Corsar® am
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORSAR® AM (CORSAR AM)
Composition:
Active substances: valsartan and amlodipine besylate;
One tablet contains amlodipine besylate (calculated as 100% anhydrous substance) – 6.94 mg, equivalent to amlodipine – 5 mg; valsartan (calculated as 100% anhydrous substance) – 80 mg, or
amlodipine besylate (calculated as 100% anhydrous substance) – 6.94 mg, equivalent to amlodipine – 5 mg; valsartan (calculated as 100% anhydrous substance) – 160 mg, or
amlodipine besylate (calculated as 100% anhydrous substance) – 13.88 mg, equivalent to amlodipine – 10 mg; valsartan (calculated as 100% anhydrous substance) – 160 mg;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Film-coating for 5 mg/80 mg tablets: Opadry II 85F 220088 Yellow (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172), red iron oxide (E 172));
Film-coating for 5 mg/160 mg tablets: Opadry II 85F 220088 Yellow (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172), red iron oxide (E 172));
Film-coating for 10 mg/160 mg tablets: Opadry II 85F 220087 Yellow (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172), red iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
5 mg/80 mg tablets: round, biconvex, film-coated tablets, yellow-brown in color;
5 mg/160 mg tablets: round, biconvex, film-coated tablets, yellow-brown in color;
10 mg/160 mg tablets: round, biconvex, film-coated tablets with a score line on one side, light yellow with a brownish tint.
Pharmacotherapeutic group. Combined angiotensin II inhibitors.
ATC code C09DB01.
Pharmacological properties.
Pharmacodynamics.
Korsar® AM contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium channel blockers, and valsartan belongs to the class of angiotensin II antagonists. The combination of these ingredients provides an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone.
Amlodipine.
Amlodipine inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscle. The antihypertensive mechanism of amlodipine is due to direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and decreased arterial blood pressure. Experimental data confirm that amlodipine binds at both dihydropyridine and non-dihydropyridine binding sites. Contractile processes in cardiac and vascular smooth muscle depend on the influx of extracellular calcium into these cells through specific ion channels.
After administration of therapeutic doses to patients with arterial hypertension, amlodipine induces vasodilation, leading to reduced arterial blood pressure in both supine and standing positions. This reduction in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels during long-term treatment.
The effect correlates with plasma concentrations in both younger and elderly patients.
In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow without changes in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or walking) in patients with normal ventricular function treated with amlodipine generally show a slight increase in cardiac index without significant effects on dP/dt, or left ventricular end-diastolic pressure or volume. Hemodynamic studies have shown that amlodipine does not exhibit negative inotropic effects when therapeutic doses are administered to healthy animals and humans, even when co-administered with beta-blockers.
Amlodipine does not alter sinus node function or atrioventricular conduction in healthy animals or humans. In clinical trials where amlodipine was used in combination with beta-blockers in patients with arterial hypertension or angina, no changes in electrocardiographic parameters were observed.
Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.
Use in patients with arterial hypertension
In a study evaluating antihypertensive and lipid-lowering therapy for prevention of cardiac events in patients with mild to moderate arterial hypertension and at least one additional risk factor for ischemic heart disease, amlodipine (at doses of 2.5–10 mg daily) or lisinopril (at doses of 10–40 mg daily) as first-line therapy were compared with the thiazide diuretic chlorthalidone (at doses of 12.5–25 mg daily). No significant differences were observed in the incidence of fatal ischemic heart disease or non-fatal myocardial infarction. The incidence of heart failure was significantly higher in the amlodipine group compared to the chlorthalidone group. However, no significant differences in all-cause mortality were observed between the amlodipine and chlorthalidone groups.
Valsartan.
Valsartan is an active, potent, and specific orally administered angiotensin II receptor antagonist. It selectively acts on AT1 receptors, which are predominantly responsible for the effects of angiotensin II. Increased levels of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate unoccupied AT2 receptors, thereby counterbalancing AT1 receptor effects. Valsartan has no partial agonist activity at AT1 receptors and has approximately 20,000 times greater affinity for AT1 receptors than for AT2 receptors.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Due to the lack of effect on ACE and no potentiation of bradykinin or substance P activity, angiotensin II receptor antagonists are generally not associated with cough. In clinical trials comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower in patients treated with valsartan than in those receiving an ACE inhibitor. In patients who previously experienced dry cough during ACE inhibitor therapy, this adverse effect occurred in 19.5% of cases during valsartan treatment and in 19% of cases during thiazide diuretic treatment, whereas cough occurred in 68.5% of cases in the group receiving ACE inhibitor therapy. Valsartan does not interact with or block receptors of other hormones or ion channels known to play important roles in cardiovascular regulation.
Administration of the drug to patients with arterial hypertension results in reduced blood pressure without affecting pulse rate.
In most patients, after a single oral dose, onset of antihypertensive activity occurs within 2 hours, and maximal reduction in blood pressure is achieved within 4–6 hours.
The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, maximal therapeutic effect is usually achieved within 2–4 weeks and is maintained during long-term therapy. Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical events.
Valsartan has been shown to significantly reduce hospitalization rates in patients with chronic heart failure (NYHA class II–IV). A more pronounced effect was observed in patients not receiving ACE inhibitors or beta-blockers. Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular pathology or left ventricular dysfunction following myocardial infarction.
According to study data, concomitant use of ACE inhibitors and angiotensin receptor antagonists (ARAs) is not recommended in patients with diabetic nephropathy due to an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. In studies evaluating the utility of adding aliskiren to ACE inhibitor/ARA therapy in patients with type 2 diabetes, chronic kidney disease, cardiovascular disease, or a combination of these conditions, an increased risk of treatment complications, adverse events, and serious adverse events of special interest (hyperkalemia, hypotension, and renal function impairment) was observed with aliskiren use.
Valsartan/amlodipine.
The combination of amlodipine and valsartan provides dose-dependent additive reduction in blood pressure across the entire therapeutic dose range. The antihypertensive effect after a single dose persists for 24 hours.
The valsartan/amlodipine combination has been studied in trials involving patients with uncomplicated mild to moderate essential hypertension, excluding those at high cardiovascular risk. Blood pressure normalization was achieved in patients whose blood pressure was not adequately controlled with monotherapy using 160 mg valsartan. Blood pressure was normalized in 75% of patients receiving 10 mg/160 mg amlodipine/valsartan, in 62% of patients receiving 5 mg/160 mg amlodipine/valsartan, compared to 53% of patients receiving 160 mg valsartan alone. Adding 10 mg and 5 mg amlodipine resulted in additional reductions in systolic/diastolic blood pressure compared to patients receiving 160 mg valsartan alone.
When valsartan was added, blood pressure normalization was achieved in patients whose blood pressure was not adequately controlled with 10 mg amlodipine monotherapy. Blood pressure was normalized in 78% of patients receiving 10 mg/160 mg amlodipine/valsartan compared to 67% of patients continuing 10 mg amlodipine alone. Adding 160 mg valsartan resulted in additional reductions in systolic/diastolic blood pressure compared to patients receiving 10 mg amlodipine alone.
The amlodipine/valsartan combination at doses from 5 mg/160 mg to 10 mg/160 mg more effectively reduces sustained arterial blood pressure in patients with essential hypertension compared to the lisinopril/hydrochlorothiazide regimen at doses from 10 mg/12.5 mg to 20 mg/12.5 mg.
The efficacy of the valsartan/amlodipine combination has been demonstrated to persist for more than 1 year. Abrupt discontinuation of the drug did not lead to rapid rebound in blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may provide similar blood pressure control with reduced edema.
Data indicate that age, sex, race, and body mass index (≥ 30 kg/m², < 30 kg/m²) do not influence the clinical response to the valsartan/amlodipine combination.
Studies of the valsartan/amlodipine combination have not been conducted in populations other than patients with arterial hypertension. However, studies with valsartan have included patients with heart failure and post-myocardial infarction. Studies with amlodipine have included patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.
Pharmacokinetics.
Linearity.
Valsartan and amlodipine exhibit linear pharmacokinetics.
Amlodipine.
Absorption. After oral administration of therapeutic doses of amlodipine alone, maximum plasma concentration (Cmax) is reached within 6–12 hours. Calculated absolute bioavailability ranges from 64% to 80%. Food intake does not affect amlodipine bioavailability.
Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that in patients with essential hypertension, approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.
Elimination. Amlodipine elimination from plasma is biphasic, with a half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous administration. 10% of the initial amlodipine dose and 60% of amlodipine metabolites are excreted in urine.
Valsartan.
Absorption. After oral administration, Cmax of valsartan in plasma is reached within 2–4 hours. The mean absolute bioavailability of the drug is approximately 23%. Food reduces exposure, as measured by AUC (plasma concentration–time), by approximately 40% and Cmax by 50%, although plasma valsartan concentrations 8 hours after administration are similar between fasting and postprandial groups. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.
Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating limited tissue distribution. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal biotransformation, with only 20% of the dose converted to metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of valsartan AUC), which is pharmacologically inactive.
Elimination. Valsartan exhibits multi-exponential elimination kinetics (half-life T1/2α < 1 hour and T1/2β approximately 9 hours). Valsartan is primarily excreted unchanged in feces (approximately 83% of dose) and urine (approximately 13% of dose). After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is approximately 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Valsartan/amlodipine.
After oral administration of Korsar® AM, Cmax of valsartan and amlodipine in plasma is reached at 3 hours and 6–8 hours, respectively. The rate and extent of absorption of Korsar® AM are bioequivalent to the bioavailability of valsartan and amlodipine when administered as separate tablets.
Special populations.
Children
Pharmacokinetic data in children are not available.
Elderly patients (aged 65 years and older)
Time to reach Cmax of amlodipine in plasma is approximately the same in younger and elderly patients. In elderly patients, amlodipine clearance tends to be reduced, leading to increased AUC and prolonged elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly individuals than in younger patients; therefore, caution is required when increasing the dose.
Renal impairment.
Renal function impairment does not significantly affect amlodipine pharmacokinetics. As expected for a compound with only 30% of total plasma clearance being renal clearance, no correlation was observed between renal function status and systemic exposure to valsartan.
Hepatic impairment.
In patients with hepatic impairment, amlodipine clearance is reduced, leading to an increase in AUC by approximately 40–60%. On average, exposure to valsartan (as measured by AUC) in patients with mild to moderate chronic liver disease is approximately twice that in healthy volunteers (matched for age, sex, and body weight). Patients with liver disease should use the drug with caution.
Clinical Characteristics.
Indications.
Essential hypertension in adult patients whose blood pressure is not controlled by monotherapy with amlodipine or valsartan.
Contraindications.
- Hypersensitivity to the active substance, dihydropyridine derivatives, or to any of the excipients of the medicinal product.
- Severe hepatic impairment, biliary cirrhosis, or cholestasis.
- Concomitant use of angiotensin II receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).
- Pregnancy and women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
- Severe hypotension.
- Shock (including cardiogenic shock).
- Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
- Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Interactions common to the combination
No drug interaction studies have been conducted with Corsar® AM and other medicinal products.
Medicinal products requiring caution when used concomitantly
Other antihypertensive agents
Commonly used antihypertensive agents (e.g., alpha-blockers, diuretics) and other medicinal products that may cause hypotensive adverse effects (e.g., tricyclic antidepressants, alpha-blockers used for the treatment of benign prostatic hyperplasia) may potentiate the antihypertensive effect of the combination.
Interactions related to amlodipine
Concomitant use not recommended
Grapefruit or grapefruit juice
The use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients bioavailability may be increased, leading to an enhanced hypotensive effect of the drug.
Medicinal products requiring caution when used concomitantly
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in systemic exposure to amlodipine. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.
CYP3A4 inducers (anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum))
When known CYP3A4 inducers are used concomitantly, plasma concentrations of amlodipine may be altered. Therefore, blood pressure should be monitored and dosage adjusted during and after concomitant use, especially with potent CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum).
Simvastatin
Repeated administration of 10 mg amlodipine with 80 mg simvastatin results in a 77% increase in simvastatin exposure compared to simvastatin alone. It is recommended to reduce the daily dose of simvastatin to 20 mg in patients taking amlodipine.
Dantrolene (infusions)
In animal studies, fatal cases of ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients predisposed to malignant hyperthermia and during treatment of malignant hyperthermia.
Other
In clinical studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.
Interactions related to valsartan
Concomitant use not recommended
Lithium
When lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists, including valsartan, reversible increases in serum lithium concentrations and lithium toxicity have been reported. Concomitant use of valsartan and lithium is not recommended. If such combination therapy is necessary, serum lithium levels should be closely monitored. The risk of increased lithium toxicity may be further elevated when combining Corsar® AM with diuretics.
Potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels
When medicinal products that affect potassium channels are prescribed in combination with valsartan, frequent monitoring of plasma potassium levels should be anticipated.
Medicinal products requiring caution when used concomitantly
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
Concomitant use of angiotensin II antagonists and NSAIDs may reduce the antihypertensive effect. Additionally, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, at the start of treatment, monitoring of renal function and ensuring adequate hydration of the patient are recommended.
Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir)
In vitro studies using human liver tissue have shown that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) may increase systemic exposure to valsartan.
Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren
Clinical trial data have shown that dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent affecting the RAAS. Therefore, concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).
Other
Clinically significant drug interactions with the following agents have not been established during monotherapy with valsartan: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide.
Special precautions for use.
The safety and efficacy of amlodipine in the treatment of hypertensive crisis have not been established.
Patients with sodium and/or circulating blood volume deficiency.
Excessive hypotension has been observed in patients with uncomplicated arterial hypertension during treatment with the valsartan/amlodipine combination in placebo-controlled studies. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (RAS) (with reduced sodium content and/or volume, or receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition is recommended before initiating therapy with Corzar® AM, or close medical supervision at the beginning of treatment.
In case of arterial hypotension during Corzar® AM therapy, the patient should be placed in a supine position and, if necessary, intravenous infusion of physiological saline should be administered. Therapy may be continued after stabilization of blood pressure.
Hyperkalemia.
Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin, etc.) should be used with caution, and frequent monitoring of serum potassium levels is recommended.
Renal artery stenosis.
Corzar® AM should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.
Renal transplantation.
Experience with the safe use of Corzar® AM in patients who have recently undergone kidney transplantation is lacking.
Hepatic impairment.
Valsartan is primarily eliminated unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC (plasma concentration–time) is higher in patients with hepatic impairment; dosage recommendations have not been established. Particular caution is required when administering Corzar® AM to patients with mild to moderate hepatic dysfunction or obstructive biliary disorders.
The maximum recommended dose for patients with mild or moderate hepatic impairment without cholestasis is 80 mg of valsartan.
Renal impairment.
No dose adjustment is required in patients with mild or moderate renal impairment (eGFR >30 mL/min/1.73 m²). In patients with moderate renal impairment, monitoring of serum potassium and creatinine levels is recommended.
Concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren is contraindicated in patients with renal impairment (eGFR <60 mL/min/1.73 m²).
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism should not receive the angiotensin II antagonist valsartan, as their renin-angiotensin system is disrupted due to the underlying disease.
Angioedema.
Angioedema, including laryngeal edema and edema of the glottis, which may lead to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, has been observed in patients taking valsartan. Some of these patients had a history of angioedema while taking other drugs, including angiotensin-converting enzyme inhibitors (ACE inhibitors). Corzar® AM should be discontinued immediately if angioedema occurs; re-administration is not recommended.
Intestinal angioedema.
Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.
Heart failure/post-myocardial infarction.
Due to suppression of the renin-angiotensin-aldosterone system (RAAS), renal dysfunction may occur in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists has led to oliguria and/or progressive azotemia, and in rare cases, acute renal failure and/or death. Similar outcomes have been observed with valsartan. Renal function should be assessed in patients with heart failure or post-myocardial infarction.
In a study of amlodipine in patients with NYHA class III and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine compared to placebo, although there was no significant difference in the development or worsening of heart failure. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.
Aortic and mitral valve stenosis.
As with other vasodilators, particular caution is required in patients with diagnosed mitral valve stenosis or severe aortic stenosis of low degree.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Data indicate that concomitant use of ACE inhibitors, ARBs, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren is not recommended.
If dual blockade is absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolyte concentrations, and blood pressure. Concomitant use of ACE inhibitors and ARBs is not recommended in patients with diabetic nephropathy.
The use of the valsartan/amlodipine combination has not been studied in patients with conditions other than arterial hypertension.
Use during pregnancy or breastfeeding.
Pregnancy
This medicinal product is contraindicated in pregnant women or women who are planning to become pregnant. If pregnancy is confirmed during treatment with this product, therapy should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.
Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Although controlled epidemiological data on angiotensin II receptor antagonists (ARBs) are lacking, a similar risk may exist with drugs of this class.
Exposure to ARBs during the second and third trimesters is known to have toxic effects on the human fetus (impaired renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalemia).
If ARBs have been used from the second trimester of pregnancy onwards, ultrasound monitoring of fetal renal function and skull ossification is recommended.
Newborns whose mothers received ARBs should be closely monitored for the development of arterial hypotension.
Breastfeeding
Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant is estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.
Due to the lack of information on the use of the valsartan/amlodipine combination during breastfeeding, the product is not recommended during this period. Alternative drugs with a well-established safety profile should be considered, especially when breastfeeding newborns or preterm infants.
Fertility
Clinical studies on the effect on fertility have not been conducted.
Valsartan
Valsartan did not cause adverse effects on the reproductive system in male and female rats following oral administration at doses up to 200 mg/kg/day. This dose is 6 times higher than the maximum recommended human dose on a mg/m² basis (based on a 320 mg daily dose for a 60 kg patient).
Amlodipine
In some patients treated with calcium channel blockers, reversible biochemical changes in sperm heads have been reported. Clinical data on the effect of amlodipine on fertility are insufficient. In one study in rats, adverse effects on male fertility were observed.
Ability to influence reaction speed when driving or operating machinery.
Dizziness or weakness may occur in patients taking Corzar® AM after administration of the drug; therefore, patients should take this into account when driving or operating potentially hazardous machinery.
Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea during treatment with amlodipine, their reaction time may be impaired.
Method of Administration and Dosage
Patients whose blood pressure is not adequately controlled with monotherapy using amlodipine or valsartan may be switched to combination therapy with the medication Corzar® AM. The recommended dose is 1 tablet per day. Corzar® AM tablets can be taken independently of food intake. It is recommended to take Corzar® AM with a small amount of water. Tablets must not be divided.
Patients currently receiving separate treatment with valsartan and amlodipine may be switched to Corzar® AM containing equivalent doses of the components.
Before switching to fixed-dose combination therapy, individual dose titration with the separate components (i.e., amlodipine and valsartan) is recommended. However, direct substitution of monotherapy with fixed-dose combination therapy may be considered if clinically indicated.
Maximum daily dose: 1 tablet of Corzar® AM 5 mg/80 mg, or 1 tablet of Corzar® AM 5 mg/160 mg, or 1 tablet of Corzar® AM 10 mg/160 mg (maximum allowable component doses are 10 mg amlodipine and 320 mg valsartan).
Dosage in Specific Patient Populations
Renal Impairment
There are no available clinical data on the use of Corzar® AM in patients with severe renal impairment.
Dose adjustment is not required in patients with mild or moderate renal impairment. In patients with moderate renal impairment, monitoring of serum potassium and creatinine levels is recommended.
Concomitant use of Corzar® AM with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).
Diabetes Mellitus
Concomitant use of Corzar® AM with aliskiren is contraindicated in patients with diabetes mellitus.
Hepatic Impairment
Corzar® AM is contraindicated in patients with severe hepatic impairment.
Corzar® AM should be used with caution in patients with hepatic impairment or biliary obstruction. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan.
Dosage recommendations for amlodipine in patients with mild or moderate hepatic impairment have not been established. When switching elderly patients with hypertension (see section "Indications") and hepatic impairment to amlodipine or Corzar® AM, the lowest recommended dose of amlodipine used in monotherapy or in combination therapy should be initiated.
Elderly Patients (aged 65 years and older)
Standard dosing regimens are recommended for elderly patients.
Caution should be exercised when increasing the dose in elderly patients.
When switching elderly patients with hypertension (see section "Indications") and hepatic impairment to amlodipine or Corzar® AM, the lowest recommended dose of amlodipine in monotherapy or in combination therapy should be initiated.
Pediatric Populations
The safety and efficacy of the valsartan/amlodipine combination in children (under 18 years of age) have not been established. Data are lacking.
Children
Studies on the treatment of children (under 18 years of age) with this medication have not been conducted. Therefore, until more complete information becomes available, Corzar® AM is not recommended for use in pediatric patients.
Overdose
Symptoms
There is currently no experience with overdose of the valsartan/amlodipine combination. The principal symptom of valsartan overdose is likely to be marked hypotension with dizziness. Overdose with amlodipine may lead to progressive peripheral vasodilation and possibly reflex tachycardia. Profound and potentially prolonged systemic hypotension has been reported, up to and including shock and fatal outcomes.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Factors contributing to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.
Treatment
If ingestion was recent, induce emesis or perform gastric lavage. Absorption of amlodipine is significantly reduced when activated charcoal is administered immediately or within 2 hours after amlodipine intake.
Clinically significant hypotension caused by Corzar® AM overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the limbs, and careful attention to circulating fluid volume and urinary output. A vasoconstrictor agent may be used to restore vascular tone and blood pressure, provided there are no contraindications to its use. In cases of persistent hypotension due to calcium channel blockade, intravenous calcium gluconate may be beneficial.
Hemodialysis is unlikely to effectively remove valsartan or amlodipine from the body.
Adverse reactions.
The safety of the valsartan/amlodipine combination was evaluated during clinical trials. The most commonly observed or significant or severe adverse reactions were: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, edema, soft tissue edema, facial edema, peripheral edema, increased fatigue, facial flushing, asthenia, and hot flushes.
The following criteria were used to assess the frequency of adverse reactions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); unknown (frequency cannot be estimated from available data).
| MedDRA system organ class |
Adverse reaction |
Frequency |
||
| Valsartan/ amlodipine |
Amlodipine |
Valsartan |
||
| Infections and infestations |
Nasopharyngitis |
Common |
-- |
-- |
| Influenza |
Common |
-- |
-- |
|
| Blood and lymphatic system disorders |
Decreased hemoglobin and hematocrit levels |
-- |
-- |
Unknown |
| Leukopenia |
-- |
Very rare |
-- |
|
| Neutropenia |
-- |
-- |
Unknown |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Unknown |
|
| Immune system disorders |
Hypersensitivity |
Uncommon |
Very rare |
Unknown |
| Nutritional and metabolism disorders |
Anorexia |
Uncommon |
-- |
-- |
| Hypercalcemia |
Uncommon |
-- |
-- |
|
| Hypoglycemia |
-- |
Very rare |
-- |
|
| Hyperlipidemia |
Uncommon |
-- |
-- |
|
| Hyperuricemia |
Uncommon |
-- |
-- |
|
| Hypokalemia |
Common |
-- |
-- |
|
| Hyponatremia |
Uncommon |
-- |
-- |
|
| Psychiatric disorders |
Depression |
-- |
Uncommon |
-- |
| Anxiety |
Uncommon |
-- |
-- |
|
| Insomnia/sleep disorders |
-- |
Uncommon |
-- |
|
| Mood swings |
-- |
Uncommon |
-- |
|
| Confusion |
-- |
Uncommon |
-- |
|
| Nervous system disorders |
Coordination disorder |
Uncommon |
-- |
-- |
| Dizziness |
Uncommon |
Common |
-- |
|
| Postural dizziness |
Uncommon |
-- |
-- |
|
| Dysgeusia |
-- |
Uncommon |
-- |
|
| Extrapyramidal syndrome |
-- |
Unknown |
-- |
|
| Headache |
Common |
Common |
-- |
|
| Hypertension |
-- |
Very rare |
-- |
|
| Paraesthesia |
Uncommon |
Uncommon |
-- |
|
| Peripheral neuropathy, neuropathy |
-- |
Very rare |
-- |
|
| Somnolence |
Uncommon |
Common |
-- |
|
| Syncope |
-- |
Uncommon |
-- |
|
| Tremor |
-- |
Uncommon |
-- |
|
| Hypoesthesia |
-- |
Uncommon |
-- |
|
| Eye disorders |
Visual disturbance |
Uncommon |
Uncommon |
-- |
| Blurred vision |
Uncommon |
Uncommon |
-- |
|
| Ear and labyrinth disorders |
Tinnitus |
Uncommon |
Uncommon |
-- |
| Dizziness |
Uncommon |
-- |
Uncommon |
|
| Cardiac disorders |
Palpitations |
Uncommon |
Common |
-- |
| Syncope |
Uncommon |
-- |
-- |
|
| Tachycardia |
Uncommon |
-- |
-- |
|
| Arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation) |
-- |
Very rare |
-- |
|
| Myocardial infarction |
-- |
Very rare |
-- |
|
| Vascular disorders |
Flushing |
-- |
Common |
-- |
| Hypotension |
Uncommon |
Uncommon |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
|
| Vasculitis |
-- |
Very rare |
Unknown |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Very rare |
Very rare |
| Dyspnea |
-- |
Uncommon |
-- |
|
| Pharyngolaryngeal pain |
Uncommon |
-- |
-- |
|
| Rhinitis |
-- |
Uncommon |
-- |
|
| Gastrointestinal disorders |
Abdominal discomfort and upper abdominal pain |
Uncommon |
Common |
Uncommon |
| Change in defecation rhythm |
-- |
Uncommon |
-- |
|
| Constipation |
Uncommon |
-- |
-- |
|
| Diarrhea |
Uncommon |
Uncommon |
-- |
|
| Dry mouth |
Uncommon |
Uncommon |
-- |
|
| Dyspepsia |
-- |
Uncommon |
-- |
|
| Gastritis |
-- |
Very rare |
-- |
|
| Gingival hyperplasia |
-- |
Very rare |
-- |
|
| Nausea |
Uncommon |
Common |
-- |
|
| Pancreatitis |
-- |
Very rare |
-- |
|
| Vomiting |
-- |
Uncommon |
-- |
|
| Intestinal angioedema |
-- |
-- |
Very rare |
|
| Hepatobiliary disorders |
Atypical liver function tests, including increased blood bilirubin levels |
-- |
Very rare* |
Unknown |
| Hepatitis |
-- |
Very rare |
-- |
|
| Intrahepatic cholestasis, jaundice |
-- |
Very rare |
-- |
|
| Skin and subcutaneous tissue disorders |
Alopecia |
-- |
Uncommon |
-- |
| Angioedema |
-- |
Very rare |
Unknown |
|
| Bullous dermatitis |
-- |
-- |
Unknown |
|
| Erythema |
Uncommon |
-- |
-- |
|
| Multiform erythema |
-- |
Very rare |
-- |
|
| Exanthema |
Uncommon |
Uncommon |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
|
| Photosensitivity reactions |
-- |
Uncommon |
-- |
|
| Pruritus |
Uncommon |
Uncommon |
Unknown |
|
| Purpura |
-- |
Uncommon |
-- |
|
| Rash |
Uncommon |
Uncommon |
Unknown |
|
| Skin discoloration |
-- |
Uncommon |
-- |
|
| Urticaria and other forms of rash |
-- |
Very rare |
-- |
|
| Exfoliative dermatitis |
-- |
Very rare |
-- |
|
| Stevens-Johnson syndrome |
-- |
Very rare |
-- |
|
| Quincke's edema |
-- |
Very rare |
-- |
|
| Toxic epidermal necrolysis |
-- |
Unknown |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
Uncommon |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
|
| Muscle pain |
-- |
Uncommon |
Unknown |
|
| Ankle swelling |
-- |
Common |
-- |
|
| Heaviness sensation |
Uncommon |
-- |
-- |
|
| Renal and urinary disorders |
Increase in blood creatinine levels |
-- |
-- |
Unknown |
| Urination disorder |
-- |
Uncommon |
-- |
|
| Nocturia |
-- |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
-- |
-- |
|
| Renal failure and kidney function disorders |
-- |
-- |
Unknown |
|
| Reproductive system disorders |
Impotence |
-- |
Uncommon |
-- |
| Erectile dysfunction |
Uncommon |
-- |
-- |
|
| Gynecomastia |
-- |
Uncommon |
-- |
|
| General disorders |
Asthenia |
Common |
Uncommon |
-- |
| Discomfort, malaise |
-- |
Uncommon |
-- |
|
| Increased fatigue |
Common |
Common |
Uncommon |
|
| Facial swelling |
Common |
-- |
-- |
|
| Flushing, hot flushes |
Common |
-- |
-- |
|
| Chest pain, not cardiac |
-- |
Uncommon |
-- |
|
| Edema |
Common |
Common |
-- |
|
| Peripheral edema |
Common |
-- |
-- |
|
| Pain |
-- |
Uncommon |
-- |
|
| Soft tissue swelling |
Common |
-- |
-- |
|
| Investigations |
Increase in blood potassium levels |
-- |
-- |
Unknown |
| Increased body weight |
-- |
Uncommon |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
|
* Mainly associated with cholestasis.
Additional information regarding the combination.
Peripheral edema, a known adverse effect of amlodipine, was generally reported at a lower frequency in patients receiving the amlodipine/valsartan combination than with amlodipine alone. The average incidence of peripheral edema, evenly distributed across the entire dose range, was 5.1% for the amlodipine/valsartan combination.
Additional information regarding the components of the medicinal product.
Adverse reactions previously observed with either component of the medicinal product (amlodipine or valsartan) may also occur with the use of the medicinal product Korzal® AM, even if they were not reported during clinical studies or in the post-marketing period.
Amlodipine.
| Common |
Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling. |
| Uncommon |
Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypesthesia, visual disturbances (including diplopia), tinnitus, hypotension, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, urinary disorders, increased frequency of urination, impotence, gynecomastia, chest pain, malaise, weight gain or weight loss. |
| Rare |
Confusion. |
| Very rare Unknown |
Leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertension, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased liver enzyme levels, usually associated with cholestasis, angioneurotic edema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity. Toxic epidermal necrolysis. |
Individual cases of extrapyramidal syndrome have been reported.
Valsartan.
The additional adverse reactions listed below have been observed during clinical trials of valsartan monotherapy, regardless of causal relationship to the investigational drug.
| Frequency unknown |
Decreased hemoglobin levels, decreased hematocrit levels, neutropenia, thrombocytopenia, increased serum potassium levels, increased liver function tests, including serum bilirubin concentration, renal failure and impaired kidney function, increased serum creatinine levels, angioedema, myalgia, vasculitis, hypersensitivity reactions, including serum sickness. |
Reporting of suspected adverse reactions.
Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Packaging. 10 tablets in a blister. 3, 5, or 6 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Farmak".
Manufacturer's address.
74 Kyrylivska Street, Kyiv, 04080, Ukraine.