Instructions for use Statorem-n tablets 20 mg/12.5 mg No. 28
Composition
active ingredients: lisinopril, hydrochlorothiazide;
1 tablet contains lisinopril dihydrate equivalent to lisinopril 20 mg and hydrochlorothiazide 12.5 mg;
excipients: mannitol (E 421), calcium hydrogen phosphate, corn starch, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white or almost white round flat tablets engraved with "K" on one side and plain on the other side.
Pharmacotherapeutic group
Angiotensin-converting enzyme inhibitors and diuretics. ATC code C09B A03.
Pharmacological properties
Pharmacodynamics.
Statorem®-N is a fixed-dose combination drug containing lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide (HCTZ), a thiazide diuretic. Both components have a similar mode of action and exhibit a synergistic hypotensive effect.
Lisinopril
Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits ACE, which catalyzes the conversion of angiotensin I to angiotensin II, a vasoconstrictor peptide. Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Inhibition of ACE leads to a decrease in the concentration of angiotensin II, which reduces the vasoconstrictor activity and secretion of aldosterone. A decrease in its secretion may lead to an increase in the concentration of potassium in the blood serum.
Lisinopril lowers blood pressure primarily by inhibiting the renin-angiotensin-aldosterone system (RAAS). Lisinopril is therefore an antihypertensive agent even in patients with low-renin hypertension. ACE is identical to kininase II, the enzyme that catalyzes the degradation of bradykinin. It remains uncertain whether elevated levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effect of lisinopril.
Hydrochlorothiazide
GCS is a diuretic and antihypertensive drug. It affects the mechanism of electrolyte reabsorption by the distal renal tubules and increases the excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. The mechanism of the hypotensive effect of thiazides is unknown. Thiazides usually do not affect normal blood pressure.
Non-melanoma skin cancer (NMSC)
Results from two pharmacoepidemiological studies based on data from the Danish National Cancer Registry demonstrated a cumulative dose-dependent association between HCT and the occurrence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). One study included a population of 71,533 BCC patients and 8,629 SCC patients, who were compared with 1,430,833 and 172,462 control patients, respectively. High-dose HCT use (≥ 50,000 mg cumulative) was associated with an adjusted hazard ratio (HR) of 1.29 (95% confidence interval (CI): 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose-dependent relationship was observed for both BCC and PCC. Another study showed a possible association between lip cancer (PCC) and HCT use: 633 cases of lip cancer (PCC) were compared with 63,067 control patients using a random sampling strategy. A cumulative dose-dependent relationship was demonstrated with an adjusted HR of 2.1 (95% CI: 1.7-2.6), increasing to HR of 3.9 (3.0-4.9) for high doses (25,000 mg) and HR of 7.7 (5.7-10.5) for the highest cumulative dose (100,000 mg) (see section 4.4).
Pharmacokinetics.
There is no clinically significant pharmacokinetic interaction between lisinopril and GCS. The combination tablet is bioequivalent to the concomitant administration of the individual components.
Lisinopril
Absorption
After oral administration of lisinopril, its maximum serum concentration (Cmax) is reached within approximately 7 hours, although in patients with acute myocardial infarction there is a tendency for a slight delay in the time required to reach Cmax. The average extent of absorption of lisinopril is approximately 25% with individual variability (6-60%) at all doses tested (5-80 mg). Absolute bioavailability is reduced by approximately 16% in patients with heart failure.
Food intake does not affect the absorption of lisinopril.
Distribution
Lisinopril does not bind to other serum proteins except circulating ACE.
According to preclinical studies, lisinopril has been shown to have poor penetration of the blood-brain barrier.
Elimination
Lisinopril is not biotransformed and is excreted entirely unchanged in the urine. After multiple doses of lisinopril, the elimination half-life is 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 ml/min. The decrease in serum concentrations shows a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturated binding to ACE and is not dose-proportional.
Impaired liver function in patients with cirrhosis results in a decrease (approximately 30%) in the absorption of lisinopril and an increase (approximately 50%) in its exposure compared to healthy volunteers (due to reduced clearance).
Kidney dysfunction
Impaired renal function reduces the clearance of lisinopril, which is excreted by the kidneys, but this reduction becomes clinically significant when the glomerular filtration rate (GFR) is below 30 ml/min.
At creatinine clearance of 30–80 ml/min, the mean area under the concentration-time curve (AUC) increases by only 13%, while at creatinine clearance of 5–30 ml/min, the AUC increases 4–5-fold.
Lisinopril is removed by hemodialysis. During 4 hours of hemodialysis, the plasma concentration of lisinopril decreased by an average of 60%, and the dialysis clearance was in the range of 40–55 ml/min.
Heart failure
Patients with heart failure are more likely to be exposed to lisinopril than healthy volunteers (AUC increases by an average of 125%), but based on urinary excretion data, absorption of lisinopril is approximately 16% reduced in patients with heart failure compared with healthy volunteers.
Elderly patients
Elderly patients have higher (approximately 60%) lisinopril blood concentrations and AUC values compared to young patients.
Hydrochlorothiazide
Absorption
When plasma levels of HCT were maintained for at least 24 hours, its plasma half-life ranged from 5.6 to 14.8 hours.
Distribution
Hydrochlorothiazide crosses the placental barrier and does not cross the blood-brain barrier.
Elimination
At least 61% of a dose of GCZ is excreted unchanged within 24 hours. After oral administration, urinary excretion of GCZ begins within 2 hours, reaches its peak at approximately 4 hours, and lasts for 6–12 hours.
Indication
The drug Statorem®-N is indicated for the treatment of mild to moderate arterial hypertension in patients whose condition has been stabilized as a result of the use of individual components in the same proportions.
Contraindication
Hypersensitivity to the active or auxiliary substances of the drug.
Hypersensitivity to any other ACE inhibitor.
Hypersensitivity to any sulfonamide drugs.
Concomitant use with sacubitril/valsartan.
Treatment with Statorem®-N can only be started 36 hours after taking the last dose of sacubitril/valsartan (see sections “Interaction with other medicinal products and other types of interactions” and “Special instructions for use”).
History of angioedema associated with previous treatment with ACE inhibitors.
Hereditary or idiopathic angioedema.
Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
Severe renal failure (creatinine clearance < 30 ml/min).
Anury.
Severe liver failure.
The simultaneous use of Statorem®-N with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR < 60 ml/min/1.73 m2) (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Antihypertensives
In combination with other antihypertensive drugs, Statorem®-N may lead to a decrease in blood pressure. Concomitant use of nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.
The combination of lisinopril with aliskiren-containing drugs should be avoided (see sections "Contraindications" and "Special warnings and precautions for use").
Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers and aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent.
of the drug (see sections "Pharmacodynamics", "Contraindications" and "Features of use").
Drugs that may increase the risk of developing angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections 4.3 and 4.4).
Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus, everolimus, temsirolimus) or vildagliptin may lead to an increased risk of angioedema (see section 4.4).
Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.
Reversible increases in serum lithium concentrations and, consequently, toxicity have been reported with concomitant use of ACE inhibitors. Diuretics and ACE inhibitors reduce the renal clearance of lithium and carry a high risk of lithium toxicity. The combination of lisinopril and hydrochlorothiazide with lithium is not recommended; if concomitant use is necessary, careful monitoring of serum lithium levels should also be performed (see section 4.4).
Potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, and other drugs that may affect serum potassium levels
The potassium-losing effect of thiazide diuretics is usually attenuated by the potassium-sparing effect of lisinopril.
Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients taking this medicine.
Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to a significant increase in serum potassium. Caution should also be exercised when using Statorem®-N concomitantly with other medicinal products that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic in the same way as amiloride. Therefore, the combination of Statorem®-N with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).
Drugs that can cause ventricular arrhythmia (torsades de pointes)
Due to the increased risk of hypokalemia when GHZ is administered concomitantly with drugs that cause ventricular arrhythmia (e.g. antiarrhythmics, some antidepressants, and other drugs that may cause ventricular arrhythmia), they should be used with caution.
Tricyclic antidepressants/antipsychotics/anesthetics
Concomitant use of some anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may further lead to a decrease in blood pressure (see section "Special warnings and precautions for use").
Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid
Prolonged use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid (> 3 g per day) and non-selective NSAIDs) may reduce the antihypertensive and diuretic effects of ACE inhibitors and thiazide diuretics. In addition, NSAIDs and ACE inhibitors may have an additive effect on serum potassium and may lead to impaired renal function. Such effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with impaired renal function (elderly or dehydrated patients).
Gold preparations
Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness, hypotension, which can be very severe) after injection of gold preparations (e.g. sodium aurothiomalate) have been reported more frequently in patients treated with ACE inhibitors.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. Thiazides may reduce arterial sensitivity to norepinephrine, but not sufficiently to eliminate the blood pressure-increasing effect of the drug.
Antidiabetic drugs
Treatment with thiazide diuretics may impair glucose tolerance. This phenomenon is more likely to occur during the first 2 weeks of combination therapy and in patients with impaired renal function. It may be necessary to adjust the dose of insulin or oral hypoglycemic agents in patients with diabetes mellitus. Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.
Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin, or laxatives
The hypokalemic effect of GHZ may be potentiated by drugs that affect potassium levels and hypokalemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, salicylic acid derivatives).
Hypokalemia may develop during the use of steroids or adrenocorticotropic hormone (ACTH).
Calcium salts
Thiazide diuretics may increase serum calcium levels by decreasing calcium excretion. If calcium or vitamin D supplements are required, serum calcium levels should be monitored and the dose adjusted accordingly.
Cardiac glycosides
Hypokalemia may increase the sensitivity or response of the heart to the toxic effects of digitalis drugs (including increased ventricular excitability).
Cholestyramine and colestipol
The absorption of GCS is reduced by colestipol or cholestyramine. Therefore, sulfonamide diuretics should be taken 1 hour before or 4–6 hours after taking these drugs.
Non-depolarizing muscle relaxants
Trimethoprim
Concomitant use of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalemia.
Sotalol
Thiazide-induced hypokalemia may increase the risk of sotalol-induced arrhythmia.
Allopurinol
Concomitant use of ACE inhibitors with allopurinol increases the risk of kidney damage, which may lead to an increased risk of leukopenia.
Cyclosporine Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal damage and hyperkalemia. Monitoring of serum potassium is recommended. Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Heparin
Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium is recommended.
Lovastatin
Concomitant use of ACE inhibitors and lovastatin increases the risk of developing hyperkalemia.
Cytostatics, immunosuppressants, procainamide
Thiazides may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects (see section "Special warnings and precautions for use").
Amantadine
Thiazides, including HTZ, may increase the risk of adverse reactions caused by amantadine.
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Patients concomitantly taking co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk of hyperkalemia (see section 4.4).
Alcohol, barbiturates, or anesthetics
Postural hypotension may be exacerbated by concomitant use of alcohol, barbiturates, or anesthetics.
Application features
Non-melanoma skin cancer (NMSC)
Two epidemiological studies using the Danish National Cancer Registry have reported an increased risk of NMSC (BCC and PCC) with increasing total hydrochlorothiazide dose. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for the development of NMSC.
Patients taking GCS should be informed of the risk of developing NMSC, the need to regularly inspect the skin for new lesions and to immediately report any suspicious skin lesions. In order to minimize the risk of developing skin cancer, patients should be advised to follow preventive measures, including limiting exposure to sunlight and UV rays, and to use appropriate protective equipment if exposed. Suspicious skin lesions should be investigated as soon as possible, including histological examination of biopsy material. In addition, the use of GCS should be reconsidered in patients with a history of NMSC (see section "Adverse reactions").
Symptomatic hypotension
Symptomatic hypotension is rare in patients with uncomplicated hypertension, but the risk of hypotension is greatest in patients who are volume-depleted, e.g. by diuretic therapy, dietary salt restriction, haemodialysis, diarrhoea or vomiting, or if the patient has severe renin-dependent hypertension (see sections 4.5 and 4.8).
In such patients, serum electrolytes should be monitored regularly. Dose selection and treatment of patients at increased risk of clinically significant hypotension should be initiated under close medical supervision.
The drug should be used with extreme caution in patients with ischemic heart disease or cerebrovascular disease, since excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular accident.
If hypotension develops, the patient should be placed on his back and, if necessary, an intravenous infusion of saline should be administered. Transient hypotension is not a contraindication to taking the next dose.
After restoration of circulating blood volume and normalization of blood pressure, therapy can be resumed at lower doses or the use of any of the components of the drug can be started as monotherapy.
In some patients with heart failure but normal or low blood pressure, a decrease in systemic blood pressure may occur with lisinopril. This effect is expected and is not usually a reason for discontinuation of the drug. If clinically significant hypotension occurs, a dose reduction or discontinuation of lisinopril and hydrochlorothiazide may be necessary.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy
As with other ACE inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction (e.g. due to aortic stenosis or hypertrophic cardiomyopathy).
The concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is known to increase the risk of hypotension, hyperkalaemia and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see section 4.5).
If double blockade is absolutely necessary, it should be performed under specialist supervision and with regular monitoring of kidney function, electrolytes, and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Kidney dysfunction
Thiazides are not recommended for use in patients with impaired renal function; thiazides are ineffective in creatinine clearance values of 30 mL/min or less (corresponding to moderate or severe renal insufficiency).
The combination of lisinopril and GCS should not be administered to patients with renal insufficiency (creatinine clearance ≤ 80 ml/min) until the doses of the individual components have been adjusted to match those in the combination product.
Hypotension occurring after initiation of treatment with ACE inhibitors in patients with heart failure may lead to further deterioration of renal function. In some cases, acute renal failure (usually reversible) has been reported.
In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, an increase in serum urea and creatinine concentrations may occur during the use of ACE inhibitors, usually reversible after discontinuation of therapy.
The likelihood of developing this condition is higher in patients with renal insufficiency. In the presence of vasorenal hypertension, there is an increased risk of developing severe arterial hypotension and renal insufficiency. Treatment of such patients is initiated under close medical supervision with the use of low doses of the drug, followed by careful dose titration. During the first weeks of treatment with a combination of lisinopril and GCS, renal function should be carefully monitored, since diuretics provoke the development of the above changes.
In some patients with arterial hypertension (without pronounced background kidney disease), with simultaneous use of lisinopril and a diuretic, an increase in the concentration of urea and creatinine in the blood serum may occur. The likelihood of developing these disorders is higher in patients with a history of renal failure. In such cases, a dose reduction and/or discontinuation of therapy with lisinopril and/or the diuretic may be required.
Previous diuretic therapy
Diuretics should be discontinued 2-3 days before starting the combination of lisinopril and GCS. If this is not possible, treatment should be initiated with lisinopril monotherapy at a dose of 5 mg.
Kidney transplant patients
Since there is no experience with the use of the combination of lisinopril and GCS in patients after kidney transplantation, prescribing Statorem®-N to this group of patients is not recommended.
Anaphylactoid reactions in patients undergoing hemodialysis
The combination of lisinopril and GCS is not indicated for the treatment of patients with renal failure requiring hemodialysis.
Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during certain types of hemodialysis (e.g., with high-flux AN69 membranes and with low-density lipoprotein (LDL) apheresis using dextran sulfate). In such cases, a different type of dialysis membrane or a different class of antihypertensive agent should be used.
Anaphylactoid reactions in patients undergoing LDL apheresis
In isolated cases, life-threatening anaphylactic reactions have been observed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent the development of anaphylactic reactions, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.
Liver dysfunction
Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, since minor changes in fluid and electrolyte balance may precipitate hepatic coma (see Contraindications). In rare cases, a syndrome of cholestatic jaundice or hepatitis with progression to fulminant hepatic necrosis, sometimes fatal, has been observed in association with ACE inhibitors. The mechanism of this syndrome is unclear. If jaundice or a significant increase in liver enzymes occurs during the use of lisinopril and GCS, Statorem®-N should be discontinued and the patient should be closely monitored.
Surgical interventions, anesthesia
Effects on metabolism and the endocrine system
Glucose tolerance may be impaired during concomitant use of ACE inhibitors and thiazides. Dosage adjustment of antidiabetic agents, including insulin, may be necessary. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, glycemia should be closely monitored during the first month of treatment with an ACE inhibitor.
Against the background of the use of thiazide diuretics, the latent form of diabetes mellitus may transition to manifest.
During thiazide therapy, cholesterol and triglyceride concentrations may increase.
In some patients, thiazide therapy may provoke the development of hyperuricemia and/or gout. However, lisinopril may accelerate the excretion of uric acid by the kidneys, thereby weakening the hyperuricemic effect of GCS.
Electrolyte imbalance
When treating with diuretics, regular determination of the electrolyte content in the patient's blood serum is indicated. When using thiazides, including GCS, a violation of water or electrolyte balance (hypokalemia, hyponatremia, hypochloremic alkalosis) is possible. Signs of a violation of water or electrolyte balance include: dry mouth, thirst, weakness, lethargy, drowsiness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, gastrointestinal disorders (nausea, vomiting). Hypervolemic hyponatremia may develop in patients with edema in hot weather. Chloride deficiency is usually insignificant and does not require treatment. Thiazides are known to increase the excretion of magnesium in the urine, which can lead to hypomagnesemia.
Thiazides may reduce urinary calcium excretion and cause a slight periodic increase in serum calcium. Marked hypercalcemia may be a sign of latent hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid function.
Hyperkalemia
ACE inhibitors may cause hyperkalemia because they inhibit aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, in patients with impaired renal function, type 2 diabetes mellitus and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, and in patients taking drugs that can increase serum potassium levels (such as heparin, trimethoprim or the combined drug co-trimoxazole known as trimethoprim/sulfamethoxazole and, in particular, aldosterone antagonists or angiotensin receptor blockers), hyperkalemia may develop. If concomitant use of the above drugs is necessary, regular monitoring of serum potassium and renal function is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Patients with diabetes
In diabetic patients receiving oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).
Hypersensitivity, angioedema
Angioedema of the face, extremities, lips, tongue, pharynx and/or larynx may occur in rare cases during treatment with ACE inhibitors, including lisinopril. Angioedema may occur at any time during treatment.
If such a reaction develops, lisinopril should be discontinued immediately, the patient should receive appropriate therapy and be under medical supervision until the symptoms have completely disappeared.
Even when only tongue swelling is observed (without respiratory function impairment), the patient is indicated for prolonged observation, because the use of antihistamines and corticosteroids may be ineffective.
In rare cases, angioedema of the larynx or tongue may be fatal. Swelling of the tongue, glottis or larynx may lead to airway obstruction, particularly in patients who have undergone respiratory surgery. In such cases, emergency treatment is indicated. It may be necessary to administer adrenaline and/or maintain a patent airway. The patient should be kept under close medical supervision until complete and sustained resolution of symptoms.
Angioedema is more common in black patients taking ACE inhibitors than in non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving ACE inhibitors (see section 4.3).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue with or without respiratory distress) (see section 4.5).
Patients already taking ACE inhibitors should be initiated with caution when starting treatment with racecadotril, mTOR inhibitors, and vildagliptin.
Thiazides
Hypersensitivity reactions may occur in patients taking thiazides, regardless of a history of allergy or bronchial asthma. Cases of the onset or exacerbation of systemic lupus erythematosus have been described in association with the use of thiazide diuretics.
Desensitization
Patients taking ACE inhibitors may experience anaphylactoid reactions during desensitization (e.g., with hymenoptera venom). These reactions can be avoided by temporarily stopping the ACE inhibitor, but adverse reactions may recur if the drug is accidentally re-administered.
Neutropenia/agranulocytosis
Cases of neutropenia (agranulocytosis), thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other complicating factors. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor. Lisinopril should be used with extreme caution in patients with systemic connective tissue diseases, on immunosuppressive therapy, with allopurinol or procainamide therapy, or with a combination of these complicating factors, especially in patients with impaired renal function. Sometimes in this category of patients the development of serious infections was observed, including those that did not respond to intensive antibiotic therapy. When prescribing lisinopril to such patients, it is recommended to periodically monitor the content of leukocytes in the blood. Patients should be informed of the need to immediately report any signs of infection to their doctor.
Ethnicity
Angioedema is more common in black patients taking ACE inhibitors than in non-black patients.
As with other ACE inhibitors, lisinopril is less effective in lowering blood pressure in black patients than in non-black patients, probably because of the predominantly low-renin status of black hypertensive patients.
Cough
Cough may develop during treatment with ACE inhibitors. Cough is typically nonproductive, persistent, and resolves after discontinuation of therapy. Cough associated with ACE inhibitors should be considered in the differential diagnosis.
Lithium preparations
The concomitant use of ACE inhibitors and lithium preparations is generally not recommended (see section “Interaction with other medicinal products and other types of interactions”).
Anti-doping test
The drug Statorem®-N contains GCTZ, the use of which may lead to positive results in an anti-doping test.
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor 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 occurs, ACE inhibitor treatment should be stopped immediately, and, if possible, alternative therapy should be started (see sections 4.4 and 4.8).
