hepatic function: in patients with mild and moderate hepatic impairment (5-9 points on the Child-Pugh scale), dose adjustment is not required. There is no experience with the use of the drug in patients with severe hepatic insufficiency.

Patients with hypovolemia: in patients with severe hypovolemia and/or hyponatremia, such as patients receiving intensive diuretic therapy or on hemodialysis, hypovolemia and hyponatremia should be corrected before starting the use of the drug Aprovel^®.

Adverse Reactions

The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Adverse events in patients taking the drug Aprovel^® were usually mild and transient, and their frequency was not related to the dose taken. The frequency of adverse events did not depend on gender, age, or race.

Below are the adverse reactions observed in clinical studies

• ¹ in patients with arterial hypertension;
• ² in patients with nephropathy in arterial hypertension and type 2 diabetes mellitus;
• ³ during post-marketing use of the drug.

Blood and lymphatic system disorders frequency unknown – thrombocytopenia, including thrombocytopenic purpura³, anemia³.

Immune system disorders frequency unknown – hypersensitivity reactions³ (such as angioedema, skin rash, urticaria, anaphylactic reactions, anaphylactic shock).

Metabolism and nutrition disorders frequency unknown – hyperkalemia³, hypoglycemia³.

Nervous system disorders common – dizziness^1,2, orthostatic dizziness², headache¹; uncommon – orthostatic dizziness¹; frequency unknown – vertigo³.

Ear and labyrinth disorders frequency unknown – tinnitus³.

Cardiac disorders common – orthostatic hypotension²; uncommon – edema¹, tachycardia¹, flushing¹.

Respiratory, thoracic and mediastinal disorders uncommon – cough¹.

Gastrointestinal disorders common – nausea¹, vomiting¹; uncommon – diarrhea¹, dyspepsia¹, heartburn¹; frequency unknown – dysgeusia¹.

Hepatobiliary disorders uncommon – jaundice³; frequency unknown – increased liver enzyme activity³ and blood bilirubin concentration³, hepatitis³.

Skin and subcutaneous tissue disorders frequency unknown – leukocytoclastic vasculitis³, psoriasis³, including exacerbation of psoriasis symptoms (see section “Special Instructions”), photosensitivity reactions³.

Musculoskeletal and connective tissue disorders common – musculoskeletal pain²; frequency unknown – myalgia³ (in some cases may be associated with increased plasma creatine kinase concentration), arthralgia³, muscle cramps³.

Renal and urinary disorders frequency unknown – renal function impairment³, including cases of renal failure in at-risk patients (see section “Special Instructions”).

Reproductive system and breast disorders uncommon – erectile dysfunction¹.

General disorders and administration site conditions common – fatigue¹; uncommon – chest pain¹; frequency unknown – asthenia³.

Investigations during controlled clinical studies in patients with arterial hypertension, no clinically significant changes in laboratory parameters were observed. No special monitoring of laboratory parameters is required for patients with arterial hypertension taking the drug Aprovel^®.

Hyperkalemia. When using the drug Aprovel^®, hyperkalemia and treatment discontinuation due to hyperkalemia were more frequently observed in patients with nephropathy in arterial hypertension and type 2 diabetes mellitus.

Contraindications

• Hypersensitivity to irbesartan or any of the excipients of the drug;
• Severe hepatic insufficiency (Child-Pugh class C or more than 9 points) (lack of clinical experience);
• Concomitant use with drugs containing aliskiren in patients with diabetes mellitus and/or with moderate to severe renal impairment (GFR<60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Pregnancy;
• Lactation period (breastfeeding);
• Age under 18 years (efficacy and safety not established);
• Hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

With caution

• In aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy;
• In hypovolemia, hyponatremia, occurring, for example, during intensive diuretic therapy, hemodialysis, diarrhea, vomiting, adherence to a salt-restricted diet (risk of excessive blood pressure reduction);
• In patients with renal function dependent on RAAS activity, such as patients with hypertension with bilateral or unilateral renal artery stenosis or patients with chronic heart failure of functional class III-IV (according to NYHA classification);
• In coronary artery disease and/or clinically significant cerebral atherosclerosis (with excessive blood pressure reduction, there is a risk of increased ischemic disorders, up to the development of acute myocardial infarction and stroke);
• In renal failure (control of potassium levels and serum creatinine concentration is required), recent kidney transplantation (lack of clinical experience);
• With concurrent use of NSAIDs, including selective COX-2 inhibitors (increased risk of impaired renal function, including the possibility of acute renal failure and increased serum potassium, especially in elderly patients, patients with hypovolemia [including patients taking diuretics] or patients with impaired renal function);
• When used in combination with ACE inhibitors or aliskiren, because, compared to monotherapy, dual blockade of the RAAS is associated with an increased risk of excessive blood pressure reduction, hyperkalemia, and impaired renal function;
• In patients with psoriasis (including history) due to the possible exacerbation of psoriasis.

Use in Pregnancy and Lactation

Pregnancy

There is no experience with the use of irbesartan during pregnancy. Given that the use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with injury and death of the developing fetus, Irbesartan, like any other drug that directly affects the RAAS, should not be used during pregnancy (I, II, III trimesters).

If pregnancy is diagnosed during treatment, the drug should be discontinued immediately.

Lactation period

Irbesartan is excreted in the milk of lactating rats. It is not known whether Irbesartan/its metabolites are excreted in human breast milk. The use of irbesartan is contraindicated during breastfeeding. Therefore, after assessing the ratio of the expected benefit of the drug for the mother and the potential risk for the child, either breastfeeding or irbesartan should be discontinued.

Fertility

In studies in male and female rats, Irbesartan did not affect fertility and reproductive performance, even at doses that had some toxic effects on the parents (up to 650 mg/kg/day). No significant effects on the number of corpora lutea, implanted embryos, or live fetuses were observed. Irbesartan did not affect the survival, development, or reproduction of the offspring.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic insufficiency (functional class C or more than 9 points on the Child-Pugh scale) (lack of clinical experience).

In patients with mild to moderate hepatic impairment, dose reduction is usually not required.

Use in Renal Impairment

The drug should be used with caution in patients with renal function dependent on RAAS activity (patients with arterial hypertension with bilateral or unilateral renal artery stenosis), in renal failure (control of potassium levels and serum creatinine concentration is required), recent kidney transplantation (lack of clinical experience).

Concomitant use with drugs containing aliskiren is contraindicated in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m²).

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

In elderly patients (over 65 years of age), dose reduction is not required.

Special Precautions

Excessive blood pressure reduction in patients with hypovolemia

Aprovel^® has rarely caused excessive blood pressure reduction in patients with hypertension without other concomitant pathology. As with the use of ACE inhibitors, excessive blood pressure reduction with corresponding symptoms may develop in patients with hypovolemia/hyponatremia (e.g., as a result of intensive diuretic therapy, diarrhea, vomiting, a salt-restricted diet), as well as in patients on hemodialysis. Hyponatremia and/or hypovolemia should be corrected before starting treatment with Aprovel^®, or the use of a lower initial dose should be considered.

Hypoglycemia

Aprovel^® may cause hypoglycemia, especially in patients receiving drugs for the treatment of diabetes mellitus. Therefore, dose adjustment of diabetes medications such as repaglinide or insulin may be required.

Fetal/neonatal morbidity and mortality

Although there is no experience with the use of Aprovel^® in pregnant women, it has been reported that in utero exposure to ACE inhibitors when used by pregnant women in the second and third trimesters can lead to impaired development and death of the fetus. Aprovel^® is contraindicated for use during pregnancy, as is any other drug that has a direct effect on the RAAS. If pregnancy is detected during treatment, the use of Aprovel^® should be discontinued as soon as possible.

Patients with renal function dependent on RAAS activity

Due to the inhibition of the RAAS, deterioration of renal function can be expected in predisposed patients. In patients with renal function dependent on RAAS activity (patients with hypertension and stenosis of the renal artery of one or both kidneys or patients with chronic heart failure of NYHA functional class III and IV), treatment with drugs that affect the RAAS has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect with the use of angiotensin II receptor antagonists, including Irbesartan, cannot be ruled out.

Renal failure and kidney transplantation

When using Aprovel^® in patients with renal failure, periodic monitoring of serum potassium and creatinine levels is recommended. There are no clinical data on the use of Aprovel^® in patients who have undergone kidney transplantation.

Patients with arterial hypertension and type 2 diabetes mellitus with impaired renal function

The beneficial effect of Aprovel^® in slowing the progression of renal and cardiovascular disorders varied in severity among different patient groups: it was less pronounced in women and patients not of Caucasian race.

In the IDNT clinical trial in patients with arterial hypertension and type 2 diabetes mellitus with proteinuria (≥900 mg/day), in the subgroup of patients at high risk of renal artery stenosis, none of the patients taking Aprovel^® experienced an acute early increase in serum creatinine associated with renal artery stenosis.

Dual blockade of the RAAS with concurrent use of irbesartan with ACE inhibitors or with aliskiren

Dual blockade of the RAAS with the combination of irbesartan with ACE inhibitors or aliskiren is not recommended, as there is an increased risk of a sharp decrease in blood pressure, hyperkalemia, and impaired renal function compared to monotherapy.

Concomitant use of irbesartan with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment with GFR <60 ml/min/1.73 m² body surface area and is not recommended in other patients.

Concomitant use of irbesartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Psoriasis

In patients with psoriasis (including history), the decision to use the drug should be made only after a thorough assessment of the risk/benefit ratio due to the possible exacerbation of psoriasis.

Hyperkalemia

As with the use of other drugs affecting the RAAS, hyperkalemia may develop during treatment with Aprovel^®, especially in the presence of renal failure and/or heart disease. In such patients, it is recommended to monitor serum potassium levels.

Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with the use of other vasodilators, caution is required when prescribing Aprovel^® to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that inhibit the RAAS. Therefore, the use of Aprovel^® in such cases is not advisable.

Coronary artery disease and/or clinically significant cerebrovascular atherosclerosis

As with the use of other antihypertensive agents, a significant decrease in blood pressure in patients with coronary artery disease and/or severe cerebrovascular atherosclerosis may lead to myocardial infarction or stroke. Treatment should be carried out under strict blood pressure control.

Effect on the ability to drive vehicles and mechanisms

The effect of the drug on the ability to drive vehicles or engage in other potentially hazardous activities requiring increased attention and high speed of psychomotor reactions has not been studied. However, based on pharmacodynamic properties, the drug should not affect the ability to drive vehicles and engage in other potentially hazardous activities (including working at heights, work of an air traffic controller, work with machinery). In case of dizziness and weakness, a decrease in attention and a slowdown in psychomotor reactions are possible, so caution should be exercised when driving vehicles and operating machinery.

Overdose

Experience with the drug in adult patients at doses up to 900 mg/day for 8 weeks did not reveal any toxicity.

Treatment There is no specific information regarding the treatment of overdose with Aprovel^®. In case of overdose, it is recommended to induce vomiting and/or perform gastric lavage. Constant monitoring of the patient’s condition should be established and, if necessary, symptomatic and supportive therapy should be carried out. Irbesartan is not removed from the body by hemodialysis.

Drug Interactions

Based on in vitro data, no interaction of irbesartan with drugs metabolized by the CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1, or CYP3A4 isoenzymes is expected. Irbesartan is mainly metabolized by the CYP2C9 isoenzyme and, to a lesser extent, undergoes glucuronidation.

No significant pharmacokinetic and pharmacodynamic interaction was observed with the combined use of irbesartan with warfarin, a drug metabolized by the CYP2C9 isoenzyme.

Irbesartan does not alter the pharmacokinetics of digoxin and simvastatin.

When used concomitantly with hydrochlorothiazide or nifedipine, the pharmacokinetics of irbesartan do not change.

Drugs containing aliskiren

Concomitant use of irbesartan with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate and severe renal impairment (GFR <60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

ACE inhibitors

The use of irbesartan in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium preparations and potassium-sparing diuretics, heparin

Based on experience with other drugs affecting the RAAS, with the concomitant use of potassium preparations; salt substitutes containing potassium; potassium-sparing diuretics or other drugs that can increase blood potassium levels (heparin), serum potassium concentration may sometimes increase significantly, which requires careful monitoring of plasma potassium levels in patients during treatment.

NSAIDs, including selective COX-2 inhibitors

With the concomitant use of angiotensin II receptor antagonists and NSAIDs (including selective COX-2 inhibitors), the antihypertensive effect of irbesartan may be weakened. In elderly patients, patients with hypovolemia, or patients with impaired renal function, the use of NSAIDs, including COX-2 inhibitors, concomitantly with angiotensin II receptor antagonists, including Irbesartan, may lead to deterioration of renal function, including the possible development of acute renal failure. These effects are usually reversible. Renal function should be periodically monitored in patients taking Irbesartan and NSAIDs, including COX-2 inhibitors, concomitantly.

Repaglinide

Irbesartan may inhibit the OATP1B1 transporter. In a clinical study, it was reported that the use of irbesartan 1 hour before taking repaglinide increased the C_max and AUC of repaglinide (a substrate of the OATP1B1 transporter) by 1.8 and 1.3 times, respectively. In another study, no significant pharmacokinetic interaction was reported with the combined use of irbesartan and repaglinide. Therefore, dose adjustment of repaglinide may be required for the treatment of diabetes mellitus in patients with hypertension.

Lithium preparations

An increase in serum lithium concentration and an increase in its toxicity have been reported with the concomitant use of lithium salts with irbesartan.

Diuretics and other antihypertensive agents

With the concomitant use of irbesartan and other antihypertensive agents, the antihypertensive effect may be enhanced. Irbesartan can be used with other antihypertensive agents, such as beta-blockers, long-acting CCBs, and thiazide diuretics.

Previous treatment with high doses of diuretics may lead to hypovolemia and increase the risk of excessive blood pressure reduction at the beginning of treatment with Aprovel^®.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years. Do not use the drug after the expiration date indicated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.