Instructions for Polapril hard capsules 10 mg blister No. 28
Composition
active ingredient: ramipril;
1 capsule contains 2.5 mg or 5 mg or 10 mg of ramipril;
excipients: pregelatinized starch, gelatin, purified water, titanium dioxide (E 171), black iron oxide (E 172), indigo carmine (E 132), yellow iron oxide (E 172).
Dosage form
The capsules are hard.
Main physicochemical properties:
for 2.5 mg dosage: hard gelatin capsule No. 4, having a light gray body marked “2.5” and a light green cap marked “R”. The capsule contains a white or almost white powder;
for 5 mg dosage: hard gelatin capsule No. 4, having a light gray body marked “5” and a green cap marked “R”. The capsule contains white or almost white powder;
for 10 mg dosage: hard gelatin capsule No. 4, having a light gray body marked “10” and a dark green cap marked “R”. The capsule contains white or almost white powder.
Pharmacotherapeutic group
Angiotensin-converting enzyme (ACE) inhibitors.
ATX code C09A A05.
Pharmacological properties
Pharmacodynamics.
Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor (vasoconstrictor) angiotensin II, as well as the breakdown of the active vasodilator bradycardin. The reduction in the formation of angiotensin II and the inhibition of the breakdown of bradykinin cause vasodilation.
Since angiotensin II also stimulates the release of aldosterone, aldosterone secretion is reduced by ramiprilat. The increased activity of bradykinin appears to be responsible for the cardioprotective and endothelioprotective effects. The extent to which this contributes to the development of certain undesirable effects (e.g., nonproductive cough) is not yet known.
ACE inhibitors are effective even in patients with hypertension who have low renin levels. The average response to ACE inhibitor monotherapy in black patients (usually a low-renin hypertensive population) was lower than in non-black patients.
Ramipril administration causes a significant decrease in peripheral arterial resistance. In general, renal plasma flow and glomerular filtration rate do not change significantly.
The use of ramipril in patients with arterial hypertension leads to a decrease in blood pressure in the supine and standing positions without a compensatory increase in heart rate.
In most patients, the antihypertensive effect of a single oral dose is apparent within 1-2 hours. The maximum effect of a single dose is usually achieved within 3-6 hours and usually lasts for 24 hours.
The maximum antihypertensive effect of long-term treatment with ramipril is generally observed after 3-4 weeks. It has been shown to persist for 2 years with long-term therapy.
In response to abrupt discontinuation of ramipril, there is no rapid and severe increase in blood pressure.
In patients with clinical manifestations of heart failure, whose treatment was initiated 3-10 days after acute myocardial infarction, ramipril reduced the risk of mortality by 27% compared with placebo.
In patients with non-diabetic or diabetic overt nephropathy, ramipril reduces the rate of progression of renal failure and the onset of end-stage renal failure, which requires dialysis or kidney transplantation. In patients with non-diabetic or diabetic initial nephropathy, ramipril reduces albumin excretion.
Ramipril significantly reduces the incidence of myocardial infarction, stroke, or cardiovascular death. In addition, ramipril reduces overall mortality and the need for revascularization, and delays the onset and progression of congestive heart failure. Ramipril reduces the risk of nephropathy in the general population and in patients with diabetes. Ramipril also significantly reduces the incidence of microalbuminuria. These effects were observed in both hypertensive and normotensive patients.
Pharmacokinetics. In the liver, the only active metabolite of ramipril is formed by hydrolysis - ramiprilat.
The bioavailability of ramiprilat after oral administration of 2.5 and 5 mg ramipril is approximately 45% compared to its availability after intravenous administration of the same doses.
After oral administration of 10 mg ramipril, approximately 40% is excreted in the feces and 60% in the urine.
Approximately 80-90% of the metabolites in urine and bile are ramiprilat or ramiprilat metabolites.
Animal studies have shown that ramipril passes into breast milk.
Peak plasma concentrations of ramipril are reached 1 hour after oral administration. The elimination half-life of ramipril is approximately 1 hour. Peak plasma concentrations of ramiprilat are observed between 2 and 4 hours after oral administration of ramiprilat.
The decline in plasma concentrations of ramiprilat occurs in several phases. The half-life of the initial distribution and elimination phase is approximately 3 hours. This is followed by a transitional phase (half-life of approximately 15 hours) and then a terminal phase (half-life of approximately 4-5 days).
The presence of the terminal phase is due to the slow dissociation of ramiprilat from the close but saturated bond with ACE.
After a single dose of ramipril at a dose of 2.5 mg and above, steady state - when plasma concentrations of ramiprilat remain constant - is reached after about 4 days. After multiple doses, the effective half-life, depending on the dose, is 13-17 hours.
The binding of ramipril and ramiprilat to serum proteins is approximately 73% and 56%, respectively.
In healthy subjects aged 65 to 76 years, the kinetics of ramipril and ramiprilat are similar to those observed in young healthy subjects.
In cases of impaired renal function, the renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat decreases in proportion to creatinine clearance. This leads to increased plasma concentrations of ramiprilat, which decrease much more slowly than in individuals with normal renal function.
When using high doses (10 mg) in patients with impaired liver function, the conversion of ramipril to ramiprilat occurs later, plasma concentrations of ramipril increase and the elimination of ramiprilat slows down.
Both in healthy subjects and in patients with arterial hypertension after oral administration
5 mg ramipril once daily for 2 weeks in patients with congestive heart failure, no significant accumulation of ramipril and ramiprilat was observed.
Indication
Treatment of arterial hypertension.
Prevention of cardiovascular disease: reduction of cardiovascular morbidity and mortality in patients with:
- severe cardiovascular disease of atherothrombotic origin (history of ischemic heart disease or stroke or peripheral vascular disease);
- diabetes, who have at least one cardiovascular risk factor (see section "Pharmacological properties").
Treatment of kidney disease:
- initial glomerular diabetic nephropathy, as evidenced by the presence of microalbuminuria;
- severe glomerular diabetic nephropathy, as evidenced by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor (see section "Pharmacological properties");
- severe glomerular non-diabetic nephropathy, as evidenced by the presence of macroproteinuria ≥ 3 g/day (see section "Pharmacological properties").
Treatment of heart failure accompanied by clinical manifestations.
Secondary prevention after acute myocardial infarction: reduction of mortality during the acute stage of myocardial infarction in patients with clinical signs of heart failure, provided that treatment is started more than 48 hours after the onset of acute myocardial infarction.
Contraindication
Hypersensitivity to the active substance or to any of the excipients included in the preparation, or to other ACE (angiotensin-converting enzyme) inhibitors (see section "Composition").
History of angioedema (hereditary, idiopathic or previously experienced while taking ACE inhibitors or angiotensin II receptor antagonists).
Significant bilateral renal artery stenosis or renal artery stenosis in the presence of a single functioning kidney.
Pregnant women or women planning to become pregnant (see section “Use during pregnancy and breastfeeding”).
Ramipril should not be used in patients with hypotension or hemodynamically unstable conditions.
Should not be used with aliskiren-containing drugs in patients with diabetes mellitus or moderate or severe renal impairment (GFR < 60 mL/min).
The concomitant use of ACE inhibitors and extracorporeal treatments that result in contact of blood with negatively charged surfaces should be avoided, as such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate.
Primary hyperaldosteronism.
Interaction with other medicinal products and other types of interactions
Extracorporeal therapy methods that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate - due to the increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, the use of a different dialysis membrane or the use of a different class of antihypertensive agents should be considered.
The combined use of Polapril with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or moderately severe renal impairment and is not recommended for other categories of patients (see sections “Contraindications” and “Special warnings and precautions for use”).
Combinations requiring precautions.
Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore careful monitoring of plasma potassium levels is necessary.
Antihypertensive drugs (e.g. diuretics) and other substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of arterial hypotension should be expected (see section "Special warnings and precautions for use" for diuretics).
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Polapril. Close monitoring of blood pressure is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may cause changes in the blood picture.
Increased likelihood of hematological reactions (see section "Special warnings and precautions for use").
Lithium salts: ACE inhibitors may reduce lithium excretion, which may lead to increased lithium toxicity. Lithium levels should be carefully monitored.
Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Close monitoring of blood glucose levels is recommended.
Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of Polapril is expected to be reduced. Furthermore, the concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening of renal function and an increase in blood potassium levels.
Salt. Excessive salt consumption may weaken the hypotensive effect of the drug.
Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also be observed for other allergens.
Application features
Special categories of patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicinal products.
Dual blockade of the renin-angiotensin-aldosterone system through the combined use of Polapril and aliskiren is not recommended, as there is an increased risk of developing arterial hypotension, hyperkalemia and changes in renal function.
The combined use of Polapril and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR less than 60 ml/min) (see section "Contraindications").
Patients at particular risk of hypotension.
Patients with a strongly activated renin-angiotensin-aldosterone system. Patients with a strongly activated renin-angiotensin-aldosterone system are at risk of a sudden significant fall in blood pressure and deterioration of renal function due to ACE inhibition, particularly when an ACE inhibitor or concomitant diuretic is given for the first time or when the dose is increased for the first time. A strongly activated renin-angiotensin-aldosterone system, requiring medical supervision, including regular monitoring of blood pressure, may be expected, for example, in patients:
- with severe arterial hypertension;
- with decompensated congestive heart failure;
- with hemodynamically significant obstruction to the inflow or outflow of blood from the left ventricle (for example, with aortic or mitral valve stenosis);
- with unilateral renal artery stenosis in the presence of a second functioning kidney;
- in whom there is or may develop a lack of fluid or electrolytes (including those receiving diuretics);
- with liver cirrhosis and/or ascites;
- who are undergoing extensive surgical interventions or during anesthesia with the use of drugs that cause arterial hypotension.
In patients with impaired liver function, the response to treatment with Polapril may be either enhanced or reduced. In addition, in patients with severe cirrhosis of the liver, accompanied by edema and/or ascites, the activity of the renin-angiotensin system may be significantly increased; therefore, special caution should be exercised when treating these patients.
Transient or persistent heart failure after myocardial infarction.
Patients at risk of cardiac or cerebral ischemia in the event of acute arterial hypotension. Special medical supervision is required in the initial phase of treatment.
Elderly patients.
See section "Method of administration and dosage".
Surgery: If possible, treatment with angiotensin-converting enzyme inhibitors such as ramipril should be discontinued 1 day before surgery.
Monitoring kidney function.
Renal function should be assessed before and during treatment and the dose adjusted, especially in the first weeks of treatment. Patients with impaired renal function should be monitored particularly closely (see section 4.2). There is a risk of worsening renal function, especially in patients with congestive heart failure or after kidney transplantation.
Angioedema.
Angioedema has been reported in patients treated with ACE inhibitors, including ramipril (see section 4.8). If angioedema develops, Polapril should be discontinued. Emergency treatment should be initiated immediately. The patient should be kept under medical observation for at least 12-24 hours and may be discharged after complete resolution of symptoms.
Cases of intestinal angioedema have been reported in patients treated with ACE inhibitors, including Polapril (see section 4.8). These patients presented with abdominal pain (with or without nausea/vomiting).
Anaphylactic reactions during desensitization. When using ACE inhibitors, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increases. Before desensitization, Polapril should be temporarily discontinued.
Control of electrolyte balance. Hyperkalemia.
Hyperkalemia has been observed in some patients treated with ACE inhibitors, including Polapril. Patients at risk for hyperkalemia include patients with renal insufficiency, patients over 70 years of age, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, and other active substances that increase plasma potassium, or patients with conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above-mentioned drugs is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Electrolyte monitoring. Hyponatremia. In some patients treated with ramipril, the syndrome of inappropriate antidiuretic hormone secretion with subsequent development of hyponatremia has been observed. It is recommended to regularly monitor serum sodium levels in the elderly and in other patients at risk of developing hyponatremia.
Neutropenia/agranulocytosis.
Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been observed rarely. Bone marrow suppression has also been reported. Monitoring of the white blood cell count is recommended to detect possible leukopenia. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or those taking other medicinal products that may cause changes in the blood picture (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).
Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in non-blacks. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients than in non-blacks. This may be because black hypertensive patients tend to have low-renin hypertension.
Cough. Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. The possibility of cough due to ACE inhibitors should be considered in the differential diagnosis of cough.
Use during pregnancy or breastfeeding
Pregnancy.
Breastfeeding: Due to the lack of information regarding the use of ramipril during breastfeeding (see section 5.1), this drug is not recommended for use in nursing mothers and alternative treatments with better established safety profiles during lactation are preferable, especially while nursing a newborn or preterm infant.
The ability to influence the reaction speed when driving vehicles or other mechanisms.
Some side effects (e.g., decreased blood pressure, drowsiness, visual disturbances, dizziness) may impair the patient's attention and reaction speed. If such reactions occur, you should refrain from driving or operating other mechanisms.
This may occur especially at the beginning of treatment or when switching from other medications. After the first dose or subsequent dose increases, it is not recommended to drive or operate machinery for several hours.
Method of administration and doses
Drug for oral use.
It is recommended to take Polapril at the same time every day. The drug can be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. Polapril tablets should be swallowed whole with water. They should not be chewed or crushed.
Adults.
Patients taking diuretics. At the beginning of treatment with Polapril, hypotension may occur, the development of which is more likely in patients who are simultaneously receiving diuretics. In such cases, caution is recommended, since these patients may experience a decrease in BCC and / or electrolytes.
It is advisable to discontinue the diuretic 2-3 days before starting treatment with Polapril, if possible (see section "Special instructions").
In patients with arterial hypertension who cannot discontinue the diuretic, treatment with Polapril should be initiated at a dose of 1.25 mg (used in an appropriate dosage). Renal function and blood potassium levels should be closely monitored. Subsequent Polapril dosage should be adjusted depending on the target blood pressure level.
Arterial hypertension.
The dose should be selected individually, depending on the characteristics of the patient's condition (see section "Special instructions for use") and the results of control blood pressure measurements. Polapril can be used as monotherapy or in combination with other classes of antihypertensive drugs.
Initial dose. Treatment with Polapril should be initiated gradually, with the recommended initial dose of 2.5 mg per day.
In patients with a strongly activated renin-angiotensin-aldosterone system, a significant decrease in blood pressure may occur after the initial dose. For such patients, the recommended starting dose is 1.25 mg (to be administered in an appropriate dosage regimen) and their treatment should be initiated under medical supervision (see section 4.4).
Dose titration and maintenance dose. The dose may be doubled every 2-4 weeks until the target blood pressure is reached; the maximum dose of Polapril is 10 mg per day. The drug should usually be taken once daily.
Prevention of cardiovascular diseases.
Initial dose. The recommended initial dose of Polapril is 2.5 mg once daily.
Dose titration and maintenance dose. Depending on individual tolerability, the dose should be increased gradually. It is recommended to double the dose after 1-2 weeks of treatment, and then - after another 2-3 weeks - increase it to the target maintenance dose of 10 mg 1 time per day.
Also see above for dosage information for patients receiving diuretics.
Treatment of kidney disease.
In patients with diabetes and microalbuminuria.
Initial dose. The recommended initial dose of Polapril is 1.25 mg (to be used in the appropriate dosage) once a day.
Dose titration and maintenance dose. Depending on individual tolerability of the drug, the dose should be increased during further treatment. After 2 weeks of treatment, it is recommended to double the single daily dose to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.
In patients with diabetes and at least one cardiovascular risk factor.
Initial dose. The recommended initial dose of Polapril is 2.5 mg once daily.
Dose titration and maintenance dose. Depending on individual tolerability of the drug, the dose should be increased during further treatment. After 1-2 weeks of treatment, it is recommended to double the daily dose of Polapril to 5 mg, and then to 10 mg after another 2-3 weeks of treatment. The target daily dose is 10 mg.
In patients with non-diabetic nephropathy, as evidenced by macroproteinuria ≥ 3 g/day.
Initial dose. The recommended initial dose of Polapril is 1.25 mg (to be used in the appropriate dosage) once a day.
Dose titration and maintenance dose. Depending on the individual patient's tolerance of the drug, the dose should be increased during further treatment. After 2 weeks of treatment, it is recommended to double the single daily dose to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.
Initial dose: For patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg (to be administered in the appropriate dosage) per day.
Dose titration and maintenance dose. The dose of Polapril should be titrated by doubling it every 1-2 weeks until a maximum daily dose of 10 mg is reached. It is advisable to divide the dose into 2 doses.
Secondary prevention after acute myocardial infarction in the presence of heart failure.
Initial dose. 48 hours after the onset of myocardial infarction, patients who are clinically and hemodynamically stable should be given an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg is poorly tolerated, a dose of 1.25 mg (used in the appropriate dosage) twice daily for 2 days should be used, followed by an increase to 2.5 mg and 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.
Also see above for dosage information for patients receiving diuretics.
Dose titration and maintenance dose: The daily dose should then be increased by doubling it at intervals of 1-3 days until the target maintenance dose of 5 mg twice daily is reached.
Whenever possible, the maintenance daily dose should be divided into 2 doses.
If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued. There is still insufficient experience in the treatment of patients with severe (NYHA class IV) heart failure immediately after myocardial infarction. If a decision is nevertheless made to treat such patients with this drug, it is recommended to start therapy with a dose of 1.25 mg (used in the appropriate dosage) once daily and any increase should be carried out with extreme caution.
Special categories of patients.
Patients with renal impairment. The daily dose for patients with renal impairment depends on the creatinine clearance (see section "Pharmacological properties"):
- if creatinine clearance is ≥ 60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 10 mg;
- if creatinine clearance is 30-60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 5 mg;
- if creatinine clearance is 10-30 ml/min, the initial daily dose is 1.25 mg/day (to be used in the appropriate dosage), and the maximum daily dose is 5 mg;
- patients with arterial hypertension undergoing hemodialysis: ramipril is excreted to a small extent during hemodialysis; the initial dose is 1.25 mg (to be used in the appropriate dosage), and the maximum daily dose is 5 mg; the drug should be taken a few hours after the hemodialysis session.
Patients with impaired hepatic function (see section "Pharmacological properties"). Treatment with Polapril in patients with impaired hepatic function should be initiated under close medical supervision, and the maximum daily dose in such cases should be 2.5 mg.
Elderly patients. The initial dose should be lower and subsequent titration should be more gradual because of the higher likelihood of adverse effects, especially in very elderly and debilitated patients. In such cases, a lower initial dose of 1.25 mg (used in an appropriate dosage) of ramipril should be prescribed.
Also see above for dosage information for patients receiving diuretics.
Children.
Polapril is not recommended for use in children, as there is insufficient data on the efficacy and safety of this drug in such patients.
Overdose
Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilation (with pronounced hypotension, shock), bradycardia, electrolyte imbalance and renal failure. The patient should be closely monitored and symptomatic and supportive therapy should be administered. The proposed treatment measures include initial detoxification (gastric lavage, administration of adsorbents) and measures aimed at restoring stable hemodynamics, including the administration of alpha-1 adrenoceptor agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from the systemic circulation by hemodialysis.
Adverse reactions
The safety profile of Polapril includes persistent cough and hypotension-related reactions. Serious adverse reactions include angioedema, hyperkalemia, hepatic or renal impairment, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.
The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each group, adverse reactions are presented in order of decreasing seriousness.
From the side of the cardiovascular system
Uncommon: myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema.
Blood and lymphatic system disorders
Rare: decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin level, decreased platelet count.
Frequency unknown: bone marrow failure, pancytopenia, hemolytic anemia.
From the nervous system
Common: headache, dizziness.
Uncommon: vertigo, paraesthesia, ageusia, dysgeusia.
Rare: tremor, balance disorder.
Frequency unknown: cerebral ischemia, including ischemic stroke and transient ischemic attack, psychomotor impairment, burning sensation, parosmia.
From the organs of vision
Uncommon: visual disturbances, including blurred vision.
Rare: conjunctivitis.
From the side of the organs of hearing and labyrinth
Rare: hearing impairment, tinnitus.
Respiratory and mediastinal disorders
Common: non-productive irritating cough, bronchitis, sinusitis, shortness of breath.
Uncommon: bronchospasm, including exacerbation of asthma; nasal congestion.
Gastrointestinal tract
Common: gastrointestinal inflammation, indigestion, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting.
Uncommon: pancreatitis (in isolated cases, fatal outcomes have been reported with the use of ACE inhibitors), increased pancreatic enzymes, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth.
Rare: glossitis.
Frequency unknown: aphthous stomatitis.
Renal and urinary tract disorders
Uncommon: renal dysfunction, including acute renal failure, increased diuresis, worsening of background proteinuria, increased blood urea, increased blood creatinine.
Skin and subcutaneous tissue disorders
Common: rashes, particularly maculopapular.
Uncommon: angioedema; in very exceptional cases, airway obstruction due to angioedema, which may be fatal; pruritus, hyperhidrosis.
Rare: exfoliative dermatitis, urticaria, onycholysis.
Very rare: photosensitivity reactions.
Frequency unknown: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.
Musculoskeletal and connective tissue disorders
Common: muscle spasms, myalgia.
Uncommon: arthralgia.
From the endocrine system
Frequency unknown: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Nutritional and metabolic
Common: increased potassium levels in the blood.
Uncommon: anorexia, decreased appetite.
Frequency unknown: decreased blood sodium levels.
From the vascular system
Common: hypotension, orthostatic hypotension, syncope.
Uncommon: sensation of hot flushes.
Rare: vascular stenosis, hypoperfusion, vasculitis.
Frequency unknown: Raynaud's phenomenon.
General condition disorder
Common: chest pain, fatigue.
Uncommon: pyrexia.
Rare: asthenia.
On the part of the immune system
Frequency unknown: anaphylactic and anaphylactoid reactions, increased antinuclear antibodies.
From the hepatobiliary system
Uncommon: increased liver enzymes and/or bilirubin conjugates.
Rare: cholestatic jaundice, liver cell damage.
Frequency unknown: acute hepatic failure, cholestatic or cytolytic hepatitis (in very exceptional cases - fatal).
Reproductive system and breast disorders
Uncommon: transient erectile impotence, decreased libido.
Frequency unknown: gynecomastia.
From the psyche
Uncommon: depressed mood, anxiety, nervousness, restlessness, sleep disturbances including drowsiness.
Rare: confusion.
Frequency unknown: disturbance in attention.
Pediatric
