Instructions for Tiara solo tablets 160mg No. 28
Composition
active ingredient: valsartan;
1 tablet contains valsartan 80 mg or 160 mg;
excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 85F pink.
Dosage form
Film-coated tablets.
Main physicochemical properties:
80 mg tablets – round tablets with a biconvex surface, coated with a pink coating, with a score;
160 mg tablets – oval-shaped tablets with a biconvex surface, coated with a pink shell, with a score.
Pharmacotherapeutic group
Simple angiotensin II antagonists. Valsartan.
ATX code C09C A03.
Pharmacological properties
Pharmacodynamics.
Valsartan is a potent, specific angiotensin II receptor antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II. Increased plasma levels of angiotensin II following blockade of the AT1 receptor with valsartan may stimulate the unblocked AT2 receptor, which counteracts the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor, but has a much higher (approximately 20,000-fold) affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. The use of the drug in patients with arterial hypertension leads to a decrease in blood pressure without affecting the pulse rate.
The onset of the hypotensive effect is noted within 2 hours, the maximum - within 4-6 hours after oral administration; the duration of action is more than 24 hours. The maximum therapeutic effect develops 4 weeks after the start of treatment and is maintained during long-term therapy. When used with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt discontinuation of the drug is not accompanied by the development of withdrawal syndrome.
With long-term use of the drug by patients with arterial hypertension, it was found that the drug had no significant effect on the level of total cholesterol, uric acid, and in fasting studies - on the concentration of triglycerides and glucose in blood serum.
The use of the drug leads to a decrease in hospitalizations for heart failure, a slowdown in the progression of heart failure, an improvement in the functional class according to the NYHA classification, an increase in the ejection fraction, as well as a decrease in heart failure symptoms and an improvement in the quality of life compared to placebo.
The VALIANT trial demonstrated the efficacy of valsartan, as well as captopril, in reducing overall mortality after myocardial infarction. Valsartan was also effective in reducing cardiovascular mortality and hospitalization for heart failure, as well as recurrent myocardial infarction. Valsartan had a positive effect on the time from acute myocardial infarction to the first manifestation of cardiovascular disease leading to death.
Children.
The antihypertensive effect of valsartan was evaluated in 4 randomized, double-blind clinical trials in 561 children aged 6 to 18 years and in 165 children aged 1 to 6 years. Renal and urinary disorders and obesity were the most common underlying medical causes of hypertension in the children included in these trials.
Clinical experience in children aged 6 years and older.
In a clinical study involving 261 children with hypertension aged 6 to 16 years, patients with a body weight of < 35 kg received 10, 40, or 80 mg of valsartan per day (low, medium, and high doses), and patients with a body weight of ≥ 35 kg received 20, 80, and 160 mg of valsartan per day (low, medium, and high doses). At the end of week 2, valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. The three valsartan dose levels (low, medium, and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from baseline, respectively.
Clinical experience in children under 6 years of age.
Valsartan is not recommended for use in this age group.
Pharmacokinetics.
Absorption.
After oral administration of valsartan, maximum plasma concentrations (Cmax) are reached within 2–4 hours, and in solution form – after 1–2 hours. The average absolute bioavailability of tablets and solution of the drug is 23% and 39%, respectively.
Food reduces the exposure (as determined by AUC) of valsartan by approximately 40% and the maximum plasma concentration (Cmax) by approximately 50%, although plasma concentrations of valsartan starting at approximately 8 hours after administration are similar in the fasted and fed groups. However, the decrease in AUC is not accompanied by a clinically significant decrease in therapeutic effect, so valsartan can be administered with or without food.
The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 L, indicating that valsartan is not extensively distributed into tissues. Valsartan is extensively bound to serum proteins (94–97%), primarily albumin.
Biotransformation.
Valsartan is not metabolized in most cases, with only approximately 20% of the dose excreted as metabolites. The hydroxymetabolite was excreted in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
Breeding.
The pharmacokinetic curve of valsartan is multiexponential (T½α < 1 h and T½ß about 9 hours). Valsartan is excreted mainly via the bile with feces (approximately 83% of the dose) and via the kidneys with urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, plasma clearance of valsartan is about 2 l/h, and renal clearance is 0.62 l/h (approximately 30% of total clearance). The half-life of valsartan is 6 hours.
Patients with heart failure (80 mg and 160 mg tablets).
The mean time to reach Cmax and the half-life of valsartan in patients with heart failure and in healthy volunteers are similar. The AUC and Cmax values of valsartan are almost proportional to the increase in dose above the clinical dosing range (40 to 160 mg 2 times a day). The average accumulation ratio is approximately 1.7. The estimated clearance of valsartan after oral administration is approximately 4.5 l/h. Age does not affect the estimated clearance in patients with heart failure.
Pharmacokinetics in certain patient groups.
Elderly patients: In some elderly patients, the systemic exposure to valsartan was somewhat greater than in younger patients, but this has not been shown to be of any clinical significance.
Patients with renal impairment. No correlation between renal function and systemic exposure to valsartan has been found. Therefore, no dose adjustment is required in patients with renal impairment (creatinine clearance > 10 ml/min). There are currently no data on the safety of use in patients with creatinine clearance < 10 ml/min or in patients undergoing dialysis, therefore valsartan should be used with caution in these patients. Valsartan is highly bound to plasma proteins, so its removal during hemodialysis is unlikely.
Patients with impaired liver function. Approximately 70% of the absorbed dose is excreted in the bile, mainly unchanged. Valsartan is not significantly metabolized, and, as expected, the systemic exposure to valsartan does not correlate with the degree of hepatic impairment. Therefore, no dose adjustment of valsartan is required in patients with non-biliary hepatic insufficiency and in the absence of cholestasis. It has been shown that the AUC of valsartan increases approximately twofold in patients with biliary cirrhosis or biliary obstruction.
Children.
In a study of 26 hypertensive children (aged 1 to 16 years) receiving a single dose of valsartan suspension (mean dose 0.9–2 mg/kg, maximum dose 80 mg), the clearance (l/h/kg) of valsartan was comparable across the age range from 1 to 16 years with similar clearance in adults receiving the same drug.
Patients with impaired renal function.
The use of the drug in children with creatinine clearance < 30 ml/min and in children undergoing dialysis has not been studied, therefore valsartan is not recommended in such patients. No dose adjustment is required in children with creatinine clearance > 30 ml/min. Renal function and serum potassium should be closely monitored.
Indication
Arterial hypertension.
Treatment of arterial hypertension in adults and children aged 6 years and older.
Post-infarction state.
Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction following a recent (12 hours - 10 days) myocardial infarction.
Heart failure.
Treatment of symptomatic heart failure in adult patients when ACE inhibitors cannot be used, or as adjunctive therapy with ACE inhibitors when β-blockers cannot be used.
Contraindication
Hypersensitivity to valsartan or to any of the excipients.
Pregnancy or planning to become pregnant (see section "Use during pregnancy or breastfeeding").
Congenital angioedema or angioedema that developed during previous treatment with an ACE inhibitor or angiotensin II receptor antagonist.
Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus (type I or II) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min).
There are no data in patients with severe renal impairment (creatinine clearance less than 10 ml/min).
Severe liver dysfunction, biliary cirrhosis and cholestasis.
Interaction with other medicinal products and other types of interactions
Concomitant use of ARBs, including valsartan, with other drugs that act on the RAAS is associated with an increased incidence of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared with monotherapy. Dual blockade of the RAAS through the combined use of ACE inhibitors, ARBs, or aliskiren is therefore not recommended. If dual RAAS blockade is considered necessary, it should be used only under specialist supervision and with close monitoring of renal function, electrolytes, and blood pressure.
The concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min).
The concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with type 1 and type 2 diabetes mellitus.
ACE inhibitors, including valsartan, and ARBs should not be used concomitantly in patients with diabetic nephropathy.
Concurrent use is not recommended.
Lithium.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of ACE inhibitors. Due to the lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If the combination is considered necessary, careful monitoring of serum lithium levels is recommended.
Potassium.
Potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium and other medicinal products that may increase potassium levels (heparin, etc.) may lead to increases in serum potassium levels and, in patients with heart failure, to increases in creatinine levels.
If the use of a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of plasma potassium levels is recommended.
Caution is required when used simultaneously.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs.
When angiotensin II antagonists are used concomitantly with NSAIDs, attenuation of the antihypertensive effect may occur. In addition, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function is recommended at the beginning of treatment, as well as adequate hydration of the patient.
Transporters.
In vitro studies have shown that valsartan is a substrate for the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use of inhibitors of the OATP1B1 transporter (e.g. rifampicin, cyclosporine) or MRP2 (e.g. ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken when initiating and discontinuing concomitant use of these medicinal products.
Others.
In drug interaction studies with valsartan, no clinically significant interactions were observed with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Children.
Caution is advised when valsartan is co-administered with other RAAS-inhibiting medicinal products in children and adolescents with hypertension, which may increase serum potassium levels. Renal function and serum potassium levels should be closely monitored.
Application features.
Hyperkalemia.
Concomitant use of potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Potassium levels should be monitored as necessary.
Renal impairment. To date, there are no data on the safety of the drug in patients with creatinine clearance < 10 ml/min and patients undergoing dialysis, therefore valsartan should be used with caution in such patients. No dose adjustment is required for adult patients with creatinine clearance > 10 ml/min.
The concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2).
Hepatic impairment: Valsartan should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.
Renal artery stenosis. The safety of valsartan has not been established in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Short-term administration of valsartan to 12 patients with vasorenal hypertension secondary to unilateral renal artery stenosis did not cause any significant changes in renal hemodynamic parameters, serum creatinine, or blood urea nitrogen. Since other drugs that affect the RAAS may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, monitoring of renal function is recommended as a safety measure during treatment with valsartan.
Kidney transplantation.
There are currently no data on the safety of valsartan in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism should not use valsartan because they do not have an activated renin-angiotensin system (RAS).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.
As with other vasodilators, the drug should be administered with extreme caution to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Pregnancy.
Angiotensin II receptor antagonists are contraindicated during pregnancy. Unless continued therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment should be stopped immediately, and, if appropriate, alternative therapy should be started.
Recently suffered a myocardial infarction.
The combination of captopril and valsartan did not show any additional clinical benefit, but the risk of adverse reactions increased compared with monotherapy with the respective drugs. Therefore, the combination of valsartan with an ACE inhibitor is not recommended.
Caution should be exercised in patients after myocardial infarction. Evaluation of patients after myocardial infarction should always include assessment of renal function.
The use of valsartan in patients after myocardial infarction often results in some reduction in blood pressure, usually leading to the need to discontinue therapy due to prolonged symptomatic hypotension, provided that the dosage instructions are followed.
Heart failure.
In patients with heart failure, the triple combination of an ACE inhibitor, a β-blocker, and valsartan has not shown any clinical benefit. This combination is likely to increase the risk of adverse effects and is therefore not recommended. The triple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist, and valsartan is also not recommended.
Such combinations should only be used under specialist supervision and with careful monitoring of kidney function, electrolyte levels, and blood pressure.
Studies on the safety and efficacy of valsartan in children have not been conducted.
History of angioedema.
Angioedema, including laryngeal and glottis edema resulting in airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue, has been reported in patients treated with valsartan; some of these patients had previously experienced angioedema while taking other drugs, including ACE inhibitors. The development of angioedema requires immediate discontinuation of valsartan, and valsartan should not be re-administered to such patients.
Other conditions with stimulation of the renin-angiotensin system (RAS).
In patients whose renal function may depend on the activity of the RAS (e.g. patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and in isolated cases with acute renal failure and/or fatal outcome. Since valsartan is an angiotensin II antagonist, it cannot be excluded that the use of valsartan may be associated with impaired renal function.
Double blockade of RAAS.
Concomitant use of angiotensin receptor antagonists, including valsartan, with other drugs that affect the RAAS is associated with an increased incidence of hypotension, hyperkalemia, and changes in renal function compared with monotherapy. Monitoring of blood pressure, renal function, and electrolytes is recommended in patients receiving valsartan and other drugs that affect the RAAS.
Children.
Kidney dysfunction.
The concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2).
Liver dysfunction.
As in adults, valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and patients with cholestasis. There is limited clinical experience with valsartan in children with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in such patients.
Use during pregnancy or breastfeeding
The use of angiotensin II receptor antagonists (ARBs) is contraindicated in pregnant women or women planning to become pregnant.
Epidemiological data on the risk of teratogenic effects following the use of ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small increase in risk cannot be excluded. Since there are no controlled epidemiological data on the risk with ARBs, the risk of teratogenic effects may also be present for this class of drugs. Unless continued therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ARB treatment should be stopped immediately and, if appropriate, replaced by another drug which is approved for use in pregnancy.
It is known that the use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces human fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
If AIIRAs have been used from the second trimester of pregnancy, ultrasound examination is recommended to check kidney function and the condition of the skull bones.
The condition of newborns whose mothers used ARAII should be carefully monitored for the development of arterial hypotension.
Due to the lack of information on the use of valsartan during breastfeeding, the drug is not recommended for use in breastfeeding women.
Fertility.
Valsartan at doses up to 200 mg/kg/day did not cause adverse effects on reproductive function in rats. The dose of 200 mg/kg/day is 6 times the maximum recommended human dose on a mg/m2 basis (calculations were made for an oral dose of 320 mg/day in patients weighing 60 kg).
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effects on the ability to drive and use machines have not been conducted. It should be borne in mind that dizziness or weakness may occur during treatment with this medicine.
Method of administration and doses
Method of application.
The medicine can be taken regardless of food intake; the tablets should be swallowed with water.
Dosage.
Arterial hypertension.
The recommended starting dose of valsartan is 80 mg once daily. The antihypertensive effect is achieved within 2 weeks and the maximum effect is reached within 4 weeks. In some patients with inadequately controlled blood pressure, the dose may be increased to 160 mg and to a maximum of 320 mg.
The drug can also be used with other antihypertensive drugs. The combined use of diuretics, such as hydrochlorothiazide, will further reduce blood pressure in patients.
Recent myocardial infarction
Therapy in clinically stable patients can be started as early as 12 hours after myocardial infarction. After an initial dose of valsartan 20 mg (tablets cannot be divided into doses, the dosage forms must be taken in the appropriate dosage) 2 times a day, the dose should be increased to 40 mg (tablets cannot be divided into doses, the dosage forms must be taken in the appropriate dosage), 80 mg and 160 mg 2 times a day over the next few weeks.
The target maximum dose is 160 mg twice daily. In general, it is recommended that a dosage level of 80 mg twice daily be reached 2 weeks after initiation of treatment and a maximum dose of 160 mg twice daily be reached after 3 months, depending on patient tolerability. If symptomatic hypotension or renal dysfunction occurs, dose reduction should be considered.
Valsartan can be used in patients who have used other medications after myocardial infarction, such as thrombolytics, acetylsalicylic acid, β-blockers, statins and diuretics. Combination with ACE inhibitors is not recommended.
Patients after myocardial infarction always need to have their kidney function monitored.
The recommended starting dose of valsartan is 40 mg (tablets cannot be divided into doses, the dosage forms should be taken in the appropriate dosage) 2 times a day. Gradual dose increases to 80 mg and 160 mg 2 times a day should be carried out at intervals of at least 2 weeks to the highest dose, depending on the patient's tolerance. A reduction in the dose of concomitant diuretics should be considered. The maximum daily dose used in clinical trials was 320 mg and was divided into several doses.
Valsartan can be used in combination with other drugs for the treatment of heart failure. However, the triple combination of an ACE inhibitor, a β-blocker, and valsartan is not recommended.
Patients with heart failure require monitoring of renal function.
Application to certain groups of patients.
Arterial hypertension in children.
Children and adolescents aged 6 to 18 years.
The initial dose is 40 mg (tablets cannot be divided into doses, the dosage forms should be taken in the appropriate dosage) 1 time per day for children weighing up to 35 kg and 80 mg 1 time per day for children weighing 35 kg or more. The dose should be adjusted depending on the blood pressure response. The maximum doses of valsartan studied in clinical trials are given in Table 1.
Doses higher than those indicated have not been studied and are therefore not recommended.
Table 1
| Patient body weight | Maximum dose of valsartan studied in clinical trials | |
| From ≥ 18 kg to < 35 kg | 80 mg |
| From ≥ 35 kg to < 80 kg | 160 mg |
| From ≥ 80 kg to ≤ 160 kg | 320 mg |
Children under 6 years old.
The safety and effectiveness of valsartan in children aged 1 to 6 years have not been established.
Children aged 6 to 18 years with renal insufficiency.
Use in children with creatinine clearance < 30 ml/min and in children undergoing dialysis has not been studied, therefore valsartan is not recommended for use in such patients. No dose adjustment is required for children with creatinine clearance > 30 ml/min. Renal function and serum potassium levels should be closely monitored.
Children aged 6 to 18 years with liver failure.
As in adults, valsartan is contraindicated in children with severe hepatic impairment, biliary cirrhosis and patients with cholestasis. Clinical experience with valsartan in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.
Heart failure and recent myocardial infarction in children.
Valsartan is not recommended for the treatment of heart failure or recent myocardial infarction in children due to a lack of data on safety and efficacy.
Elderly patients.
Elderly patients do not require dose adjustment.
Kidney failure.
No dose adjustment is required in adult patients with creatinine clearance > 10 ml/min. Concomitant use of valsartan with aliskiren is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2).
Diabetes.
Concomitant use of valsartan with aliskiren is contraindicated in patients with diabetes mellitus.
Liver failure.
The drug is contraindicated in patients with severe hepatic insufficiency, biliary cirrhosis and patients with cholestasis. For patients with mild to moderate hepatic insufficiency without cholestasis, the dose of valsartan should not exceed 80 mg.
Children.
The drug is used to treat hypertension in children aged 6 to 18 years. The safety and efficacy of valsartan in children aged 1 to 6 years have not been established. The drug is not recommended for the treatment of heart failure or post-infarction conditions in children due to the lack of data on safety and efficacy.
Overdose
Overdose of valsartan may result in severe hypotension, which may lead to depression of consciousness, vascular collapse and/or shock. Therapeutic measures depend on the time of administration and the type and severity of symptoms; stabilization of the circulatory system is of paramount importance. If hypotension occurs, the patient should be placed in the supine position and volume correction should be performed.
It is unlikely that valsartan can be removed from the body by hemodialysis.
Adverse reactions
Arterial hypertension/heart failure/myocardial infarction
In controlled clinical trials in adult patients with hypertension, the incidence of adverse reactions with placebo was similar to that with valsartan. The incidence of adverse reactions was not related to dose or duration of treatment, nor to gender, age or race.
Adverse reactions reported during clinical, post-marketing and laboratory studies are listed by system organ class.
The frequency of adverse reactions is estimated as follows: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/100000), including isolated reports. Within each frequency group, adverse reactions are presented in order of decreasing incidence.
Adverse reactions reported during post-marketing and laboratory studies for which it is not possible to determine the frequency of occurrence are listed with a frequency of "not known".
From the side of the organs of hearing and vestibular apparatus: infrequently - vertigo.
Respiratory, thoracic and mediastinal disorders: infrequently - cough.
Gastrointestinal: infrequently - diarrhea, abdominal pain; very rarely - nausea##, vomiting.
Hepatobiliary disorders: unknown - increased liver function tests, including increased serum bilirubin levels.
Renal and urinary disorders: very rare – renal failure**##, acute renal failure**, renal dysfunction**.
Metabolism and metabolism: infrequently - hyperkalemia*#.
Nervous system disorders: common: postural dizziness#; uncommon: syncope*; rare: dizziness##; very rare: headache##.
On the part of the psyche: infrequently - insomnia, decreased libido.
Cardiac disorders: infrequently - heart failure*; very rarely - cardiac arrhythmias.
Vascular disorders: often - orthostatic hypotension#; infrequently - hypotension*##; very rarely - vasculitis.
Blood and lymphatic system disorders: uncommon – neutropenia; very rare – thrombocytopenia.
Immune system disorders: very rarely - hypersensitivity reactions, including serum sickness.
Skin and subcutaneous tissue disorders: very rare - angioedema**, rash, pruritus, exanthema; unknown - bullous dermatitis.
Musculoskeletal and connective tissue disorders: uncommon – back pain; very rare –
arthralgia, myalgia.
Pregnancy and perinatal conditions: very rarely - complications of fetal development.
General disorders: infrequently - fatigue, asthenia, edema.
Infections: often - viral infections; infrequently - upper respiratory tract infections, pharyngitis, sinusitis; very rarely - rhinitis.
Laboratory results: often - increased serum creatinine, increased blood urea; very rarely - increased serum bilirubin, decreased hemoglobin/hematocrit, liver function parameters outside the normal range.
* reported by patients in a post-infarction state.
# reported by patients with heart failure.
** reported uncommonly in patients in the post-infarction state.
## reported more frequently in patients with heart failure (common: dizziness, renal impairment, hypotension; uncommon: headache, nausea).
Laboratory test results.
In isolated cases, valsartan has caused decreases in hemoglobin and hematocrit. In controlled clinical trials, 0.8% and 0.4% of patients treated with valsartan experienced significant (> 20%) decreases in hematocrit and hemoglobin, respectively. This was compared with 0.1% of patients treated with placebo who experienced decreases in both hematocrit and hemoglobin.
In controlled clinical trials, neutropenia was observed in 1.9% of patients treated with valsartan compared to 1.6% of patients treated with an ACE inhibitor.
In controlled clinical trials in patients with hypertension, significant increases in serum creatinine, potassium and total bilirubin were observed in 0.8%, 4.4% and 6% of patients treated with valsartan, respectively, compared with 1.6%, 6.4% and 12.9% of patients treated with an ACE inhibitor.
Isolated cases of elevations in liver function tests have been reported in patients treated with valsartan.
Patients with arterial hypertension do not require any special monitoring of laboratory parameters.
