Instructions for use: Kombisart film-coated tablets 5 mg/160 mg blister No. 30
Composition
active ingredients: amlodipine, valsartan;
1 tablet of 5 mg/160 mg contains: amlodipine besylate 6.94 mg, corresponding to 5 mg of amlodipine, valsartan 160 mg;
excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
shell: Opadry II Yellow film coating mixture (hypromellose (hydroxypropylmethylcellulose), lactose monohydrate, titanium dioxide (E 171), polyethylene glycol (macrogol), iron oxide yellow (E 172));
or
active ingredients: amlodipine, valsartan;
1 tablet of 10 mg/160 mg contains: amlodipine besylate 13.87 mg, corresponding to 10 mg of amlodipine, valsartan 160 mg;
excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
shell: Opadry II Pink film-coating mixture (hypromellose (hydroxypropylmethylcellulose), lactose monohydrate, titanium dioxide (E 171), polyethylene glycol (macrogol), red iron oxide (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties:
5 mg/160 mg tablets: oval-shaped tablets with a flat surface with beveled edges, film-coated, light brownish-yellow in color;
10 mg/160 mg tablets: oval-shaped tablets with a flat surface with beveled edges, film-coated, light pink in color.
Pharmacotherapeutic group
Combination drugs of angiotensin II inhibitors.
ATX code C09D B01.
Pharmacological properties
Pharmacodynamics
Combisart contains two antihypertensive components with additional mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, and valsartan belongs to the class of angiotensin II antagonists. The combination of these ingredients has an additive antihypertensive effect and reduces blood pressure to a greater extent than either component alone.
Amlodipine.
Amlodipine inhibits the transmembrane penetration of calcium ions into the smooth muscles of the heart and blood vessels. The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle, which causes a decrease in peripheral vascular resistance and leads to a decrease in blood pressure. Experimental data confirm that amlodipine binds to dihydropyridine and nonhydropyridine binding sites. Contractile processes of the heart muscle and vascular smooth muscle depend on the passage of extracellular calcium into these cells through specific ion channels.
After administration of therapeutic doses to patients with hypertension, amlodipine causes vasodilation, resulting in a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by a significant change in heart rate or plasma catecholamine levels with prolonged use.
The effect correlates with plasma concentrations in young and elderly patients.
In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine lead to a decrease in renal vascular resistance and an increase in glomerular filtration rate, as well as effective renal plasma flow without changes in the filtered 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 showed a small increase in cardiac index without a significant effect on dP/dt or end-diastolic pressure or left ventricular volume. In hemodynamic studies, amlodipine did not exhibit a negative inotropic effect at therapeutic doses, even when co-administered with beta-blockers.
Amlodipine does not alter the function of the sinoatrial node or atrioventricular conduction. When amlodipine is used in combination with beta-blockers in patients with arterial hypertension or angina pectoris, no changes in electrocardiogram parameters are observed.
Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed coronary artery disease.
Valsartan.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Because of the lack of effect on ACE and the lack of potentiation of bradykinin or substance P activity, angiotensin II receptor antagonists are not usually associated with cough. Studies comparing valsartan with an ACE inhibitor have shown that the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in patients treated with an ACE inhibitor (2.6% vs. 7.9%, respectively). Patients previously treated with an ACE inhibitor developed dry cough. This complication was observed in 19.5% of patients treated with valsartan and 19% of patients treated with thiazide diuretics, while in the group of patients treated with ACE inhibitors, cough was observed in 68.5% of cases (P < 0.05). Valsartan does not interact with or block receptors for other hormones or ion channels, which are known to play an important role in the regulation of cardiovascular function.
Prescribing the drug to patients with arterial hypertension leads to a decrease in blood pressure without affecting the pulse rate.
In most patients, after oral administration of a single dose of the drug, the onset of antihypertensive activity is noted within 2 hours, and the maximum 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 use of the drug, the maximum therapeutic effect is usually achieved within 2-4 weeks and is maintained at the achieved level during long-term therapy. Abrupt withdrawal of valsartan does not lead to the resumption of arterial hypertension or other adverse clinical events.
Valsartan has been shown to significantly reduce hospitalization rates in patients with chronic heart failure (NYHA class II–IY). The effect was more pronounced 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 disease or left ventricular dysfunction after myocardial infarction.
Valsartan/amlodipine.
The combination of amlodipine and valsartan provides a dose-dependent additive reduction in blood pressure across the therapeutic dose range. The hypotensive effect after a single dose of the combination is maintained for 24 hours.
Pharmacokinetics
Linearity.
Valsartan and amlodipine exhibit linear pharmacokinetics.
Amlodipine
Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations (Cmax) are reached within 6–12 hours. The estimated absolute bioavailability is 64 to 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 the circulating drug is bound to plasma proteins.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: Elimination of amlodipine 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 dosing. 10% of the parent amlodipine and 60% of the metabolites of amlodipine are excreted in the urine.
Valsartan
Absorption: After oral administration, Cmax of valsartan in plasma is reached within 2–4 hours. The average absolute bioavailability of the drug is 23%.
Food reduces valsartan exposure, as measured by AUC (plasma concentration-time), by approximately 40% and Cmax by 50%, although 8 hours after administration, plasma valsartan concentrations are similar in the fasted and fed groups. The decrease in AUC is not associated with a clinically significant reduction in therapeutic effect, and valsartan can be taken without regard to food intake.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating that valsartan is not extensively distributed into tissues. Valsartan is highly bound to plasma proteins (94–97%), mainly to serum albumin.
Biotransformation: Valsartan is not significantly transformed, with only 20% of the dose converted to metabolites. A hydroxymetabolite, which is pharmacologically inactive, has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan).
Elimination: Valsartan exhibits multi-exponential elimination kinetics (half-life T1/2a < 1 hour and T1/2b approximately 9 hours). Valsartan is excreted mainly unchanged in the feces (approximately 83% of the dose) and urine (approximately 13% of the dose). After intravenous administration, the plasma clearance of valsartan is approximately 2 l/h, and its renal clearance is approximately 0.62 l/h (approximately 30% of the total clearance). The elimination half-life of valsartan is 6 hours.
Valsartan/amlodipine
After oral administration of the drug Combisart Cmax of valsartan and amlodipine in blood plasma is achieved in 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 monodrugs.
Special populations
Children
Elderly patients (aged 65 years and over)
The time to reach Cmax of amlodipine in plasma is approximately the same in young and elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, which leads to an increase in AUC and a prolongation of the half-life. The average systemic AUC of valsartan in elderly patients is 70% higher than in younger patients, so caution should be exercised when increasing the dose.
Kidney failure
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. For valsartan, renal clearance of which accounts for only 30% of total plasma clearance, there was no correlation between renal function status and its systemic exposure.
Liver dysfunction
In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in an increase in AUC by approximately 40–60%. On average, in patients with mild to moderate chronic liver disease, the exposure (determined by AUC values) of valsartan is on average twice that of healthy volunteers (selected for age, sex and body weight). Patients with liver disease should use the drug with caution.
Indication
Essential hypertension in adult patients whose blood pressure is not controlled with amlodipine or valsartan monotherapy.
Contraindication
Hypersensitivity to the active substance, dihydropyridine derivatives or to any of the excipients of the medicinal product.
Severe liver dysfunction, biliary cirrhosis or cholestasis.
Severe renal impairment (glomerular filtration rate (GFR) < 30 mg/min/1.73 m2); also contraindicated in patients on dialysis.
Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mg/min/1.73 m2).
Pregnancy or planning to become pregnant (see section "Use during pregnancy or breastfeeding").
Severe hypotension.
Shock (including cardiogenic shock).
Left ventricular outflow tract obstruction (e.g. hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
Inter-physician interactions
Drug-drug interactions of Combisart with other drugs have not been studied.
Medicines that require caution when used concomitantly
Other antihypertensive drugs
Commonly used antihypertensive drugs (e.g. alpha-blockers, diuretics) and other drugs that can cause hypotensive adverse events (e.g. tricyclic antidepressants, alpha-blockers used to treat benign prostatic hyperplasia) may enhance the hypotensive effect of the combination.
Interactions related to amlodipine
Concomitant use not recommended
Grapefruit or grapefruit juice
The use of amlodipine with grapefruit juice or grapefruit is not recommended, as in some patients the bioavailability of the drug may be increased, leading to an increase in the hypotensive effect.
Medicines that require caution when used concomitantly
CYP3A4 inhibitors
Concomitant use of amlodipine with more or less potent 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. The clinical manifestations of such pharmacokinetic changes may be enhanced 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))
Plasma concentrations of amlodipine may be altered when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and the dosage adjusted during and after concomitant use, especially with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
Simvastatin
Multiple administration of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. It is recommended that the daily dose of simvastatin be reduced to 20 mg for patients taking amlodipine.
Dantrolene (infusion)
Fatal cases of ventricular fibrillation and cardiovascular collapse have been observed in animals due to hyperkalemia following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that concomitant use of calcium channel blockers such as amlodipine be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.
Others
Amlodipine did not affect the pharmacokinetics of atorvastatin, dioxin, warfarin, or cyclosporine.
Interactions related to valsartan
Concomitant use not recommended
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium with ACE inhibitors or angiotensin II receptor antagonists, including valsartan. Concomitant use of valsartan and lithium is not recommended. If the combination proves necessary, serum lithium levels should be closely monitored. The risk of lithium toxicity may be further increased by concomitant use of Combisart and diuretics.
Potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels
If drugs that affect potassium channels are prescribed in combination with valsartan, frequent monitoring of plasma potassium should be considered.
Medicines that require caution when used concomitantly
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs
Concomitant use of angiotensin II antagonists and NSAIDs may result in attenuation of the hypotensive effect. Concomitant use of angiotensin II antagonists and NSAIDs may also increase the risk of worsening of renal function and an increase in serum potassium. Therefore, at the beginning of treatment, it is recommended to monitor renal function and ensure adequate fluid intake.
Inhibitors of the accumulation transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir)
Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of the uptake transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir) may increase systemic exposure to valsartan.
Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren
Dual blockade of the RAAS with the combined use of ACE inhibitors, ARBs or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with treatment with a single drug that affects the RAAS. Therefore, the concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (GFR < 60 mg/min/1.73 m2).
Others
With valsartan monotherapy, no clinically significant drug interactions have been established with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Application features
Patients with a deficiency in the body of sodium and/or circulating blood volume.
Excessive hypotension has been observed in patients with uncomplicated hypertension (0.4%). Symptomatic hypotension may occur in patients with an activated renin-angiotensin system (with reduced sodium and/or volume depletion and in the case of receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition before the use of the drug Kombisart or careful medical supervision at the beginning of therapy is recommended.
If hypotension occurs during the use of the drug Kombisart, the patient should be placed on his back and, if necessary, an intravenous infusion of saline should be performed. After stabilization of blood pressure, treatment can be continued.
Hyperkalemia.
Concomitant treatment with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.) should be undertaken with caution, and frequent monitoring of potassium levels is necessary.
Renal artery stenosis.
The drug Combisart should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation.
There is no experience of the safe use of the drug Kombisart in patients with a recent kidney transplant.
Liver dysfunction.
Valsartan is excreted mainly unchanged in the bile. The half-life of amlodipine is prolonged and the AUC (plasma concentration-time) is increased in patients with impaired liver function; dosage recommendations have not been established. Special caution is required when using the drug Kombisart in patients with mild to moderate liver dysfunction or obstructive gallbladder disease.
The maximum recommended dose for patients with mild or moderate hepatic impairment without cholestasis is 80 mg of valsartan.
Kidney dysfunction.
No dose adjustment is required in patients with mild or moderate renal impairment (GFR > 30 ml/min/1.73 m2). In patients with moderate renal impairment, monitoring of potassium and creatinine levels in the blood is recommended.
Concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mg/min/1.73 m2).
Patients with primary hyperaldosteronism should not take the angiotensin II antagonist valsartan because their renin-angiotensin system is impaired due to the underlying disease.
Angioedema.
Angioedema, including swelling of the larynx and glottis, which 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 while taking other drugs, including angiotensin-converting enzyme (ACE) inhibitors. The use of the drug Kombisart should be discontinued immediately if angioedema occurs; repeated use is not recommended.
Heart failure/condition after myocardial infarction.
Due to inhibition of the renin-angiotensin-aldosterone system, renal function may be impaired in susceptible patients. In patients with severe heart failure, in whom renal function may depend on the activity of the renin-angiotensin-aldosterone system, the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with the development of oliguria and/or progressive azotemia, and (in rare cases) acute renal failure and/or death. Similar results have been observed with valsartan. Patients with heart failure or after myocardial infarction should have their renal function assessed.
In a study of amlodipine in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema was higher with amlodipine than with placebo, but there was no significant difference in the incidence or worsening of heart failure. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure because they may increase the risk of cardiovascular events and mortality.
Aortic and mitral valve stenosis.
As with other vasodilators, particular caution should be exercised in patients with known mitral valve stenosis or severe low-grade aortic stenosis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that the combined use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by the combined use of ACE inhibitors, ARBs or aliskiren is not recommended.
If dual blockade is absolutely necessary, it should only be carried out under specialist supervision with frequent close monitoring of renal function, electrolyte concentrations and blood pressure. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
The use of the drug Kombisart in patients with diseases other than arterial hypertension has not been studied.
The medicinal product contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take it.
Use during pregnancy or breastfeeding
Pregnancy
The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnant women.
Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy have not been conclusive; however, a small increased risk cannot be excluded. Although there are no data from controlled epidemiological studies with angiotensin II receptor antagonists (ARBs), a similar risk may exist with this class of drugs.
Exposure to ARAII in the second and third trimesters is known to have toxic effects on the human fetus (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the newborn (renal failure, hypotension, hyperkalemia).
If AIIRAs have been used from the second trimester of pregnancy, ultrasound check of renal function and fetal skull is recommended.
Infants whose mothers have taken ARVIs should be closely observed for the development of arterial hypotension.
Breastfeeding period
Amlodipine is excreted in breast milk. The proportion of the maternal dose received by the infant is estimated with an interquartile range of 3–7%, with a maximum of 15%. The effects of amlodipine on the infant are unknown.
Since no information is available on the use of Combisart during breastfeeding, the drug is not recommended for use during breastfeeding; alternative drugs with better established safety profiles are preferable, especially while breastfeeding a newborn or premature infant.
Fertility
Clinical studies on the effect on fertility have not been conducted.
Valsartan did not cause adverse reproductive effects in male and female rats when administered orally at doses up to 200 mg/kg/day, which is 6 times the maximum recommended human dose on a mg/m2 basis (calculated using a dose of 320 mg/day for an oral dose of 60 kg).
Amlodipine
Reversible biochemical changes in the heads of sperm have been reported in some patients treated with calcium channel blockers. Clinical data on the effects 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 vehicles or other mechanisms
Patients using the drug Kombisart may experience dizziness or a feeling of weakness after taking the drug, so they should take this into account when driving vehicles and working with potentially dangerous mechanisms.
Amlodipine may have minor or moderate influence on the ability to drive and use machines. If patients experience dizziness, headache, fatigue or nausea while taking amlodipine, their reactions may be impaired.
Method of administration and doses
Patients whose blood pressure is inadequately controlled with amlodipine or valsartan monotherapy may be switched to combination therapy with the drug Combisart. The recommended dose is 1 tablet per day. Combisart tablets can be taken regardless of meals. It is recommended to take Combisart with a small amount of water.
Patients taking valsartan and amlodipine separately can be switched to Combisart, which contains the same doses of the components.
Individual dose titration of the components (i.e. amlodipine and valsartan) is recommended before switching to a fixed-dose combination. If clinically indicated, direct conversion from monotherapy to a fixed-dose combination may be considered.
The maximum daily dose of the drug Combisart is 1 tablet of 5 mg/160 mg, or 1 tablet of 10 mg/160 mg (the maximum permissible doses of the drug components are 10 mg of amlodipine content, 320 mg of valsartan content).
Dosage for specific patient groups
Kidney dysfunction
The drug Combisart is contraindicated in patients with severe renal impairment.
No dose adjustment is required in patients with mild or moderate renal impairment. In patients with moderate renal impairment, it is recommended to monitor potassium and creatinine levels in the blood.
Concomitant use of Combisart with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mg/min/1.73 m2).
Diabetes mellitus
Concomitant use of Combisart with aliskiren is contraindicated in patients with diabetes mellitus.
Liver dysfunction
The drug 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 tract diseases.
For patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan.
No dosage recommendations have been developed for amlodipine in patients with mild or moderate hepatic impairment. When transferring such patients with arterial hypertension and hepatic impairment to amlodipine or Combisart, the lowest recommended dose of amlodipine should be used in monotherapy or combination therapy.
Elderly patients (aged 65 years and over)
For elderly patients, usual dosage regimens are recommended.
Caution should be exercised when increasing the dose of the drug in elderly patients.
When transferring such patients with arterial hypertension and impaired liver function to amlodipine or Combisart, it is necessary to prescribe the lowest recommended dose of amlodipine in monotherapy or as part of combination therapy.
Pediatric population
The safety and efficacy of the drug Kombisart in children (under 18 years of age) have not been studied. Data are not available.
Children
This medicine has not been studied in children (under 18 years of age). Therefore, until more information is available, Kombisart is not recommended for use in children.
Overdose
Symptoms. There is no experience of overdose with the drug Kombisart. The main symptom of valsartan overdose is likely to be severe arterial hypotension with dizziness. Overdose of amlodipine may lead to increasing peripheral vasodilation and, possibly, to reflex tachycardia. There is evidence of significant and potentially prolonged systemic hypotension, up to shock and death.
Clinically significant hypotension caused by an overdose of Combisart requires active support of the cardiovascular system, including frequent monitoring of cardiac and respiratory function, elevation of the patient's lower extremities, attention to the volume of circulating fluid and urination. To restore vascular tone and blood pressure, a vasoconstrictor can be used in the absence of contraindications to its use. In case of persistent decrease in blood pressure, which is a consequence of calcium channel blockade, intravenous administration of calcium gluconate may be appropriate.
Removal of valsartan and amlodipine by hemodialysis is unlikely.
Side effects
The most frequently observed or significant or severe adverse reactions were: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, edema, soft tissue edema, facial edema, peripheral edema, fatigue, facial flushing, asthenia, and hot flashes.
The following adverse reactions may occur during use of the drug:
Blood and lymphatic system disorders: decreased hemoglobin and hematocrit, leukopenia, neutropenia, thrombocytopenia, sometimes with purpura;
from the immune system: hypersensitivity;
from the organs of vision: visual impairment, vision impairment;
Mental: depression, anxiety, insomnia/sleep disorders, mood swings, confusion;
from the nervous system: headache, coordination disorder, dizziness, postural dizziness, dysgeusia, extrapyramidal syndrome, hypertension, paresthesia, peripheral neuropathy, neuropathy, drowsiness, fainting, tremor, hypoesthesia;
from the organs of hearing and labyrinth: dizziness, tinnitus;
Cardiac: tachycardia, palpitations, fainting; arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction;
from the vascular system: hyperemia, hypotension, orthostatic hypotension, vasculitis;
from the respiratory system: cough, shortness of breath, pharyngolaryngeal pain, rhinitis;
Nutritional and metabolic: anorexia, hypokalemia, hyperglycemia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia;
from the digestive system: abdominal discomfort and pain in the upper abdomen, change in the rhythm of defecation, constipation, diarrhea, nausea, vomiting, dry mouth, dyspepsia, gastritis, pancreatitis, gingival hyperplasia;
Skin and subcutaneous tissue disorders: alopecia, angioedema, bullous dermatitis, erythema, erythema multiforme, exanthema, increased sweating, photosensitivity, pruritus, purpura, rash, skin discoloration, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis;
Musculoskeletal system: joint swelling, back pain, arthralgia, muscle cramps, feeling of heaviness, muscle pain, ankle swelling;
from the kidneys and urinary system: increased blood creatinine levels, urination disorder, increased urine output, nocturia, pollakiuria, renal failure and renal dysfunction;
from the reproductive system: impotence, erectile dysfunction, gynecomastia;
Hepatobiliary system: atypical liver function tests, including increased bilirubin levels in the blood (mainly associated with cholestasis), hepatitis, intrahepatic cholestasis, jaundice;
general disorders: edema, facial edema, peripheral edema, pain, soft tissue edema, asthenia, discomfort, malaise, fatigue, flushing, hot flashes, non-cardiac chest pain;
infections: nasopharyngitis, influenza;
– research: increased stool levels
