Amlodipine + Valsartan (Tablets) Instructions for Use

ATC Code

C09DB01 (Valsartan and Amlodipine)

Active Substances

Valsartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined antihypertensive drug (slow calcium channel blocker + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Combined antihypertensive agent (slow calcium channel blocker + angiotensin II receptor antagonist)

Pharmacological Action

A combined antihypertensive drug containing: Amlodipine (a dihydropyridine derivative) and Valsartan (an angiotensin II receptor antagonist). The combination of these components has a mutually complementary antihypertensive effect, leading to a more pronounced reduction in blood pressure than when they are used separately.

The clinical efficacy of the Amlodipine/Valsartan combination has been proven in patients with mild to moderate arterial hypertension (mean diastolic BP ≥95 mm Hg and <110 mm Hg) without complications compared to placebo. The level of BP reduction in the sitting position in arterial hypertension with diastolic BP ≥110 mm Hg and <120 mm Hg is comparable to the use of a combination of an ACE inhibitor and a thiazide diuretic. When using the Amlodipine/Valsartan combination, comparable BP control is achieved with a lower likelihood of developing peripheral edema in patients with previously achieved BP control and significant peripheral edema during amlodipine therapy.

When taking the Amlodipine/Valsartan combination in a single dose, the hypotensive effect persists for 24 hours. The antihypertensive effect is long-lasting. Sudden discontinuation of the drug is not accompanied by a sharp increase in BP (no withdrawal syndrome). Therapeutic efficacy does not depend on the patient’s age, sex, race, or BMI.

Amlodipine is a dihydropyridine derivative, a calcium channel blocker. It has antianginal and hypotensive effects. It inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells. The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells. The mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects: it causes dilation of peripheral arterioles, reducing total peripheral resistance (afterload), which leads to a decrease in myocardial oxygen demand; it causes dilation of coronary arteries and arterioles in both intact and ischemic areas of the myocardium, increasing oxygen delivery to the myocardium, including in patients with Prinzmetal’s angina. Amlodipine reduces the severity of left ventricular hypertrophy. It does not affect myocardial contractility and conduction, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect.

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in BP (in the supine and standing positions) over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical. In patients with angina, taking amlodipine once a day increases exercise tolerance, time to onset of angina attack and to ischemic ST segment depression, and reduces the frequency of angina attacks and the need for nitroglycerin (short-acting forms).

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

Amlodipine does not have an undesirable effect on lipid metabolism and does not cause changes in the plasma lipid profile. Amlodipine can be used in patients with bronchial asthma, diabetes mellitus, and gout.

After a single oral dose, the effect of amlodipine begins in 2-4 hours and lasts for 24 hours. The maximum hypotensive effect is achieved no earlier than 4 weeks from the start of taking the drug. The hemodynamic effects of the drug remain unchanged with long-term use.

Valsartan is a selective orally active antagonist of angiotensin II (type AT₁) receptors. It selectively blocks AT₁ subtype receptors, which are responsible for the effects of angiotensin II. An increase in the plasma concentration of angiotensin II due to the blockade of AT₁ receptors under the action of valsartan may stimulate unblocked AT₂ subtype receptors, which counteract the effects of AT₁ receptor stimulation. Valsartan does not possess agonistic activity towards AT₁ receptors. The affinity of valsartan for AT₁ subtype receptors is approximately 20,000 times higher than for AT₂ subtype receptors.

Valsartan does not interact with or block receptors of other hormones or ion channels involved in the regulation of cardiovascular function.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and breaks down bradykinin. Due to the lack of effect on ACE, the effects of bradykinin or substance P are not potentiated, so the development of dry cough is unlikely when using angiotensin II receptor antagonists. It has been proven that the incidence of dry cough during treatment with valsartan is significantly lower than when using ACE inhibitors. In the treatment of arterial hypertension, Valsartan reduces BP without affecting heart rate.

After a single oral dose of valsartan, the hypotensive effect develops within 2 hours, and the maximum reduction in BP is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours after its administration. With repeated use of valsartan, the maximum reduction in BP, regardless of the dose, is achieved after 2-4 weeks and is maintained at the achieved level during long-term therapy. Sudden discontinuation of valsartan is not accompanied by a significant increase in BP or other adverse events (withdrawal syndrome).

Pharmacokinetics

The pharmacokinetics of amlodipine and valsartan are linear.

Amlodipine/Valsartan

After oral administration of the Amlodipine/Valsartan combination, the C_max of valsartan and amlodipine in plasma is reached after 3 hours and 6-8 hours, respectively. The rate and extent of absorption are equivalent to the bioavailability of valsartan and amlodipine when each is taken separately.

Amlodipine

After oral administration, Amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of amlodipine. C_max in plasma is reached 6-12 hours after administration. The mean absolute bioavailability is 64-80%. The mean V_d is 21 L/kg of body weight, indicating that most of the amlodipine is in the tissues and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. C_ss in plasma is achieved after 7-8 days of continuous amlodipine use. Amlodipine crosses the blood-brain barrier and the placental barrier.

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity.

After a single dose of amlodipine, T_1/2 ranges from 35 to 50 hours; with repeated use, it is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys, mainly in the form of metabolites, 10% unchanged, and 20-25% through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg). Amlodipine is not removed by hemodialysis.

Prolongation of T_1/2 in patients with hepatic impairment suggests that with long-term use, the accumulation of amlodipine in the body will be higher (increases to 60 hours).

Valsartan

After oral administration of valsartan, C_max is reached in 2-3 hours. The mean absolute bioavailability is 23%. When valsartan is taken with food, a decrease in bioavailability (by AUC value) of approximately 40% is noted, and C_max is reduced by approximately 50%. Approximately 8 hours after oral administration, the plasma concentrations of valsartan in the group of patients taking the drug with food and in the group taking the drug on an empty stomach level out. The reduction in AUC is not clinically significant, so Valsartan can be taken regardless of food intake.

The V_d of valsartan at steady state after IV administration is about 17 L, indicating the absence of extensive distribution of valsartan in tissues. Valsartan is largely bound to serum proteins (94-97%), mainly to serum albumin.

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

Valsartan is excreted in two phases: an α-phase with T_1/2α of less than 1 hour and a β-phase with T_1/2β of about 9 hours. Valsartan is excreted mainly unchanged through the intestine (about 83%) and by the kidneys (about 13%). After IV administration, the plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The T_1/2 of valsartan is 6 hours.

On average, in patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment, the bioavailability (by AUC value) of valsartan is doubled compared to healthy volunteers of the corresponding age, sex, and body weight.

Indications

• Arterial hypertension in patients for whom combination therapy with amlodipine and valsartan is indicated.

ICD codes

Dosage Regimen

Tablets

The drug should be taken orally, once a day, regardless of meals, with a small amount of water.

The recommended daily dose is 1 tablet of the drug containing the Amlodipine/Valsartan combination in a dose of 5 mg/80 mg, 5 mg/160 mg, 10 mg/160 mg, 5 mg/320 mg, or 10 mg/320 mg.

The initial dose of the drug is 5 mg/80 mg once a day. The dose can be increased 1-2 weeks after the start of therapy.

The maximum daily dose is 5 mg/320 mg (in terms of Valsartan) or 10 mg/160 mg (in terms of Amlodipine) or 10 mg/320 mg.

In patients with impaired renal function (CrCl >30 ml/min), adjustment of the initial dose of the drug is not required.

Patients with impaired liver function should use the drug with caution. The maximum daily dose of valsartan in mild to moderate hepatic insufficiency is 80 mg. The drug is contraindicated in patients with severe hepatic insufficiency, biliary cirrhosis, and cholestasis.

In elderly patients, dose adjustment is not required.

Adverse Reactions

Classification of the frequency of side effects according to WHO: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (from <1/10,000), frequency unknown (cannot be estimated from the available data).

Amlodipine/Valsartan

Infections and infestations: common – influenza.

Metabolism and nutrition disorders: common – hypokalemia; uncommon – hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia.

Nervous system disorders: common – headache; uncommon – coordination impaired, dizziness, postural dizziness, paresthesia, somnolence; rare – anxiety.

Eye disorders: uncommon – vision blurred; rare – visual impairment.

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

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

Respiratory, thoracic and mediastinal disorders: common – nasopharyngitis; uncommon – cough, pharyngolaryngeal pain.

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

Skin and subcutaneous tissue disorders: uncommon – erythema, skin rash; rare – exanthema, hyperhidrosis, pruritus.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, joint swelling; rare – muscle spasms, feeling of heaviness in the whole body.

Renal and urinary disorders: rare – pollakiuria, polyuria.

Reproductive system and breast disorders: rare – erectile dysfunction.

Immune system disorders: rare – hypersensitivity.

General disorders and administration site conditions: common – asthenia, increased fatigue, facial edema, feeling of skin flushing, edema, peripheral edema, puffiness; uncommon – anorexia, back pain.

In patients treated with the Amlodipine/Valsartan combination, peripheral edema occurred less frequently (5.8%) than in patients treated with amlodipine monotherapy (9%).

Amlodipine

Common: somnolence, dizziness, palpitations, abdominal pain, nausea, ankle edema.

Uncommon: insomnia, mood changes (including anxiety), depression, tremor, taste perversion, syncope, hypoesthesia, visual disturbances (including diplopia), tinnitus, marked decrease in blood pressure, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, micturition frequency, impotence, gynecomastia, chest pain, malaise, weight increase, weight decrease.

Rare: confusion.

Very rare: leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, muscle hypertonia, peripheral neuropathy, myocardial infarction, arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased liver enzyme activity (most often due to cholestasis), angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.

Isolated cases of extrapyramidal syndrome have been described.

Valsartan

Frequency unknown: decrease in hemoglobin and hematocrit, neutropenia, thrombocytopenia, increased serum potassium, increased liver enzyme activity, increased plasma bilirubin concentration, increased plasma creatinine concentration, impaired renal function, including renal failure, angioedema, myalgia, vasculitis, hypersensitivity, including serum sickness.

Contraindications

• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Biliary cirrhosis and cholestasis;
• Severe renal impairment (CrCl <30 ml/min);
• Use in patients undergoing hemodialysis;
• Severe arterial hypotension (systolic BP <90 mm Hg);
• Collapse, shock (including cardiogenic shock);
• Obstruction of the left ventricular outflow tract (including hypertrophic obstructive cardiomyopathy and severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Concomitant use with aliskiren in patients with diabetes mellitus or impaired renal function (CrCl less than 60 ml/min);
• Primary hyperaldosteronism;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to amlodipine, other dihydropyridine derivatives, valsartan, or other components of the drug.

The safety of using the drug in patients after kidney transplantation, as well as in children and adolescents under 18 years of age, has not been established.

This combination should be prescribed with caution in mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment; obstructive biliary tract diseases; mild to moderate renal impairment (CrCl 30-50 ml/min); unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney; chronic heart failure NYHA class III-IV; hyperkalemia; hyponatremia; adherence to a salt-restricted diet; reduced circulating blood volume (including with diarrhea, vomiting); in patients with hereditary angioedema, or angioedema due to previous therapy with angiotensin II receptor antagonists; in patients with mild to moderate mitral and aortic stenosis.

Use in Pregnancy and Lactation

The use of this combination is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

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

This combination should be prescribed with caution in mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment; obstructive biliary tract diseases.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (CrCl <30 ml/min); in patients undergoing hemodialysis.

This combination should be prescribed with caution in mild to moderate renal impairment (CrCl 30-50 ml/min); unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney.

The safety of using the drug in patients after kidney transplantation has not been established.

Pediatric Use

The safety of using the drug in children and adolescents under 18 years of age has not been established.

Geriatric Use

In elderly patients, dose adjustment is not required.

Special Precautions

In patients with uncomplicated arterial hypertension receiving therapy with the Amlodipine/Valsartan combination, marked arterial hypotension was observed in 0.4% of cases.

In patients with activated RAAS (for example, in patients with dehydration and/or hyponatremia taking high doses of diuretics), symptomatic arterial hypotension may develop when taking angiotensin II receptor antagonists. Before starting treatment, sodium levels should be restored and/or circulating blood volume should be replenished, in particular, by reducing the doses of diuretics, or therapy should be started under close medical supervision.

In case of development of a pronounced decrease in blood pressure, the patient should be placed in a horizontal position with a low headboard and, if necessary, intravenous infusion of 0.9% sodium chloride solution should be performed. Therapy with the drug can be continued after hemodynamic parameters have stabilized.

When used concomitantly with potassium-sparing diuretics, potassium preparations, dietary supplements containing potassium, or other drugs that can increase plasma potassium levels (for example, heparin), caution should be exercised. It is necessary to regularly monitor plasma potassium levels.

The drug should be used with caution in patients with arterial hypertension and unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, considering the possibility of increased serum concentrations of urea and creatinine.

In patients with moderate renal impairment, it is recommended to monitor plasma potassium levels and creatinine concentrations.

Given the involvement of the RAAS in primary hyperaldosteronism, patients in this group should not be prescribed angiotensin II receptor antagonists, including Valsartan.

Among patients with angioedema (including laryngeal and vocal cord edema causing airway obstruction and/or edema of the face, lips, pharynx, and/or tongue) during therapy with the drug, there were indications in the medical history of previous angioedema, including with ACE inhibitors. If angioedema develops, the drug should be discontinued immediately and the possibility of re-administration should be excluded.

In patients whose renal function may depend on the activity of the RAAS (for example, in severe chronic heart failure), therapy with ACE inhibitors and angiotensin II receptor antagonists is accompanied by oliguria and/or increasing azotemia, and in rare cases, by acute renal failure and/or death. Such outcomes have been described with the use of valsartan. In patients with chronic heart failure or a history of myocardial infarction, renal function should always be assessed.

In patients with chronic heart failure of non-ischemic etiology, NYHA functional class III-IV, the use of amlodipine was associated with an increased incidence of pulmonary edema compared with placebo, without a significant difference in the frequency of worsening chronic heart failure between the two groups. Calcium channel blockers, including Amlodipine, should be used with caution in patients with chronic heart failure, as an increased risk of cardiovascular complications and death is possible.

The combination of Amlodipine/Valsartan has been studied only in patients with arterial hypertension.

Effect on the ability to drive vehicles and mechanisms

When using the drug, caution should be exercised when driving vehicles and other technical devices requiring increased concentration and speed of psychomotor reactions, as the development of dizziness, fatigue, and nausea is possible.

Drug Interactions

Amlodipine/Valsartan

Other antihypertensive drugs (for example, alpha-blockers, diuretics) and drugs with hypotensive effects (for example, tricyclic antidepressants, alpha-blockers for the treatment of benign prostatic hyperplasia) may enhance the antihypertensive effect.

Amlodipine

Concomitant use with grapefruit or grapefruit juice is not recommended, considering the possibility of increased bioavailability in some patients and enhanced antihypertensive effect.

Concomitant use with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, verapamil or diltiazem, antifungal agents from the azole group, antibiotics from the macrolide group, such as erythromycin or clarithromycin) may lead to a significant increase in the systemic exposure of amlodipine. In elderly patients, these changes are of clinical significance, therefore medical supervision and dose adjustment are necessary.

Caution should be exercised when used concomitantly with inducers of the CYP3A4 isoenzyme (anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, herbal preparations containing St. John’s wort), as a decrease in the plasma concentration of amlodipine is possible.

Concomitant repeated administration of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg increases the exposure of simvastatin by 77% compared with simvastatin monotherapy. For patients receiving Amlodipine, it is recommended to use simvastatin at a dose not exceeding 20 mg/day.

In experimental studies in animals, after oral administration of verapamil and intravenous administration of dantrolene, cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed. Given the risk of hyperkalemia, the concomitant use of calcium channel blockers, including amlodipine, should be avoided in patients prone to developing malignant hyperthermia.

Clinical studies have not revealed significant interaction 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, NSAIDs, antibiotics, and oral hypoglycemic agents.

Valsartan

Concomitant use of angiotensin II receptor antagonists, including Valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus and renal impairment (creatinine clearance less than 60 ml/min).

Concomitant use with lithium preparations is not recommended, as a reversible increase in plasma lithium concentration and the development of intoxication are possible. If concomitant use with lithium preparations is necessary, plasma lithium concentration should be carefully monitored.

If concomitant use with drugs affecting potassium levels (potassium-sparing diuretics, potassium preparations, potassium-containing dietary supplements and other medicines and substances that can increase serum potassium levels (for example, heparin)) is necessary, it is recommended to monitor plasma potassium levels.

When used concomitantly with NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid at doses greater than 3 g/day, and non-selective NSAIDs, a weakening of the antihypertensive effect, an increased risk of renal function impairment, and an increase in plasma potassium levels are possible. At the start of therapy, it is recommended to assess renal function and correct water and electrolyte balance disorders.

According to in vitro study results, Valsartan is a substrate for the OATP1B1 and MRP2 transporter proteins. Concomitant use of valsartan with inhibitors of the OATP1B1 transporter protein (for example, rifampicin, cyclosporine) and inhibitors of the MRP2 transporter protein (for example, ritonavir) may increase the systemic exposure of valsartan (C_max and AUC). This should be considered at the start and end of concomitant therapy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.