Enalapril-Zdorovye tablets 10 mg blister No. 20

Instructions Enalapril-Zdorovye tablets 10 mg blister No. 20

Composition

active ingredient: 1 tablet contains enalapril maleate 5 mg or 10 mg or 20 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, copovidone, calcium stearate.

Dosage form

Pills.

Main physicochemical properties: 5 mg tablets, white or almost white, biconvex; 10 mg or 20 mg tablets, white or almost white, flat-cylindrical with a bevel, with the inscription "ЗТ" embossed on one side, or without inscription.

Pharmacotherapeutic group

Angiotensin-converting enzyme inhibitors, monocomponent. ATC code C09A A02.

Pharmacological properties

Pharmacodynamics. Enalapril maleate is the maleic acid salt of enalapril, a derivative of two amino acids, L-alanine and L-proline.

Angiotensin-converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE causes a decrease in plasma angiotensin II levels, which leads to an increase in plasma renin activity (due to inhibition of the negative feedback between angiotensin II activity and renin release) and a decrease in aldosterone secretion.

ACE is identical to kininase II. Thus, the drug can also block the cleavage of bradykinin, a potent vasodepressor peptide. However, the significance of this phenomenon for the therapeutic effect of the drug remains unclear.

The mechanism by which the drug lowers blood pressure is primarily associated with inhibition of the renin-angiotensin-aldosterone system. The drug may have an antihypertensive effect even in patients with low-renin hypertension.

The use of the drug in case of arterial hypertension causes a decrease in blood pressure in patients in horizontal and vertical positions without a significant increase in heart rate.

Symptomatic postural hypotension is uncommon. In some patients, achieving optimal blood pressure control may require several weeks of therapy. Abrupt withdrawal of the drug has not been associated with a rapid increase in blood pressure.

Effective inhibition of ACE activity is usually achieved 2-4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive activity is usually observed after 1 hour, and the peak reduction in blood pressure is achieved 4-6 hours after taking the drug. The duration of the effect is dose-dependent. However, when used in recommended doses, the antihypertensive and hemodynamic effects were maintained for at least 24 hours.

There is evidence that in hemodynamic studies in patients with essential hypertension, a decrease in blood pressure is usually accompanied by a decrease in peripheral arterial resistance with an increase in cardiac output and little or no increase in heart rate. Renal blood flow usually increases after administration; glomerular filtration rate is usually unchanged. There is no evidence of sodium or water retention. However, in patients with low initial glomerular filtration rates, these rates are usually increased.

In patients with or without diabetes mellitus and renal disease, reductions in albuminuria, urinary IgG excretion, and total urinary protein were observed after enalapril administration.

When used concomitantly with thiazide diuretics, the hypotensive effects of the drug are at least additive. The drug may reduce or prevent the development of thiazide-induced hypokalemia.

In patients with heart failure receiving cardiac glycosides and diuretics, oral or injectable enalapril was associated with a decrease in peripheral resistance and blood pressure. Cardiac output increased and heart rate (usually increased in patients with heart failure) decreased. Pulmonary end-capillary pressure also decreased. Exercise tolerance improved and the severity of heart failure, as assessed by the New York Heart Association (NYHA) criteria, decreased. These effects were maintained during long-term treatment.

In patients with mild to moderate heart failure, enalapril slowed the progression of myocardial dilatation/enlargement and heart failure, as evidenced by reduced left ventricular end-diastolic and systolic volumes and improved ejection fraction.

Pharmacokinetics. After oral administration, enalapril is rapidly absorbed, with Cmax of enalapril in serum occurring within 1 hour after ingestion. The extent of absorption of enalapril from oral tablets is approximately 60%. The presence of food in the gastrointestinal tract does not affect absorption of the drug. After absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Cmax of enalaprilat in serum is observed approximately 4 hours after an oral dose of enalapril.

The effective T½ of enalaprilat after multiple oral administration is 11 hours.

Within the entire therapeutic concentration range, no more than 60% of enalaprilat binds to serum proteins.

With the exception of conversion to enalaprilat, there is no further evidence of significant metabolism of enalapril.

Enalaprilat is excreted primarily by the kidneys. The major components in the urine are enalaprilat, which accounts for approximately 40% of the dose, and unchanged enalapril (approximately 20%).

In patients with renal insufficiency, exposure to enalapril and enalaprilat is increased. In patients with mild to moderate renal impairment (CLcr 40-60 mL/min), the steady-state AUC of enalaprilat was approximately 2-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal insufficiency (CLcr ≤ 30 mL/min), the AUC increased approximately 8-fold. With increasing renal insufficiency, the effective T½ of enalaprilat is prolonged and the time to steady state is delayed.

Enalaprilat can be removed from the general circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 ml/min.

Indication

Treatment of arterial hypertension.

Treatment of clinically significant heart failure.

Prevention of clinically significant heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 35%).

Contraindication

Hypersensitivity to the components of the drug or to any other ACE inhibitor.

History of angioedema associated with the use of ACE inhibitors.

Hereditary or idiopathic angioedema.

Pregnant women or women planning to become pregnant (see section “Use during pregnancy or breastfeeding”).

Enalapril should not be used with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).

Interaction with other medicinal products and other types of interactions

Antihypertensive therapy. Concomitant administration of these drugs may enhance the hypotensive effect of enalapril. Concomitant administration with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.

Potassium-sparing diuretics or potassium supplements. ACE inhibitors increase the potassium loss caused by diuretics. The use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride) and the use of potassium-containing food supplements or salt substitutes may lead to significant increases in serum potassium. If the above agents are indicated in association with hypokalemia, they should be used with caution, with regular monitoring of serum potassium.

Diuretics (thiazide or loop diuretics). Previous treatment with high doses of diuretics may result in volume depletion and an increased risk of hypotension at the start of enalapril therapy. Hypotensive effects may be reduced by discontinuing the diuretic, increasing salt intake, or initiating therapy with a low dose of enalapril.

Antidiabetic agents: Epidemiological data have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may lead to a decrease in blood glucose levels with a risk of hypoglycaemia. This phenomenon is most likely during the first weeks of concomitant use and in patients with renal insufficiency.

Serum lithium. Reversible increases in serum lithium levels and toxicity have been reported with concomitant use of ACE inhibitors and lithium. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. The use of enalapril with lithium is not recommended, but if the combination proves necessary for the patient, careful monitoring of serum lithium levels should be performed.

Tricyclic antidepressants/neuroleptics/anesthetics/hypnotics: Concomitant use of certain anesthetics, tricyclic antidepressants, and neuroleptics with ACE inhibitors may lead to an additional decrease in blood pressure.

Concomitant use of NSAIDs, including COX-2 inhibitors, and angiotensin II receptor antagonists or ACE inhibitors has an additive effect on serum potassium and may lead to deterioration of renal function. These effects are usually reversible.

Acute renal failure may occur rarely, especially in some patients with impaired renal function (e.g. elderly patients or patients with reduced circulating blood volume, including those taking diuretics). Therefore, this combination should be administered with caution to patients with impaired renal function. Patients should be adequately hydrated and renal function should be closely monitored at the beginning of concomitant therapy and periodically during such treatment.

Dual blockade of the renin-angiotensin-aldosterone system. Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to isolated cases with close monitoring of blood pressure, renal function, and electrolytes. In patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the renin-angiotensin-aldosterone system has been reported in several studies to be associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a single agent acting on the renin-angiotensin-aldosterone system. Enalapril with aliskiren should not be used in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).

Gold preparations. Nitritoid reactions (symptoms including facial swelling, nausea, vomiting, and hypotension) have been reported rarely in patients treated with injectable gold preparations (sodium aurothiomalate) and concomitant ACE inhibitors, including enalapril.

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Alcohol. Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and β-blockers. Enalapril can be safely used concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics and β-blockers.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been reported to be associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a renin-angiotensin-aldosterone system agent alone. Dual blockade (e.g., by combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually determined cases and accompanied by close monitoring of renal function, potassium levels, and blood pressure.

Application features

Symptomatic hypotension. Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. In hypertensive patients receiving enalapril, symptomatic hypotension develops more often in cases of hypovolemia, which occurs, for example, as a result of diuretic therapy, salt restriction, in patients undergoing hemodialysis, as well as in patients with diarrhea or vomiting. Symptomatic hypotension has also been observed in patients with heart failure, which was accompanied or not accompanied by renal failure. Symptomatic hypotension developed more often in patients with more severe forms of heart failure, who were treated with higher doses of loop diuretics, with hyponatremia or impaired renal function. In such patients, treatment with the drug should be initiated under medical supervision. When changing the dose of the drug and/or diuretic, monitoring should be especially careful. Similarly, patients with ischemic heart disease and cerebrovascular disease should be monitored, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If hypotension develops, the patient should be placed in a horizontal position and, if necessary, intravenous saline should be administered. Transient hypotension during treatment with the drug is not a contraindication for further administration, which can usually be continued without complications after normalization of blood pressure by restoring fluid volume.

In some patients with heart failure with normal or low blood pressure, the drug may further reduce blood pressure. This reaction to the drug is expected and is usually not a reason to stop treatment. If hypotension becomes resistant to treatment, the dose should be reduced and/or the diuretic and/or the drug should be discontinued.

Renal impairment: In patients with renal impairment (CLcr < 80 mL/min), the initial dose of enalapril should be titrated according to CLcr and then adjusted according to response to treatment. In such patients, regular monitoring of potassium and creatinine levels is standard medical practice.

Renal impairment has been reported in association with enalapril, primarily in patients with severe heart failure or renal disease, including renal artery stenosis. With timely recognition and appropriate treatment, renal impairment associated with enalapril therapy is usually reversible.

In some hypertensive patients with no known renal disease prior to treatment, enalapril has been associated with diuretics, usually with minor and transient increases in blood urea and serum creatinine. In such cases, dose reduction and/or discontinuation of the diuretic may be necessary. This situation raises the possibility of pre-existing renal artery stenosis.

Renovascular hypertension. There is an increased risk of hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with minimal changes in serum creatinine. In such patients, treatment should be initiated at low doses under close medical supervision with careful titration and monitoring of renal function.

Kidney transplantation: There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Therefore, treatment with the drug is not recommended in these patients.

Hepatic failure. Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome remains unclear. Patients taking ACE inhibitors who develop jaundice or marked elevations of liver enzymes should discontinue the ACE inhibitor and receive appropriate medical attention.

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia has been reported rarely in patients with normal renal function and in the absence of other complicating factors. Enalapril should be used with great caution in patients with collagen vascular disease who are receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing renal impairment. Some of these patients have developed serious infections, sometimes unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should report any signs of infection.

Hypersensitivity/angioedema. Isolated cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported with ACE inhibitors, including enalapril, occurring at different times during treatment. In such cases, treatment with the drug should be discontinued immediately and the patient should be monitored closely to ensure complete resolution of symptoms. Only after this monitoring should be discontinued. Even when only swelling of the tongue occurs without respiratory distress, patients may require prolonged monitoring, as treatment with antihistamines and corticosteroids may be inadequate.

Very rarely, fatal outcomes have been reported from angioedema of the larynx or tongue. If the swelling is localized to the tongue, glottis or larynx, especially in patients with a history of airway surgery, airway obstruction may occur. When there is involvement of the tongue, pharynx or larynx and this may cause airway obstruction, appropriate therapy should be initiated immediately, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and/or measures to maintain a patent airway.

Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of developing angioedema while receiving ACE inhibitor therapy.

Anaphylactoid reactions during hymenoptera venom allergen desensitization. Rarely, patients receiving ACE inhibitors during hymenoptera venom allergen desensitization have developed anaphylactoid reactions, which may be life-threatening. Such reactions can be avoided by temporarily stopping the ACE inhibitor before the desensitization begins.

Patients undergoing hemodialysis. Anaphylactoid reactions have occasionally been reported in patients undergoing dialysis using high-flux membranes (e.g. AN 69) and concomitantly receiving an ACE inhibitor. Therefore, it is recommended that a different type of dialysis membrane or a different class of antihypertensive agent be considered in such patients.

Hypoglycemia: Diabetic patients taking oral antidiabetic agents or insulin and initiating therapy with an ACE inhibitor should be advised to closely monitor blood sugar levels, especially during the first few months of concomitant use.

Cough: Cough has been reported with ACE inhibitors. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. Cough due to ACE inhibitor therapy should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: During major surgery or during anesthesia with drugs that cause hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension develops, which can be explained by these mechanisms of interaction, it is corrected by increasing the volume of fluid.

Hyperkalemia. During treatment with ACE inhibitors, including enalapril, increases in blood potassium levels have been observed in some patients. The risk of hyperkalemia is increased in patients with renal insufficiency, with impaired renal function, age > 70 years, with diabetes mellitus, with transient conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride); with the use of food supplements or salt substitutes containing potassium; and in patients taking other drugs that may increase blood potassium (e.g. heparin). In particular, the use of potassium-sparing diuretics, food supplements or salt substitutes containing potassium in patients with impaired renal function may lead to a significant increase in blood potassium levels. Hyperkalemia may cause serious, sometimes fatal arrhythmias. If concomitant use of enalapril and any of the above-mentioned drugs is considered necessary, they should be used with caution and with regular monitoring of serum potassium.

Lithium: The combination of lithium and enalapril is generally not recommended.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist: The combination of an ACE inhibitor with an angiotensin II receptor antagonist should be limited to individually defined cases, accompanied by careful monitoring of renal function, potassium levels and blood pressure.

The drug contains lactose, which should be taken into account in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

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 discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women.

ACE inhibitors when used during the II and III trimesters of pregnancy may cause fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) or neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors were taken during the second trimester of pregnancy, an ultrasound examination of the kidneys and skull is recommended.

Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Breastfeeding. Limited pharmacokinetic data indicate very low concentrations in breast milk. Although these concentrations are considered to be clinically insignificant, the use of the drug is not recommended during breastfeeding in premature infants and infants in the first few weeks after birth because of the hypothetical risk of cardiovascular and renal effects and because of insufficient experience in this regard. In the case of older infants, use of the drug during breastfeeding may be considered if treatment is necessary for the mother and the child is observed for any adverse effects.

Ability to influence reaction speed when driving vehicles or other mechanisms

When driving or operating other machinery, the possible development of dizziness or increased fatigue should be taken into account.

Method of administration and doses

Food intake does not affect the absorption of tablets. Since the tablet is not divided, if the drug is prescribed in a dose of less than 5 mg, enalapril preparations with the possibility of such a dosage should be used.

Arterial hypertension. The dose of the drug is from an initial 5 mg to a maximum of 20 mg depending on the degree of arterial hypertension and the patient's condition (see below). The drug should be taken once a day. In mild arterial hypertension, the recommended initial dose is 5-10 mg.

In patients with a strongly activated renin-angiotensin-aldosterone system (e.g. renovascular hypertension, salt and/or fluid imbalance, cardiac decompensation or severe hypertension), an excessive decrease in blood pressure may occur after the initial dose. In such patients, a starting dose of 5 mg or less is recommended and initiation of treatment should be under medical supervision.

Previous treatment with high doses of diuretics may lead to fluid depletion and a risk of hypotension at the start of enalapril therapy. In such patients, a starting dose of 5 mg or less is recommended. If possible, diuretic treatment should be discontinued 2-3 days before starting treatment with the drug. Renal function and serum potassium should be monitored.

The usual maintenance dose is 20 mg once daily. The maximum maintenance dose is 40 mg daily.

Heart failure/asymptomatic left ventricular dysfunction. For the treatment of clinically pronounced heart failure, the drug should be used together with diuretics and, if necessary, digitalis or beta-blockers. The initial dose of the drug for patients with clinically pronounced heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, while the use of the drug should be carried out under careful medical supervision in order to establish the initial effect of the drug on blood pressure. In the absence of effect or after appropriate correction of symptomatic hypotension that occurred at the beginning of treatment of heart failure with the drug, the dose should be gradually increased to the usual maintenance dose of 20 mg, which is administered once or divided into 2 doses, depending on what is better tolerated by the patient. Dose selection is recommended to be carried out within 2-4 weeks. Such a therapeutic regimen effectively reduces mortality rates in patients with clinically pronounced heart failure. The maximum dose is 40 mg per day in 2 divided doses.

Suggested dose titration for patients with heart failure/asymptomatic left ventricular dysfunction:

*The drug should be used with caution in patients with impaired renal function or those taking diuretics.

Blood pressure and renal function should be closely monitored both before and after initiation of treatment, as hypotension and (rarely) subsequent renal failure have been reported. Patients taking diuretics should have their dose reduced if possible before initiating treatment with the drug. The development of hypotension after the initial dose of the drug does not mean that hypotension will persist with continued treatment and does not indicate the need to discontinue the drug. Serum potassium and renal function should also be monitored.

Dosage in renal failure. In general, the interval between enalapril doses should be increased and/or the dosage of the drug should be reduced.

**Enalapril is removed by hemodialysis. Dosage adjustment on days when hemodialysis is not performed should be based on blood pressure.

Elderly patients: The dose should be adjusted based on renal function.

Children with hypertension aged 6 years and older. Clinical experience in children with hypertension is limited. For children who can swallow tablets, the dose should be individualized based on the patient's condition, blood pressure response to treatment, and body weight. The recommended initial dose is 2.5 mg for patients weighing 20 to 50 kg and 5 mg for patients weighing ≥ 50 kg. The drug should be taken once daily. The dosage should be adjusted as needed up to a maximum of 20 mg per day for patients weighing 20 to 50 kg and 40 mg for patients weighing ≥ 50 kg.

The drug is not recommended for newborns and children with glomerular filtration rate < 30 ml/min/1.73 m2 due to lack of data.

Children

Use for children aged 6 and over.

The drug is not recommended for newborns and children with glomerular filtration rate < 30 ml/min/1.73 m2 due to lack of data.

Overdose

There are limited data on overdose. The main signs of overdose, according to available data, are pronounced arterial hypotension, which begins approximately 6 hours after taking the drug and coincides with the blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdose with ACE inhibitors may include circulatory shock, electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. Plasma levels of enalaprilat, which exceed 100 and 200 times the maximum levels achieved with therapeutic doses, have been reported after taking 300 mg and 440 mg of enalapril, respectively.

For the treatment of overdose, intravenous infusions of isotonic solution are recommended. If hypotension occurs, the patient should be placed in a horizontal position. The need for infusions of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug has been taken recently, measures to eliminate enalapril maleate (such as induced emesis, gastric lavage, administration of absorbents and sodium sulfate) are recommended. Enalaprilat can be removed from the systemic circulation by hemodialysis. Pacemaker therapy is indicated for bradycardia resistant to therapeutic agents. Vital signs, electrolyte concentrations and serum creatinine should be monitored continuously.

Adverse reactions

When using the drug, in most cases, side effects were minor, temporary, and did not require discontinuation of therapy.

From the blood system: anemia (including aplastic and hemolytic), neutropenia, decreased hemoglobin, decreased hematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune diseases.

On the part of the endocrine system: syndrome of inappropriate antidiuretic hormone secretion.

Metabolic disorders: hypoglycemia.

From the nervous system and psyche: depression, headache, confusion, drowsiness, insomnia, nervousness, paresthesia, vertigo, sleep disorders, abnormal dreams.

On the part of the organs of vision: blurred vision.

Cardiovascular system: dizziness, hypotension (including orthostatic hypotension), syncope, chest pain, arrhythmia, angina pectoris, tachycardia, palpitations, myocardial infarction or stroke, possibly due to excessive blood pressure reduction in high-risk patients, Raynaud's phenomenon.

Respiratory system: cough, shortness of breath, rhinorrhea, sore throat and hoarseness, bronchospasm/asthma, pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal: nausea, diarrhea, abdominal pain, taste perversion, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers, stomatitis/aphthous ulcers, glossitis, intestinal angioedema.

Hepatobiliary system: hepatic failure, hepatitis (hepatocellular or cholestatic), hepatitis, including necrosis, cholestasis (including jaundice).

Skin and subcutaneous tissue disorders: rash, hypersensitivity/angioedema of the face, extremities, lips, tongue, glottis and/or larynx, increased sweating, itching, urticaria, alopecia, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, Lyell's syndrome, pemphigus, erythroderma.