Combisart

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KOMBISART (KOMBISART)

Composition:

Active substances: amlodipine, valsartan;

1 tablet of 5 mg/160 mg contains: amlodipine besylate 6.94 mg, equivalent to 5 mg of amlodipine, valsartan 160 mg;

Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: film-coating mixture Opadry II Yellow (hypromellose (hydroxypropylmethylcellulose), lactose monohydrate, titanium dioxide (E 171), polyethylene glycol (macrogol), iron oxide yellow (E 172));

or

Active substances: amlodipine, valsartan;

1 tablet of 10 mg/160 mg contains: amlodipine besylate 13.87 mg, equivalent to 10 mg of amlodipine, valsartan 160 mg;

Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: film-coating mixture Opadry II Pink (hypromellose (hydroxypropylmethylcellulose), lactose monohydrate, titanium dioxide (E 171), polyethylene glycol (macrogol), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

Tablets 5 mg/160 mg: oval-shaped tablets with a flat surface and bevelled edges, film-coated, light brownish-yellow in colour;

Tablets 10 mg/160 mg: oval-shaped tablets with a flat surface and bevelled edges, film-coated, light pink in colour.

Pharmacotherapeutic group. Combined angiotensin II inhibitors preparations.

ATC code: C09D B01.

Pharmacological properties.

Pharmacodynamics.

Combisart contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine, which belongs to the class of calcium channel blockers, and valsartan, which belongs to the class of angiotensin II antagonists. The combination of these ingredients provides an additive antihypertensive effect and reduces blood pressure to a greater extent than either component alone.

Amlodipine.

Amlodipine inhibits transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells. The antihypertensive mechanism of amlodipine is due to direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and consequent lowering of arterial blood pressure. Experimental data confirm that amlodipine binds to 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 causes vasodilation, leading to reduction in 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 young 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, end-diastolic pressure, or left ventricular volume. Hemodynamic studies have shown that amlodipine has no negative inotropic effect when used at therapeutic doses, even when co-administered with beta-blockers.

Amlodipine does not alter sinus node function or atrioventricular conduction. No changes in electrocardiographic parameters have been observed when amlodipine is used in combination with beta-blockers in patients with arterial hypertension or angina.

Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.

Valsartan.

Valsartan is an active, potent, and specific oral angiotensin II receptor antagonist. It acts selectively on AT1 receptors, which mediate the effects of angiotensin II. Elevated levels of angiotensin II resulting from AT1 receptor blockade by valsartan may stimulate unoccupied AT2 receptors, counterbalancing the effects of AT1 receptor activation. Valsartan has no partial agonist activity at AT1 receptors and has much greater (approximately 20,000 times) affinity for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit ACE (angiotensin-converting enzyme), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Because of its 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 studies comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who had previously been treated with an ACE inhibitor and developed dry cough, this adverse event occurred in 19.5% of cases when treated with valsartan and in 19% of cases when treated with a thiazide diuretic, compared to 68.5% in the group receiving an ACE inhibitor (P < 0.05). Valsartan does not interact with or block receptors of other hormones or ion channels known to play an important role in cardiovascular regulation.

Administration of the drug to patients with arterial hypertension results in reduced blood pressure without affecting heart rate.

In most patients, after oral administration of a single dose, antihypertensive activity begins within 2 hours, and maximal blood pressure reduction is achieved within 4–6 hours.

The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximal therapeutic effect is usually achieved within 2–4 weeks and is maintained at that level during long-term therapy. Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical effects.

It has been established that valsartan significantly reduces 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.

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 of the combination lasts for 24 hours.

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. Absolute bioavailability is estimated to be between 64% and 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution. The volume of distribution is approximately 21 L/kg. In patients with essential hypertension, approximately 97.5% of circulating amlodipine is plasma protein-bound.

Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.

Elimination. Amlodipine is eliminated in a biphasic manner, with a terminal elimination half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous administration. About 10% of unchanged amlodipine and 60% of its 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 valsartan exposure, as measured by AUC (plasma concentration–time), by approximately 40% and Cmax by 50%. However, plasma concentrations of valsartan 8 hours after administration are similar in fasting and postprandial conditions. The reduction in AUC is not associated with clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.

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 about 20% of the dose converted to metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of valsartan AUC) and is pharmacologically inactive.

Elimination. Valsartan exhibits multi-exponential elimination kinetics (elimination 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 Combisart, Cmax of valsartan and amlodipine in plasma are reached at 3 and 6–8 hours, respectively. The rate and extent of absorption of the drug are equivalent to the bioavailability of valsartan and amlodipine when administered as individual agents.

Special populations

Children

Pharmacokinetic data in pediatric patients are lacking.

Elderly patients (aged 65 years and older)

Time to reach Cmax of amlodipine in plasma is similar in younger and elderly patients. In elderly patients, clearance of amlodipine tends to be reduced, leading to increased AUC and prolonged elimination half-life. Mean systemic AUC of valsartan in elderly individuals is 70% higher than in younger patients; therefore, caution is required when increasing the dose.

Renal impairment

Renal function impairment does not significantly affect the pharmacokinetics of amlodipine. For valsartan, whose renal clearance accounts for only 30% of total plasma clearance, no correlation has been observed between renal function status and systemic exposure.

Hepatic impairment

In patients with hepatic insufficiency, clearance of amlodipine is reduced, resulting in 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.
• Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min/1.73 m²); the drug is also contraindicated in patients undergoing dialysis.
• Concomitant use of angiotensin receptor antagonists (ARAs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
• Pregnancy or planned pregnancy (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

Drug-drug interactions

Studies on drug-drug interactions of the medicinal product Combisart with other medicinal products have not been conducted.

Medicinal products requiring caution during concomitant use

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 hypotensive 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 the bioavailability of the drug may be increased, leading to an enhanced hypotensive effect.

Medicinal products requiring caution during concomitant use

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungal agents, 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. A daily simvastatin dose reduction to 20 mg is recommended for patients taking amlodipine.

Dantrolene (infusions)

In animal studies, lethal 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.

Others

Amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.

Interactions related to valsartan

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been observed when lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists, including valsartan. 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 Combisart is used concomitantly with diuretics.

Potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels

When agents affecting potassium levels are prescribed in combination with valsartan, frequent monitoring of plasma potassium levels should be anticipated.

Medicinal products requiring caution during concomitant use

Nonsteroidal 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 result in reduced antihypertensive efficacy. Additionally, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, renal function should be monitored at the start of treatment, and adequate hydration should be ensured.

Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir)

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 ARAs, ACE inhibitors, or aliskiren

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, ARAs, 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 RAAS-acting agent. Therefore, concomitant use of ARAs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).

Others

During monotherapy with valsartan, no clinically significant drug interactions have been observed with the following agents: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.

Special precautions for use.

Patients with sodium and/or circulating blood volume deficiency.

Excessive hypotension was observed in patients with uncomplicated arterial hypertension (0.4%). Symptomatic hypotension may occur in patients with activated renin-angiotensin system (with reduced sodium levels and/or circulating blood volume, or receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition is recommended prior to initiation of therapy with the medicinal product CombiSart, or close medical monitoring at the beginning of treatment.

In case of arterial hypotension during treatment with CombiSart, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Therapy may be continued once blood pressure has stabilized.

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 administered with caution, and frequent monitoring of serum potassium levels is required.

Renal artery stenosis.

CombiSart should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, as serum urea and creatinine levels may increase.

Kidney transplantation.

Experience with the safe use of CombiSart in patients who have recently undergone kidney transplantation is lacking.

Hepatic impairment.

Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC (plasma concentration–time) is increased in patients with hepatic impairment; dosage recommendations have not been established. Particular caution is required when administering CombiSart to patients with mild to moderate hepatic dysfunction or obstructive biliary disorders.

The maximum recommended dose in patients with mild or moderate hepatic impairment without cholestasis is 80 mg of valsartan.

Renal impairment.

Dose adjustment is not 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 already suppressed due to the underlying disease.

Angioedema.

Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or swelling of the face, lips, pharynx, and/or tongue, has been reported in patients taking valsartan. Some of these patients had a history of angioedema during treatment with other drugs, including angiotensin-converting enzyme inhibitors (ACE inhibitors). Administration of CombiSart must be discontinued immediately if angioedema occurs; re-administration is not recommended.

Heart failure/post-myocardial infarction state.

Due to suppression of the renin-angiotensin-aldosterone system, renal dysfunction may occur in susceptible patients. In patients with severe heart failure, in whom renal function may depend on the activity of the renin-angiotensin-aldosterone system, 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 following 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 than with 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 renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren is not recommended.

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and ARBs is not recommended in patients with diabetic nephropathy.

The use of CombiSart has not been studied in patients with conditions other than arterial hypertension.

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 complete symptom resolution.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this product, administration must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the teratogenic risk 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 were used during the second trimester of pregnancy, ultrasound assessment of fetal renal function and skull ossification is recommended.

Infants born to mothers who received ARBs should be closely monitored for the development of arterial hypotension.

Breastfeeding period

Amlodipine is excreted in 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.

Since information on the use of CombiSart during breastfeeding is lacking, the product is not recommended during lactation; alternative drugs with a well-established safety profile should be preferred, 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 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 CombiSart; 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.

Administration and Dosage.

Patients whose blood pressure is not adequately controlled with monotherapy using amlodipine or valsartan alone may be switched to combination therapy with the medicinal product Combisart. The recommended dose is 1 tablet daily. Combisart tablets may be taken independently of food intake. It is recommended to take Combisart with a small amount of water.

Patients currently receiving valsartan and amlodipine separately may be switched to Combisart containing the same component doses.

Prior to switching to a fixed-dose combination, individual dose titration of the components (i.e., amlodipine and valsartan) is recommended. However, in cases of clinical necessity, direct substitution of monotherapy with a fixed-dose combination may be considered.

The maximum daily dose of Combisart is 1 tablet of 5 mg/160 mg or 1 tablet of 10 mg/160 mg (maximum permitted doses of the components are 10 mg amlodipine and 320 mg valsartan).

Dosing for Specific Patient Groups

Renal Impairment

The medicinal product Combisart is contraindicated 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 Combisart with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

Diabetes Mellitus

Concomitant use of Combisart with aliskiren is contraindicated in patients with diabetes mellitus.

Hepatic Impairment

Combisart is contraindicated in patients with severe hepatic impairment. Combisart should be used with caution in patients with mild or moderate hepatic impairment or obstructive biliary disorders.

For patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan.

Dosing recommendations for amlodipine in patients with mild or moderate hepatic impairment have not been established. When switching such patients with arterial hypertension and hepatic impairment to amlodipine or Combisart, the lowest recommended dose of amlodipine used in monotherapy or combination therapy should be prescribed.

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 arterial hypertension and hepatic impairment to amlodipine or Combisart, the lowest recommended dose of amlodipine used in monotherapy or combination therapy should be prescribed.

Paediatric Population

The safety and efficacy of Combisart in children (under 18 years of age) have not been established. Data are lacking.

Children. Studies on treatment with this medicinal product in children (under 18 years of age) have not been conducted. Therefore, until more comprehensive information becomes available, Combisart is not recommended for use in children.

Overdose.

Symptoms. There is currently no experience with Combisart overdose. 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. Available data indicate significant and potentially prolonged systemic hypotension, up to shock and fatal outcome.

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. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.

Treatment. If ingestion was recent, induce emesis or perform gastric lavage. Absorption of amlodipine is significantly reduced by administration of activated charcoal immediately or within two hours after amlodipine intake.

Clinically significant hypotension caused by Combisart overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory functions, elevation of the lower limbs, attention to circulating fluid volume, and urine 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 remove valsartan or amlodipine effectively.

Adverse Reactions

The most frequently observed or clinically significant and severe adverse reactions include: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, edema, soft tissue edema, facial edema, peripheral edema, fatigue, facial flushing, asthenia, and hot flushes.

The following adverse reactions may occur during treatment with the medicinal product:

• Blood and lymphatic system disorders: decreased hemoglobin and hematocrit levels, leukopenia, neutropenia, thrombocytopenia, occasionally with purpura;
• Immune system disorders: hypersensitivity;
• Eye disorders: visual disturbances, blurred vision;
• Psychiatric disorders: depression, anxiety, insomnia/sleep disturbances, mood swings, confusion;
• Nervous system disorders: headache, coordination disturbances, dizziness, postural dizziness, dysgeusia, extrapyramidal syndrome, hypertension, paresthesia, peripheral neuropathy, neuropathy, somnolence, syncope, tremor, hypesthesia;
• Ear and labyrinth disorders: dizziness, tinnitus;
• Cardiac disorders: tachycardia, palpitations, syncope; arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction;
• Vascular disorders: hyperemia, hypotension, orthostatic hypotension, vasculitis;
• Respiratory system disorders: cough, dyspnea, pharyngolaryngeal pain, rhinitis;
• Metabolism and nutrition disorders: anorexia, hypokalemia, hyperglycemia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia;
• Gastrointestinal disorders: abdominal discomfort and upper abdominal pain, changes in defecation rhythm, constipation, diarrhea, nausea, vomiting, dry mouth, dyspepsia, gastritis, pancreatitis, gingival hyperplasia;
• Skin and subcutaneous tissue disorders: alopecia, angioneurotic edema, bullous dermatitis, erythema, erythema multiforme, exanthema, increased sweating, photosensitivity, pruritus, purpura, rash, skin discoloration, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, toxic epidermal necrolysis;
• Musculoskeletal and connective tissue disorders: joint swelling, back pain, arthralgia, muscle cramps, heaviness sensation, muscle pain, ankle swelling;
• Renal and urinary disorders: increased blood creatinine levels, urinary disorders, increased urine output, nocturia, polyuria, renal failure and impaired kidney function;
• Reproductive system disorders: impotence, erectile dysfunction, gynecomastia;
• Hepatobiliary disorders: atypical liver function tests, including increased blood bilirubin levels (mainly associated with cholestasis), hepatitis, intrahepatic cholestasis, jaundice;
• General disorders: edema, facial edema, peripheral edema, pain, soft tissue swelling, asthenia, discomfort, malaise, fatigue, hyperemia, hot flushes, chest pain unrelated to the heart;
• Infections: nasopharyngitis, influenza;
• Investigations: increased blood potassium levels, increased body weight, decreased body weight.

Additional information regarding the combination

Peripheral edema, a known adverse effect of amlodipine, generally occurred less frequently in patients treated with the amlodipine/valsartan combination than with amlodipine alone.

Additional information regarding the components of the medicinal product

Adverse reactions previously reported with either component of the medicinal product (amlodipine or valsartan) may also occur with the use of Combisart, even if they were not observed during clinical trials or in the post-marketing period.

Adverse reactions characteristic of amlodipine

Vomiting, nausea, alopecia, dyspepsia, dyspnea, rhinitis, gastritis, abdominal pain, gingival hyperplasia, gynecomastia, hyperglycemia, impotence, urinary disorders, increased frequency of urination, leukopenia, general malaise, tinnitus, hypotension, mood changes (including anxiety), myalgia, muscle cramps, ankle swelling, peripheral neuropathy, pancreatitis, hepatitis, thrombocytopenia, vasculitis, allergic reactions, angioneurotic edema, Quincke's edema, erythema multiforme, insomnia, depression, confusion, syncope, dizziness, somnolence, tremor, dysgeusia, hypesthesia, visual disturbances (including diplopia), skin color changes, hyperhidrosis, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, increased or decreased body weight, jaundice, urticaria, purpura, exanthema, pruritus; isolated cases of extrapyramidal syndrome, elevated liver enzymes (usually associated with cholestasis), chest pain, palpitations, hypertension, arrhythmia, myocardial infarction (including bradycardia, ventricular tachycardia, and atrial fibrillation).

Adverse reactions characteristic of valsartan

Decreased hemoglobin levels, decreased hematocrit levels, neutropenia, thrombocytopenia, increased serum potassium levels, elevated liver function tests, including increased serum bilirubin levels, renal failure and impaired renal function, increased serum creatinine levels, angioneurotic edema, myalgia, vasculitis, hypersensitivity reactions, including serum sickness. Gastrointestinal tract – very rarely: intestinal angioneurotic edema.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging. 10 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua