Sartavel^® Amlo (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

C09DB01 (Valsartan and Amlodipine)

Active Substances

Valsartan (Rec.INN WHO registered)

Amlodipine (Rec.INN WHO registered)

Dosage Forms

	Sartavel^® Amlo	Film-coated tablets, 5 mg+80 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 210, 240, 270 or 300 pcs.
		Film-coated tablets, 5 mg+160 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 210, 240, 270 or 300 pcs.
		Film-coated tablets, 10 mg+160 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 210, 240, 270 or 300 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; on the cross-section, two layers are visible – a core of white or almost white color and a film coating.

	1 tab.
Amlodipine besylate	6.94 mg,
Equivalent to amlodipine content	5 mg
Valsartan	80 mg

Excipients: microcrystalline cellulose – 76.76 mg, croscarmellose sodium – 7 mg, povidone K25 – 5 mg, colloidal silicon dioxide – 2.7 mg, magnesium stearate – 1.6 mg.

Film coating composition: hypromellose – 3.42 mg, macrogol-4000 – 0.9 mg, titanium dioxide – 1.68 mg.

10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
10 pcs. – contour cell packaging (7) – cardboard packs.
10 pcs. – contour cell packaging (8) – cardboard packs.
10 pcs. – contour cell packaging (9) – cardboard packs.
10 pcs. – contour cell packaging (10) – cardboard packs.
20 pcs. – contour cell packaging (2) – cardboard packs.
20 pcs. – contour cell packaging (3) – cardboard packs.
20 pcs. – contour cell packaging (4) – cardboard packs.
20 pcs. – contour cell packaging (5) – cardboard packs.
20 pcs. – contour cell packaging (6) – cardboard packs.
20 pcs. – contour cell packaging (7) – cardboard packs.
20 pcs. – contour cell packaging (8) – cardboard packs.
20 pcs. – contour cell packaging (9) – cardboard packs.
20 pcs. – contour cell packaging (10) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.
30 pcs. – contour cell packaging (3) – cardboard packs.
30 pcs. – contour cell packaging (4) – cardboard packs.
30 pcs. – contour cell packaging (5) – cardboard packs.
30 pcs. – contour cell packaging (6) – cardboard packs.
30 pcs. – contour cell packaging (7) – cardboard packs.
30 pcs. – contour cell packaging (8) – cardboard packs.
30 pcs. – contour cell packaging (9) – cardboard packs.
30 pcs. – contour cell packaging (10) – cardboard packs.
10 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
40 pcs. – polymer jars (1) – cardboard packs.
50 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
70 pcs. – polymer jars (1) – cardboard packs.
80 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.

Film-coated tablets from pink to light pink, round, biconvex; on the cross-section, two layers are visible – a core of white or almost white color and a film coating.

	1 tab.
Amlodipine besylate	6.94 mg,
Equivalent to amlodipine content	5 mg
Valsartan	160 mg

Excipients: microcrystalline cellulose – 160.46 mg, croscarmellose sodium – 14 mg, povidone K25 – 10 mg, colloidal silicon dioxide – 5.4 mg, magnesium stearate – 3.2 mg.

Film coating composition: hypromellose – 6.84 mg, macrogol-4000 – 1.8 mg, iron oxide red dye – 0.12 mg, titanium dioxide – 3.24 mg.

Film-coated tablets white or almost white, round, biconvex; on the cross-section, two layers are visible – a core of white or almost white color and a film coating.

	1 tab.
Amlodipine besylate	13.88 mg,
Equivalent to amlodipine content	10 mg
Valsartan	160 mg

Excipients: microcrystalline cellulose – 153.52 mg, croscarmellose sodium – 14 mg, povidone K25 – 10 mg, colloidal silicon dioxide – 5.4 mg, magnesium stearate – 3.2 mg.

Film coating composition: hypromellose – 6.84 mg, macrogol-4000 – 1.8 mg, titanium dioxide – 3.36 mg.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + CCB)

Pharmacological Action

The drug is a combination of two antihypertensive components with complementary mechanisms for controlling blood pressure (BP): Amlodipine, a dihydropyridine derivative, belongs to the group of slow calcium channel blockers (CCBs) and Valsartan belongs to the group of angiotensin II receptor antagonists (ARBs). The combination of these components has a mutually complementary antihypertensive effect, leading to a more pronounced reduction in BP compared to monotherapy with each component.

Amlodipine

Amlodipine, which is part of the drug Sartavel^® Amlo, inhibits the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscles, causing a decrease in total peripheral vascular resistance (TPR) and a reduction in BP.

After administration in therapeutic doses in patients with arterial hypertension, Amlodipine causes vasodilation, leading to a decrease in BP (in both supine and standing positions). The reduction in BP is not accompanied by a significant change in heart rate (HR) and catecholamine levels during long-term use.

The plasma concentration of amlodipine correlates with the clinical effect in both young and elderly patients.

In arterial hypertension in patients with normal renal function, Amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in glomerular filtration rate and effective renal plasma flow without changing the filtration fraction and the degree of proteinuria.

As with the use of other CCBs, the administration of amlodipine in patients with normal left ventricular (LV) function caused changes in hemodynamic parameters of heart function at rest and during exercise: a slight increase in cardiac index was noted, without significant effect on the maximum rate of pressure rise in the LV (dP/dt) and end-diastolic pressure and LV volume. Hemodynamic studies in intact animals and humans have shown that the reduction in BP under the influence of amlodipine in the therapeutic dose range is not accompanied by a negative inotropic effect even with simultaneous use with beta-blockers.

Amlodipine does not change the function of the sinoatrial node or atrioventricular conduction in intact animals and humans. When using amlodipine in combination with beta-blockers in patients with arterial hypertension or angina, the reduction in BP is not accompanied by undesirable changes in ECG parameters.

The clinical efficacy of amlodipine has been proven in patients with chronic stable angina, vasospastic angina, and angiographically confirmed coronary artery disease.

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist intended for oral administration. It acts selectively on the AT₁ receptor subtype, which is responsible for the known effects of angiotensin II. The increase in plasma concentration of free angiotensin II due to the blockade of AT₁ receptors under the influence of valsartan may stimulate the unblocked AT₂ receptors, which counteract the effects of AT₁ receptor stimulation. Valsartan does not have any significant agonistic activity towards AT₁ receptors. The affinity of valsartan for the AT₁ receptor subtype is approximately 20,000 times higher than for the AT₂ receptor subtype.

Valsartan does not inhibit angiotensin-converting enzyme, also known as kininase II, which converts angiotensin I to angiotensin II and causes the breakdown of bradykinin.

Since the use of angiotensin II antagonists does not involve inhibition of ACE and accumulation of bradykinin or substance P, the development of dry cough is unlikely. Valsartan does not interact with or block receptors of other hormones or ion channels that are important for the regulation of cardiovascular functions.

When treating patients with arterial hypertension with valsartan, a decrease in BP is observed, which is not accompanied by a change in HR.

The antihypertensive effect occurs within 2 hours in most patients after a single dose of the drug. The maximum reduction in BP develops after 4-6 hours. After taking the drug, the duration of the antihypertensive effect persists for more than 24 hours. With repeated use, the maximum reduction in BP, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained at the achieved level during long-term therapy. Abrupt discontinuation of valsartan is not accompanied by a sharp increase in BP or other undesirable clinical consequences. The use of valsartan in patients with chronic heart failure (NYHA functional classes II-IV) leads to a significant reduction in the number of hospitalizations. This effect is most pronounced in patients not receiving ACE inhibitors or beta-blockers. When taking valsartan, patients with left ventricular failure (stable clinical course) or with impaired LV function after myocardial infarction show a reduction in cardiovascular mortality.

Amlodipine/Valsartan

The combination of amlodipine and valsartan reduces BP additively and dose-dependently in the therapeutic dose range. When taking a single dose of the Amlodipine/Valsartan combination, the hypotensive effect persists for 24 hours.

The clinical efficacy of the amlodipine/valsartan combination has been proven in patients with mild to moderate arterial hypertension (mean diastolic BP (DBP) >95 mm Hg and <110 mm Hg) without complications compared to placebo.

The magnitude of BP reduction in the sitting position in arterial hypertension with DBP >110 mm Hg and <120 mm Hg is comparable to the use of a combination of an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic. The hypotensive effect is long-lasting. Sudden discontinuation of the drug is not accompanied by a sharp increase in BP (there is no "withdrawal" syndrome). Therapeutic efficacy does not depend on the patient's age, gender, race, or body mass index.

When using combination therapy with Amlodipine/Valsartan, comparable BP control is achieved with a lower likelihood of developing peripheral edema in patients with previously achieved BP control and pronounced peripheral edema during amlodipine therapy.

Pharmacokinetics

The pharmacokinetics of amlodipine and valsartan are characterized by linearity.

Amlodipine

Absorption

After oral administration, Amlodipine is slowly absorbed from the gastrointestinal tract (GIT).

After oral administration in therapeutic doses, the C_max of amlodipine in plasma is reached after 6-12 hours. The absolute bioavailability value averages 64%-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The volume of distribution is approximately 21 L/kg. In in vitro studies with amlodipine, it was shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

Amlodipine is extensively (approximately 90%) metabolized in the liver to form active metabolites.

Excretion

The elimination of amlodipine from plasma is biphasic with a terminal half-life (T_1/2) of approximately 30 to 50 hours. Steady-state plasma concentrations are reached after prolonged use for 7-8 days. 10% of unchanged amlodipine and 60% of amlodipine in the form of metabolites are excreted by the kidneys.

Amlodipine is not removed from the body by dialysis.

Valsartan

Absorption

After oral administration of valsartan, C_max in plasma is reached after 2-3 hours. The mean absolute bioavailability is 23%.

The pharmacokinetic curve of valsartan has a descending multi-exponential character (T_1/2α<1 hour and T_1/2β about 9 hours). When taking valsartan with food, a decrease in bioavailability (by the area under the curve “concentration-time”, AUC value) by 40% and the maximum concentration (C_max) in plasma by almost 50% is noted, although approximately 8 hours after taking the drug, the plasma concentrations of valsartan when taken with food and on an empty stomach level out. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so Valsartan can be prescribed regardless of meal time.

Distribution

The volume of distribution (V_d) of valsartan at steady state after oral administration was about 17 L, indicating no extensive distribution of valsartan in tissues. Valsartan is largely bound to serum proteins (94-97%), mainly albumin.

Metabolism

Valsartan does not undergo significant metabolism (about 20% of the administered dose is determined as metabolites). The hydroxyl metabolite is detected in plasma in low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically active.

Elimination

Valsartan is primarily eliminated unchanged via the intestine (about 83% of the dose) and via the kidneys (about 13% of the dose). The T_1/2 of valsartan is 6 hours.

Amlodipine /Valsartan

After oral administration of Sartavel^® Amlo, C_max of valsartan and amlodipine is reached within 3 and 6-8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from Sartavel^® Amlo are equivalent to the bioavailability of valsartan and amlodipine when each is administered separately.

Pharmacokinetics in special patient groups

The pharmacokinetics of the combination of Amlodipine and Valsartan in children and adolescents under 18 years of age have not been established.

The time to reach C_max of amlodipine in plasma is the same in young and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, leading to an increase in AUC and T_1/2. In elderly patients, the systemic exposure to valsartan was somewhat more pronounced than in younger patients; however, this was not clinically significant. Since the tolerability of the drug components is equally good in elderly and younger patients, the usual dosing regimens are recommended.

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. No correlation was found between renal function (CrCl) and systemic exposure to valsartan (AUC) in patients with varying degrees of renal impairment. No initial dose adjustment is required in patients with mild to moderate renal impairment (CrCl 30-50 ml/min).

Patients with hepatic impairment have reduced clearance of amlodipine, leading to an increase in AUC of approximately 40-60%. On average, in patients with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) hepatic impairment, the bioavailability (AUC) of valsartan is doubled compared to healthy volunteers (of corresponding age, sex, and body weight).

Indications

Arterial hypertension (for patients who are indicated for combination therapy).

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

The drug should be taken orally, with a small amount of water, once a day, regardless of the time of food intake. The recommended daily dose is 1 tablet of Sartavel^® Amlo, containing Amlodipine/Valsartan in a dose of 5/80 mg, 5/160 mg, 10/160 mg. The recommended maximum daily dose is 10/160 mg.

It is recommended to start taking the drug with a dose of 5/80 mg once a day. The dose can be increased after 1-2 weeks from the start of therapy.

No dose adjustment of the drug is required for patients over 65 years of age.

For patients with mild or moderate renal impairment (CrCl >30 ml/min), no adjustment of the initial dose of the drug is required.

In severe hepatic impairment, Sartavel^® Amlo is contraindicated. The maximum daily dose of valsartan in mild and moderate hepatic impairment is 80 mg; the use of Sartavel^® Amlo in doses of 5/160 mg and 10/160 mg in these patients is contraindicated.

Adverse Reactions

The following criteria were used to assess the frequency of adverse effects: the term “very common” is used if adverse events are noted in more than 10% of patients; “common” – in 1%-10%; “uncommon” – in 0.1%-1%; “rare” – in 0.001%-0.1%; “in isolated cases” – in less than 0.001% of patients; “frequency unknown” – cannot be calculated from the available data.

Combination of amlodipine and valsartan

Infections and infestations common – nasopharyngitis, influenza.

Immune system disorders rare – hypersensitivity.

Eye disorders rare – visual impairment.

Ear and labyrinth disorders uncommon – vertigo; rare – tinnitus.

Psychiatric disorders rare – anxiety.

Nervous system disorders common – headache; uncommon – dizziness, somnolence, postural dizziness, paresthesia.

Cardiac disorders uncommon – tachycardia, palpitations, orthostatic hypotension; rare – syncope, marked decrease in blood pressure.

Respiratory, thoracic and mediastinal disorders uncommon – cough, pharyngeal and laryngeal pain.

Gastrointestinal disorders uncommon – diarrhea, nausea, abdominal pain, constipation, dry mouth.

Skin and subcutaneous tissue disorders uncommon – skin rash, erythema; rare – hyperhidrosis (increased sweating), exanthema, pruritus.

Musculoskeletal and connective tissue disorders uncommon – joint swelling, back pain, arthralgia; rare – muscle spasms, feeling of heaviness throughout the body.

Renal and urinary disorders rare – pollakiuria, polyuria, erectile dysfunction.

General disorders and administration site conditions common – puffy face, facial edema, increased fatigue, asthenia, flushing, peripheral edema, feeling of heat.

Investigations increased serum urea nitrogen concentration (more than 3.1 mmol/l).

Amlodipine

When amlodipine was used in monotherapy, other adverse effects were also noted.

Blood and lymphatic system disorders very rare – leukopenia, thrombocytopenia.

Immune system disorders very rare – allergic reactions.

Metabolism and nutrition disorders very rare – hyperglycemia.

Psychiatric disorders uncommon – insomnia, mood swings.

Nervous system disorders uncommon – taste perversion, hypoesthesia, tremor, dysgeusia; very rare – muscle hypertonia, peripheral neuropathy.

Eye disorders uncommon – diplopia.

Ear and labyrinth disorders uncommon – tinnitus.

Cardiac disorders very rare – arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction, vasculitis.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinitis.

Gastrointestinal disorders uncommon – dyspepsia, vomiting; very rare – gastritis, gingival hyperplasia, pancreatitis.

Hepatobiliary disorders very rare – hepatitis, jaundice.

Skin and subcutaneous tissue disorders uncommon – alopecia, purpura, skin discoloration, photosensitivity; very rare – angioedema, erythema multiforme, Stevens-Johnson syndrome, urticaria.

Musculoskeletal and connective tissue disorders uncommon – myalgia.

Renal and urinary disorders uncommon – micturition disorders, nocturia.

Reproductive system and breast disorders uncommon – gynecomastia.

General disorders and administration site conditions uncommon – malaise, chest pain, pain of various localization.

Investigations uncommon – increase or decrease in body weight; very rare – increased activity of liver transaminases (usually associated with cholestasis).

Valsartan

Blood and lymphatic system disorders frequency unknown – decrease in hemoglobin and hematocrit, neutropenia, thrombocytopenia.

Immune system disorders frequency unknown – hypersensitivity reactions, including serum sickness.

Ear and labyrinth disorders uncommon – vertigo.

Cardiac disorders frequency unknown – vasculitis.

Respiratory, thoracic and mediastinal disorders uncommon – cough.

Gastrointestinal disorders uncommon – abdominal discomfort, upper abdominal pain.

Hepatobiliary disorders frequency unknown – impaired liver function, increased activity of liver enzymes, increased plasma bilirubin concentration.

Skin and subcutaneous tissue disorders very rare – angioedema; frequency unknown – pruritus, rash, bullous dermatitis.

Musculoskeletal and connective tissue disorders frequency unknown – myalgia.

Renal and urinary disorders frequency unknown – increased plasma creatinine concentration, impaired renal function, including acute renal failure.

General disorders and administration site conditions uncommon – increased fatigue, asthenia.

Investigations frequency unknown – increased plasma potassium levels.

Contraindications

Hypersensitivity to amlodipine, other dihydropyridine derivatives, valsartan, or other excipients of the drug;
Hereditary angioedema, or angioedema in patients during previous therapy with angiotensin II receptor antagonists;
Severe hepatic impairment (>9 points on the Child-Pugh scale), biliary cirrhosis, cholestasis;
Severe renal impairment (CrCl less than 30 ml/min);
Use in patients undergoing hemodialysis;
Pregnancy, use when planning pregnancy;
Period of breastfeeding;
Severe arterial hypotension (systolic BP less than 90 mm Hg);
Age under 18 years (efficacy and safety have not been established);
Shock (including cardiogenic), collapse;
Obstruction of the left ventricular outflow tract (including hypertrophic obstructive cardiomyopathy (HOCM)), severe aortic stenosis;
Hemodynamically unstable heart failure after acute myocardial infarction;
Primary hyperaldosteronism;
Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (CrCl less than 60 ml/min);
The safety of using the drug Amlodipine+Valsartan in patients after kidney transplantation has not been established.

With caution mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) hepatic impairment, obstructive biliary tract diseases, mild to moderate renal failure (CrCl 30-50 ml/min), unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, chronic heart failure (CHF) NYHA functional class III-IV, acute coronary syndrome, after myocardial infarction, hyperkalemia, hyponatremia, salt-restricted diet, reduced circulating blood volume (CBV) (including diarrhea, vomiting), hypertrophic obstructive cardiomyopathy, concomitant use of drugs containing angiotensin II receptor antagonists (ARAs) with other agents that inhibit the renin-angiotensin-aldosterone system, such as ACE inhibitors or aliskiren, including in patients with renal impairment.

Use in Pregnancy and Lactation

Like any other drug that affects the renin-angiotensin-aldosterone system (RAAS), Sartavel^® Amlo should not be used in women planning pregnancy. When prescribing Sartavel^® Amlo, like any other drug affecting the RAAS, the physician should inform women of childbearing potential about the possible risk to the fetus associated with the use of the drug.

The use of Sartavel^® Amlo during pregnancy is contraindicated. Given the mechanism of action of angiotensin II receptor antagonists, a risk to the fetus cannot be ruled out.

It is known that the use of ACE inhibitors, which affect the RAAS, by pregnant women in the II and III trimesters led to the development of fetotoxic effects (impaired renal function, delayed ossification of the fetal skull bones, oligohydramnios) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia) and death of the developing fetus. According to a retrospective analysis, the use of ACE inhibitors during the first trimester of pregnancy was accompanied by the development of fetal and neonatal pathology. Cases of spontaneous abortions, oligohydramnios, and impaired renal function in newborns have been described with unintentional use of valsartan in pregnant women. There are insufficient data on the use of amlodipine in pregnant women to judge its effect on the fetus. If pregnancy is diagnosed during therapy with Sartavel^® Amlo, the drug should be discontinued as soon as possible.

It is not known whether Valsartan and/or Amlodipine pass into breast milk. Since experimental studies have noted the excretion of valsartan in the milk of lactating animals, it is not recommended to use Sartavel^® Amlo during breastfeeding.

If it is necessary to take the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (>9 points on the Child-Pugh scale), biliary cirrhosis, cholestasis.

Use in Renal Impairment

For patients with mild or moderate renal impairment (CrCl >30 ml/min), no adjustment of the initial dose of the drug is required.

The use of the drug is contraindicated in severe renal impairment (CrCl less than 30 ml/min).

Pediatric Use

The drug is contraindicated for use under the age of 18 years (efficacy and safety have not been established).

Geriatric Use

No dose adjustment of the drug is required for patients over 65 years of age.

Special Precautions

Sodium deficiency and/or reduced CBV

In patients with uncomplicated arterial hypertension, marked arterial hypotension was observed in 0.4% of cases. In patients with activated RAAS (e.g., with CBV and/or sodium deficiency in patients receiving high doses of diuretics), symptomatic arterial hypotension may develop when taking ARAs. Before starting treatment with Sartavel^® Amlo, sodium levels and/or CBV should be corrected, or therapy should be initiated under close medical supervision. If arterial hypotension develops, the patient should be placed in a supine position with legs elevated, and, if necessary, intravenous infusion of 0.9% sodium chloride solution should be performed. After BP stabilization, treatment with Sartavel^® Amlo can be continued.

Hyperkalemia

When using the drug concomitantly with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in blood potassium levels (e.g., heparin), caution should be exercised and regular monitoring of blood potassium levels should be performed.

Renal artery stenosis

In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, taking Sartavel^® Amlo may be accompanied by an increase in serum urea and creatinine concentrations, so the drug should be used with caution in such patients.

Renal impairment

No dose adjustment of Sartavel^® Amlo is required for patients with mild to moderate renal impairment.

Hepatic impairment

Valsartan is primarily eliminated unchanged via the intestine with bile, while Amlodipine is extensively metabolized in the liver. Caution should be exercised when using Sartavel^® Amlo in patients with liver diseases (especially with obstructive biliary tract diseases) accompanied by impaired liver function.

Angioedema

Angioedema, including laryngeal and vocal cord edema leading to airway obstruction, and/or edema of the face, lips, pharynx, and/or tongue, has occurred in patients taking Valsartan; in some of these patients, angioedema had previously occurred while using other drugs, including ACE inhibitors. Administration of Sartavel^® Amlo in case of angioedema development should be immediately discontinued; resumption of Sartavel^® Amlo is prohibited.

Heart failure, condition after myocardial infarction

It is recommended to use calcium channel blockers (including Amlodipine) with caution in patients with chronic heart failure NYHA functional class III-IV. In patients whose renal function depends on the activity of the RAAS, therapy with ACE inhibitors and ARAs may be accompanied by the development of oliguria and/or progressive azotemia, and, in rare cases, acute renal failure and/or death. Assessment of patients with heart failure or after myocardial infarction should include assessment of renal function.

Acute myocardial infarction

After initiation of therapy (or dose increase) with amlodipine, an angina attack or myocardial infarction may occur, especially in patients with severe coronary artery disease.

Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy

As with the use of other vasodilators, caution should be exercised when using amlodipine in patients with aortic or mitral valve stenosis or with hypertrophic obstructive cardiomyopathy.

Effect on ability to drive vehicles and operate machinery

There are no data on the effect of the drug on the ability to drive vehicles and operate machinery. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Overdose

Symptoms there are currently no data on cases of drug overdose. With an overdose of valsartan, a marked decrease in BP accompanied by dizziness can be expected. Overdose of amlodipine may lead to excessive peripheral vasodilation and possible reflex tachycardia. The occurrence of marked and prolonged systemic arterial hypotension up to the development of shock with a fatal outcome has also been reported.

Treatment induce vomiting (if the drug was taken recently) or perform gastric lavage. The use of activated charcoal in healthy volunteers immediately or within 2 hours after taking amlodipine significantly reduced its absorption. In case of clinically significant decrease in BP caused by Sartavel^® Amlo, the patient should be placed in a supine position, legs elevated, and active measures should be taken to maintain cardiovascular activity, including regular monitoring of heart and respiratory function, CBV, and urine output. If there are no contraindications, a vasoconstrictor may be used (with caution) to restore vascular tone and BP.

Removal of valsartan and amlodipine during hemodialysis is unlikely.

Drug Interactions

Amlodipine

Simvastatin. Concomitant long-term use of simvastatin at a dose of 80 mg/day and amlodipine at a dose of 10 mg/day leads to a 77% increase in simvastatin exposure. It is recommended to reduce the dose of simvastatin in patients taking Amlodipine to 20 mg/day.

Inhibitors of the CYP3A4 isoenzyme. When amlodipine is used together with diltiazem in elderly patients, a slowdown in amlodipine metabolism is observed, probably due to inhibition of the CYP3A4 isoenzyme, leading to an approximately 50% increase in amlodipine plasma concentration and an enhancement of the clinical effect. When amlodipine is used together with strong inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, and ritonavir), a pronounced increase in the systemic exposure of amlodipine is possible.

Inducers of the CYP3A4 isoenzyme. Since the use of amlodipine together with inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampicin, grapefruit juice, herbal preparations containing St. John’s wort) may lead to a pronounced decrease in its plasma concentration, the clinical effect of amlodipine should be monitored when used with CYP3A4 isoenzyme inducers. No clinically significant interaction was observed with amlodipine monotherapy with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, Maalox (aluminum- or magnesium-containing antacids, simethicone), cimetidine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

Valsartan

It has been established that valsartan monotherapy has no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, Amlodipine, glibenclamide.

Drugs and substances affecting serum potassium levels when co-administered with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in blood potassium levels (e.g., heparin), caution should be exercised and regular monitoring of blood potassium levels should be performed.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors administration of angiotensin II receptor antagonists concurrently with NSAIDs may lead to a weakening of the antihypertensive effect. In elderly patients, patients with volume depletion (including those receiving diuretic therapy) or with impaired renal function, concurrent administration of angiotensin II receptor antagonists and NSAIDs may lead to an increased risk of worsening renal function. When initiating or changing the regimen of concurrent use of angiotensin II receptor antagonists and NSAIDs, regular monitoring of renal function is recommended.

Transport proteins. Concomitant use of valsartan with inhibitors of the OATP1B1 transport protein (rifampicin, cyclosporine) and with an inhibitor of the MRP2 transport protein (ritonavir) may lead to an increase in the systemic bioavailability of valsartan.

Dual blockade of the RAAS with ARB, ACE inhibitor, or aliskiren use. Concomitant use of angiotensin II receptor antagonists with other drugs affecting the RAAS leads to an increased incidence of arterial hypotension, hyperkalemia, and impaired renal function. Blood pressure, renal function, and plasma electrolyte levels should be monitored when using the drug Amlodipine+Valsartan with other drugs affecting the RAAS. Simultaneous use of drugs containing ARBs, including Sartavel^® Amlo, with other agents affecting the RAAS should be avoided in patients with diabetes mellitus and severe renal impairment.

Lithium preparations. When lithium preparations were used concomitantly with ACE inhibitors and ARBs, a reversible increase in serum lithium levels and a consequent enhancement of lithium toxic manifestations were observed, therefore monitoring of serum lithium levels is recommended. The risk of toxic manifestations associated with the use of lithium preparations may be further increased with the concomitant use of Sartavel^® Amlo and diuretics.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years.

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.

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