Co-diroton®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CO-DIROTON® (CO-DIROTON®)
Composition:
Active substances: lisinopril, hydrochlorothiazide;
1 tablet of Co-Diroton**®** 10 mg/12.5 mg contains lisinopril 10 mg (in the form of lisinopril dihydrate 10.88 mg) and hydrochlorothiazide 12.5 mg;
Excipients: mannitol (E 421), indigotine (E 132), maize starch, pregelatinized starch, calcium hydrogen phosphate dihydrate, partially pregelatinized starch, magnesium stearate;
1 tablet of Co-Diroton**®** 20 mg/12.5 mg contains lisinopril 20 mg (in the form of lisinopril dihydrate 21.76 mg) and hydrochlorothiazide 12.5 mg;
Excipients: mannitol (E 421), indigotine (E 132), yellow iron oxide (E 172), maize starch, pregelatinized starch, calcium hydrogen phosphate dihydrate, partially pregelatinized starch, magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
Co-Diroton® 10 mg/12.5 mg: round, flat on both sides, with beveled edges, light blue tablets with few darker specks. Embossed with "C 43" on one side. Diameter approximately 8 mm.
Co-Diroton® 20 mg/12.5 mg: round, flat on both sides, with beveled edges, light green tablets with few darker specks. Embossed with "C 44" on one side. Diameter approximately 8 mm.
Pharmacotherapeutic group.
Angiotensin-converting enzyme inhibitors (ACE inhibitors) and diuretics.
ATC code C09B A03.
Pharmacological properties.
Co-Diroton® is a fixed-dose combination drug containing lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide, a thiazide diuretic. Both components exhibit complementary and additive antihypertensive effects.
Pharmacodynamics
Lisinopril. Mechanism of action.
Lisinopril is an inhibitor of the enzyme peptidyl dipeptidase. Lisinopril inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I into the vasoconstrictive peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. As a result of ACE inhibition, angiotensin II concentration decreases, leading to reduced vasoconstrictive activity and aldosterone secretion. This effect leads to increased serum potassium concentration.
Lisinopril is believed to lower blood pressure primarily through inhibition of the renin-angiotensin-aldosterone system (RAAS). However, lisinopril exerts antihypertensive effects even in hypertension with low renin activity. ACE is identical to kininase II, an enzyme involved in bradykinin degradation. It is not known whether increased bradykinin levels (a potent vasodilatory peptide) contribute to the therapeutic effect of lisinopril.
Clinical efficacy and safety
Agents affecting the renin-angiotensin system (RAS)
It is known that two large-scale randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]) evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker.
The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ ischemia. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.
In these trials, no significant beneficial effect on renal and/or cardiovascular outcomes or mortality was demonstrated, while there was a higher risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. These findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers due to their similar pharmacodynamic properties. Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
It is known that the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was conducted to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse events. The rate of fatal outcomes due to cardiovascular disease and stroke was higher in the aliskiren group than in the placebo group, and adverse reactions, including serious ones (hyperkalemia, hypotension, and renal failure), occurred more frequently in the aliskiren group compared to placebo.
Hydrochlorothiazide. Mechanism of action.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal renal tubules and increases the excretion of sodium and chloride ions to a similar extent. Natriuresis may be accompanied by some loss of potassium and bicarbonate. The mechanism of antihypertensive action of thiazide diuretics is not fully understood.
Thiazides generally do not affect normal blood pressure.
Non-melanoma skin cancer (NMSC)
Based on available data from epidemiological studies, an association has been described between cumulative hydrochlorothiazide dose and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), with control groups of 1,430,833 and 172,462 individuals, respectively. High-dose hydrochlorothiazide use (cumulative dose ≥50,000 mg) was associated with the following adjusted odds ratios: 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship between cumulative dose and skin cancer risk was observed for both BCC and SCC. Another study suggested a possible association between lip cancer (SCC) and hydrochlorothiazide use: 633 cases of lip cancer were compared with 63,067 control subjects using a case-control method. A dose-dependent association was demonstrated with an odds ratio of 2.1 (95% CI: 1.7–2.6), increasing to 3.9 (3.0–4.9) with high-dose hydrochlorothiazide (~25,000 mg) and up to 7.7 (5.7–10.5) with the highest cumulative doses (~100,000 mg) (see section "Special precautions for use").
Pharmacokinetics.
Concomitant administration of lisinopril and hydrochlorothiazide has minimal (or no) effect on the bioavailability of each component. The combination drug is bioequivalent to the co-administration of the components as separate dosage forms.
Lisinopril.
Absorption. After oral administration, peak plasma concentration of lisinopril is reached within approximately 7 hours, although there is a tendency toward slight delay in time to peak concentration in patients with acute myocardial infarction. Based on urinary excretion data, the mean absorption of lisinopril across the studied dose range (5–80 mg) is approximately 25%, with inter-individual variability ranging from 6% to 60%. Absolute bioavailability is reduced by approximately 16% in patients with heart failure. Absorption of lisinopril is not affected by food intake.
Distribution. Lisinopril does not bind to other serum proteins except circulating angiotensin-converting enzyme (ACE).
It is known that lisinopril poorly penetrates the blood-brain barrier.
Elimination. Lisinopril is not metabolized, and all absorbed drug is excreted unchanged by the kidneys. With repeated dosing, lisinopril has an effective accumulation half-life of 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. Decreasing serum concentration indicates a prolonged terminal phase, which is not due to drug accumulation. This terminal phase may reflect saturable binding to ACE and is not dose-dependent.
Hepatic impairment.
Compared to healthy volunteers, patients with liver dysfunction due to cirrhosis showed reduced absorption (approximately 30% lower based on urinary excretion data), but increased lisinopril effect (approximately 50% higher) due to reduced clearance.
Renal impairment.
In renal impairment, elimination of lisinopril, which is excreted by the kidneys, is slowed. However, this delay becomes clinically significant only when glomerular filtration rate decreases to <30 mL/min.
Table 1
Pharmacokinetic parameters of lisinopril after repeated administration of 5 mg dose in various patient groups with kidney disease
| Renal function according to creatinine clearance rate |
Number |
Cmax (ng/mL) |
Tmax (h) |
AUC (0–24 h) (ng·h/mL) |
t1/2 (h) |
| >80 mL/min |
6 |
40.3 |
6 |
492+/-172 |
6.0+/-1.1 |
| 30–80 mL/min |
6 |
36.6 |
8 |
555+/-364 |
11.8+/-1.9 |
| 5–30 mL/min |
6 |
106.7 |
8 |
2228+/-938 |
19.5+/-5.2 |
In patients with creatinine clearance of 30−80 mL/min, an increase in the mean AUC (area under the concentration-time curve) is observed by only 13%; in patients with creatinine clearance of 5−30 mL/min, a 4−5-fold increase in the mean AUC is observed.
Lisinopril can be removed from the body by hemodialysis. After a 4-hour hemodialysis session, a mean reduction of 60% in plasma lisinopril concentration was observed (with a dialysis clearance rate of 40−55 mL/min).
Heart failure. Patients with heart failure are subject to a greater effect of lisinopril compared to healthy volunteers (an average increase in AUC of 125%), but based on data on urinary excretion of lisinopril, it has been established that their absorption is reduced by approximately 16% compared to healthy volunteers.
Elderly patients. Elderly patients have higher plasma AUC values (increased by approximately 60%) compared to younger volunteers.
Hydrochlorothiazide
When monitoring hydrochlorothiazide plasma concentrations for at least 24 hours, its elimination half-life ranged from 5.6 to 14.8 hours.
At least 61% of the drug is excreted unchanged within 24 hours. After oral administration of hydrochlorothiazide, the diuretic effect develops within 2 hours, reaches its maximum at 4 hours, and persists for 6−12 hours.
Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.
Clinical characteristics.
Indications.
Treatment of patients with mild to moderate stable arterial hypertension receiving monotherapy with the same individual components at equivalent doses.
Contraindications.
- Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition".
- Hypersensitivity to other angiotensin-converting enzyme (ACE) inhibitors.
- Hypersensitivity to any sulfonamide derivatives.
- History of angioedema associated with previous use of ACE inhibitors.
- Hereditary or idiopathic angioedema.
- Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation").
- Severe renal impairment (creatinine clearance <30 mL/min).
- Anuria.
- Severe hepatic impairment.
- Concomitant use of Co-Diroton**®** with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate <60 mL/min/1.73 m²) (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").
- Concomitant use with sacubitril/valsartan; initiation of Co-Diroton**®** should not begin earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
Interaction with other medicinal products and other forms of interaction.
Antihypertensive medicinal products
Concomitant use with other antihypertensive agents may enhance antihypertensive effects. Combined use with nitroglycerin, other nitrates, or vasodilators may potentiate the antihypertensive effect.
Co-administration of lisinopril with aliskiren-containing products should be avoided (see sections "Contraindications" and "Special precautions for use").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy affecting the RAAS (see sections "Contraindications" and "Special precautions for use").
Medicinal products that may increase the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").
Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase inhibitors (e.g., racecadotril), tissue plasminogen activator, or vildagliptin may increase the risk of angioedema.
Lithium-containing products
Cases of reversible increases in serum lithium levels and signs of lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Diuretics and ACE inhibitors reduce renal lithium clearance, increasing the risk of lithium toxicity. Therefore, the combination of lisinopril and hydrochlorothiazide with lithium-containing products is not recommended. If such combination therapy is necessary, serum lithium levels should be monitored carefully (see section "Special precautions for use").
Potassium-sparing diuretics, potassium-containing dietary supplements or salt substitutes, and other medicinal products that may increase plasma potassium levels
Although serum potassium levels usually remain within normal limits during lisinopril therapy, hyperkalemia may occur in some patients. Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium-containing dietary supplements, or salt substitutes may significantly increase serum potassium levels, particularly in patients with renal impairment or type 2 diabetes mellitus. Caution is advised when lisinopril is used concomitantly with other agents that increase serum potassium, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim has effects similar to potassium-sparing diuretics like amiloride. Therefore, concomitant use of lisinopril with the above-mentioned agents is not recommended. If concomitant use is necessary, caution should be exercised and periodic monitoring of serum potassium levels is recommended (see section "Special precautions for use").
Heparin
Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.
Medicinal products capable of inducing ventricular tachycardia of the torsades de pointes type
Due to the risk of hypokalemia, caution should be exercised when hydrochlorothiazide is used concomitantly with medicinal products capable of inducing torsades de pointes ventricular tachycardia (e.g., certain antiarrhythmics, antipsychotics, and other agents).
Tricyclic antidepressants / antipsychotics / anesthetics
Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to additional reduction in blood pressure (see section "Special precautions for use").
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid
Prolonged use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid at doses > 3 g/day, non-selective NSAIDs) may reduce the antihypertensive and diuretic effects of ACE inhibitors and thiazides. Concomitant use of NSAIDs and ACE inhibitors may increase serum potassium levels and worsen renal function. These effects are usually reversible. In rare cases, renal failure may develop, particularly in patients with pre-existing renal impairment, such as elderly patients or those with dehydration.
Gold preparations
Nitritoid (vasomotor) reactions have been observed more frequently in patients receiving ACE inhibitors who are also treated with injectable gold preparations (e.g., sodium aurothiomalate). Nitritoid reactions are characterized by symptoms of vasodilation (flushing), nausea, dizziness, and hypotension, which may be severe.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. Thiazides may reduce vascular responsiveness to norepinephrine, but not sufficiently to preclude the pressor effect of vasoactive agents.
Antidiabetic agents
Thiazide use may impair glucose tolerance. This effect most commonly occurs during the first weeks of combination therapy in patients with impaired renal function. Dose adjustments of hypoglycemic agents, including insulin, may be required in patients with diabetes mellitus.
Thiazide diuretics may potentiate the hyperglycemic effect of diazoxide.
Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH), or stimulant laxatives
The hypokalemic effect of hydrochlorothiazide may be enhanced by medicinal products affecting potassium levels and promoting hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin B, carbenoxolone, salicylate derivatives).
Hypokalemia may develop during concomitant use of corticosteroids or ACTH.
Calcium salts
Thiazide diuretics may increase serum calcium levels due to reduced excretion. If concomitant use of calcium or vitamin D supplements is required, careful monitoring of serum calcium levels is recommended, with dose adjustments as necessary.
Cardiac glycosides
Hypokalemia may increase cardiac sensitivity or the toxic effects of digitalis preparations (including increased ventricular excitability).
Cholestyramine and colestipol
Concomitant use with cholestyramine and colestipol reduces the absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be administered at least 1 hour before or 4–6 hours after these agents.
Non-depolarizing muscle relaxants (e.g., tubocurarine chloride)
Thiazides may enhance sensitivity to non-depolarizing muscle relaxants (e.g., tubocurarine).
Sotalol
Hypokalemia induced by thiazide use may increase the risk of arrhythmias during sotalol therapy.
Allopurinol
Concomitant use of ACE inhibitors and allopurinol increases the risk of renal impairment and leukopenia.
Cyclosporine
Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal impairment and hyperkalemia. Monitoring of serum potassium levels is recommended.
Lovastatin
Concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.
Cytostatics, immunosuppressants, procainamide
Thiazides may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects (see section "Special precautions for use").
Other concomitant medicinal products
Thiazides may increase the risk of adverse reactions associated with amantadine.
Alcohol, barbiturates, and anesthetics may enhance orthostatic hypotension.
Special precautions for use.
Symptomatic arterial hypotension
Rarely, symptomatic arterial hypotension may occur in patients with uncomplicated arterial hypertension. The risk of decreased blood pressure is greatest in patients with reduced circulating blood volume, e.g., due to diuretic therapy, salt-restricted diet, hemodialysis, diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").
In such patients, serum electrolyte levels 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 medicinal product should be used with particular caution in patients with ischemic heart disease or cerebrovascular disorders, since excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular accident.
If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, intravenous infusion of physiological saline solution should be administered. Transient hypotension is not a contraindication for taking the next dose. After restoration of circulating blood volume and normalization of blood pressure, therapy may be resumed at lower doses or one of the components may be used as monotherapy.
In some patients with heart failure but with normal or low blood pressure on lisinopril therapy, a reduction in systemic arterial pressure may occur. This effect is expected and usually does not require discontinuation of the drug. If clinically significant hypotension develops, dose reduction or discontinuation of lisinopril and hydrochlorothiazide therapy 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 or left ventricular outflow tract obstruction (e.g., due to aortic stenosis or hypertrophic cardiomyopathy).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
It is known that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal dysfunction (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 "Interaction with other medicinal products and other forms of interaction").
If dual blockade is absolutely necessary, it should be performed under specialist supervision with regular monitoring of renal function, electrolyte levels, and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Renal impairment
Thiazides may not be recommended for use in patients with renal impairment; thiazides are ineffective when creatinine clearance is ≤30 mL/min or lower (corresponding to moderate or severe renal insufficiency).
The combination of lisinopril and hydrochlorothiazide should not be prescribed to patients with renal insufficiency (creatinine clearance ≤80 mL/min) until doses of individual components corresponding to those in the combined product have been established.
Arterial hypotension occurring after initiation of ACE inhibitor therapy 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 of a solitary kidney, ACE inhibitor therapy may lead to increased serum urea and creatinine concentrations, usually reversible upon discontinuation of therapy. The likelihood of this condition is higher in patients with pre-existing renal insufficiency. In patients with renovascular hypertension, there is an increased risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under close medical supervision using low doses of the drug with careful dose titration. During the first weeks of treatment with the combination of lisinopril and hydrochlorothiazide, renal function should be carefully monitored, as diuretics may promote the development of the aforementioned changes.
In some patients with arterial hypertension (without significant underlying kidney disease), concomitant use of lisinopril and a diuretic may lead to increased serum urea and creatinine concentrations. The likelihood of these disturbances is higher in patients with a history of renal insufficiency. In such cases, dose reduction and/or discontinuation of lisinopril and/or diuretic therapy may be required.
Previous diuretic therapy
Diuretic therapy should be discontinued 2–3 days before initiating treatment with the combination of lisinopril and hydrochlorothiazide. If this is not possible, treatment should be initiated with lisinopril monotherapy at a dose of 5 mg.
Post-kidney transplantation state
As there are no data on the use of lisinopril in patients after kidney transplantation, the use of Co-Diroton**®** in this patient group is not recommended.
Anaphylactoid reactions in patients undergoing hemodialysis
The combination of lisinopril and hydrochlorothiazide is not indicated for the treatment of patients with renal insufficiency requiring hemodialysis.
There have been reports of anaphylactoid reactions in patients receiving ACE inhibitors during certain types of hemodialysis (e.g., using high-flux AN69 membranes) and during low-density lipoprotein (LDL) apheresis using dextran sulfate. In such cases, dialysis membranes of another type should be used or antihypertensive agents from other classes should be administered.
Anaphylactoid reactions during low-density lipoprotein (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 such reactions, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.
Liver disease
Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as minor disturbances in fluid and electrolyte balance may precipitate hepatic coma (see section "Contraindications"). Rarely, cholestatic jaundice or hepatitis progressing to fulminant hepatic necrosis, sometimes fatal, has been observed during ACE inhibitor therapy. The mechanism of this syndrome is unclear. If jaundice or a significant increase in liver enzymes occurs during treatment with the combination of lisinopril and hydrochlorothiazide, Co-Diroton**®** should be discontinued and the patient should remain under close medical supervision.
Surgery and anesthesia
During surgical procedures or anesthesia with agents causing arterial hypotension, lisinopril may block angiotensin II formation in response to compensatory renin release. If arterial hypotension occurs due to this mechanism, volume expansion is indicated.
Effects on metabolism and the endocrine system
Impaired glucose tolerance may occur during therapy with ACE inhibitors and thiazides. Adjustment of antidiabetic drug doses, including insulin, may be required. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy.
Latent diabetes mellitus may become manifest during thiazide diuretic therapy.
Therapy with thiazides may increase serum cholesterol and triglyceride concentrations.
In some patients, thiazide therapy may provoke hyperuricemia and/or gout. However, lisinopril may enhance renal excretion of uric acid, thereby attenuating the hyperuricemic effect of hydrochlorothiazide.
Electrolyte imbalance
Regular monitoring of serum electrolytes is recommended during diuretic therapy. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid or electrolyte balance (hypokalemia, hyponatremia, hypochloremic alkalosis). Signs of fluid or electrolyte imbalance include dry mouth, thirst, weakness, lethargy, somnolence, muscle pain or cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting). In patients with edema during hot weather, hyperchloremic hyponatremia may develop. Chloride deficiency is usually mild and does not require treatment. Thiazides are known to increase urinary magnesium excretion, which may lead to hypomagnesemia.
Thiazides may reduce calcium excretion in urine and cause slight periodic increases in serum calcium levels. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretics should be discontinued before parathyroid function testing.
Hyperkalemia
ACE inhibitors may cause hyperkalemia as they suppress aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, in patients with renal impairment, type 2 diabetes mellitus, and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, or medicinal products capable of increasing serum potassium levels (such as heparin, trimethoprim, or the combination drug co-trimoxazole, known as trimethoprim/sulfamethoxazole, and particularly aldosterone antagonists or angiotensin II receptor blockers), hyperkalemia may develop. If concomitant use of these medicinal products is necessary, regular monitoring of serum potassium levels and renal function is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Patients with diabetes mellitus
In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Hypersensitivity, angioedema
ACE inhibitors
Angioedema of the face, extremities, lips, tongue, pharynx, and/or larynx may occur rarely during therapy with ACE inhibitors, including lisinopril, at any time during treatment. Angioedema may occur at any time during therapy. If such a reaction occurs, lisinopril should be discontinued immediately; the patient should receive appropriate treatment and remain under medical supervision until symptoms have completely resolved. Even if only tongue swelling occurs (without respiratory impairment), prolonged observation is required, as antihistamines and corticosteroids may be ineffective.
In rare cases, angioedema of the larynx or tongue may be fatal. Swelling of the tongue, vocal cords, or larynx may lead to airway obstruction, particularly in patients who have undergone surgery on the respiratory tract. In such cases, emergency treatment is indicated. Administration of epinephrine solution and/or securing airway patency may be required. The patient should remain under close medical supervision until symptoms have completely and stably resolved.
Angioedema occurs more frequently in patients of non-Caucasian race receiving ACE inhibitors than in patients of other races.
Patients with a history of angioedema unrelated to ACE inhibitor use may be more susceptible to developing angioedema during ACE inhibitor therapy (see section "Contraindications").
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of lisinopril. Treatment with lisinopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., swelling of the airways or tongue with or without respiratory insufficiency) (see section "Interaction with other medicinal products and other forms of interaction").
Patients already receiving ACE inhibitors should begin treatment with racécadotril, mTOR inhibitors, or vildagliptin with caution.
Thiazides
Hypersensitivity reactions may occur in patients receiving thiazides, regardless of a history of allergy or bronchial asthma. Cases of development or exacerbation of systemic lupus erythematosus have been reported during thiazide diuretic therapy.
Acute respiratory toxicity
Rare but severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after administration of hydrochlorothiazide. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening of lung condition, and arterial hypotension. If ARDS is suspected, Co-Diroton**®** should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients with a history of ARDS after hydrochlorothiazide administration.
Desensitization
Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization procedures (e.g., insect venom). These reactions may be avoided by temporarily discontinuing the ACE inhibitor, but adverse reactions may recur upon accidental re-administration.
Non-melanoma skin cancer
In two epidemiological studies using the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (NMSC) (BCC and SCC) was observed with increasing cumulative doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC, the need for regular skin examinations for new lesions, and the necessity to promptly report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to follow preventive measures, including limiting exposure to sunlight and UV radiation, and using appropriate protective measures when exposure occurs. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. Additionally, the possibility of using hydrochlorothiazide in patients with a history of NMSC should be reconsidered (see section "Contraindications").
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 risk factors. Neutropenia and agranulocytosis are reversible and resolve after discontinuation of the ACE inhibitor. Lisinopril should be used with extreme caution in patients with connective tissue diseases, immunosuppressive therapy, allopurinol or procainamide therapy, or a combination of these risk factors, particularly in patients with renal impairment. Serious infections, including those unresponsive to intensive antibiotic therapy, have occasionally been observed in this patient group. Periodic monitoring of white blood cell counts is recommended when prescribing lisinopril to such patients. Patients should be informed to immediately report any signs of infection to their physician.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical, surgical, or pharmacological interventions may be necessary. A history of allergy to sulfonamides or penicillin is a risk factor for acute angle-closure glaucoma.
Ethnicity
Angioedema occurs more frequently in patients of non-Caucasian race receiving ACE inhibitors than in patients of other races.
As with other ACE inhibitors, lisinopril is less effective in lowering blood pressure in patients of non-Caucasian race compared to patients of other races. This is likely related to the predominantly low renin levels in non-Caucasian patients with arterial hypertension.
Cough
Cough may develop during ACE inhibitor therapy. The cough is non-productive, persistent, and resolves after discontinuation of therapy. Cough due to ACE inhibitor use should be considered in differential diagnosis.
Lithium-containing medicinal products
Concomitant use of ACE inhibitors and lithium-containing medicinal products is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Antidoping test
The medicinal product Co-Diroton**®** contains hydrochlorothiazide, the use of which may lead to positive results in antidoping tests.
Use during pregnancy or breastfeeding
Pregnancy
ACE inhibitors
ACE inhibitors are contraindicated during pregnancy (see section "Contraindications").
Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy do not allow definitive conclusions. However, the possibility of such risk cannot be excluded. Alternative antihypertensive therapy with a proven safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy occurs during therapy, the ACE inhibitor should be discontinued immediately and, if possible, alternative therapy initiated.
It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may lead to fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If an ACE inhibitor has been used from the second trimester of pregnancy, ultrasound examination of fetal kidneys and skull bones is recommended. Newborns whose mothers received ACE inhibitors should be closely monitored due to the possible development of arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy (particularly in the first trimester) is limited. Animal studies are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to its pharmacological mechanism of action, use of hydrochlorothiazide during the second and third trimesters of pregnancy may impair circulation in the fetoplacental complex and lead to jaundice, electrolyte imbalance, and thrombocytopenia in the newborn.
Hydrochlorothiazide should not be used for gestational edema, pregnancy-induced hypertension, or preeclampsia, as it may reduce plasma volume and cause placental hypoperfusion, without any beneficial effect on the disease course.
Hydrochlorothiazide should not be used for the treatment of essential arterial hypertension in pregnant women except in rare cases where alternative therapy is not possible.
Breastfeeding period
ACE inhibitors
Due to lack of information on the use of the combination of lisinopril and hydrochlorothiazide during breastfeeding, use of this combination is not recommended (see section "Contraindications"). During breastfeeding, medicinal products with a better-established safety profile should be used, especially when caring for a newborn or premature infant.
Hydrochlorothiazide
Hydrochlorothiazide passes into breast milk in small amounts. High doses of thiazides cause intense diuresis and may suppress breast milk production. Use of the combination of lisinopril and hydrochlorothiazide during breastfeeding is not recommended. If the combination of lisinopril and hydrochlorothiazide is used during breastfeeding, the lowest possible dose of this combined product should be prescribed.
Ability to influence reaction speed when driving vehicles or operating machinery
During antihypertensive therapy (including use of the combination of lisinopril and hydrochlorothiazide), a slight or moderate effect on the ability to drive vehicles or operate machinery may occur. Difficulties in driving vehicles or operating machinery are individual and occur more frequently at the beginning of therapy or after dose changes, as well as with alcohol consumption.
When driving a vehicle or operating machinery, it should be considered that dizziness and fatigue may occur during treatment with Co-Diroton**®** (see section "Undesirable effects").
Dosage and Administration
Essential arterial hypertension
Fixed-dose combination therapy is not suitable for initiating treatment. The fixed-dose combination product may replace the combination of 10 mg or 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide in patients whose condition has been stabilized on therapy with the individual active substances at the same doses administered as separate medications. The standard dose is 1 tablet once daily. As with any other medication taken once daily, Co-Diroton**®** should be taken approximately at the same time each day.
If the desired therapeutic effect is not achieved within 2−4 weeks of treatment, the dose may be increased to 2 tablets once daily.
Renal impairment
Thiazide diuretics are not recommended for patients with impaired renal function; thiazides are ineffective when creatinine clearance is ≤30 mL/min (i.e., in moderate or severe renal insufficiency).
Co-Diroton**®** must not be used as initial therapy in patients with renal insufficiency. In patients with creatinine clearance >30 and <80 mL/min, Co-Diroton**®** may be used only after individual dose titration of each component of the medication. The recommended dose of lisinopril when used as monotherapy in mild renal insufficiency is 5−10 mg.
Previous diuretic therapy
Symptomatic arterial hypotension may develop after administration of the first dose of Co-Diroton**®. This condition is more likely to occur in patients with disturbances in fluid and electrolyte balance due to prior diuretic therapy. Diuretic treatment should be discontinued 2−3 days before starting therapy with Co-Diroton®**. If this is not possible, treatment should be initiated with monotherapy using lisinopril 5 mg.
Elderly patients
Dose adjustment is not required in elderly patients.
It is known that the efficacy and tolerability profiles of lisinopril and hydrochlorothiazide when used concomitantly are similar in elderly and younger patients with arterial hypertension. The efficacy of lisinopril administered at doses of 20 to 80 mg was comparable in elderly patients (over 65 years of age) and younger patients; monotherapy with lisinopril also effectively reduced diastolic blood pressure, as did monotherapy with hydrochlorothiazide or atenolol. According to available clinical trial data, age does not affect the tolerability of lisinopril.
Children
The safety and efficacy of this medicinal product for use in children have not been established.
Overdose.
Human data on overdose are limited. In cases of ACE inhibitor overdose, the following symptoms may occur: arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
In case of overdose, infusion of physiological saline is indicated. If arterial hypotension develops, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines may be necessary. If the drug has been recently ingested, measures aimed at eliminating lisinopril should be undertaken (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate).
Lisinopril can be removed from systemic circulation by hemodialysis (see section "Special instructions"). In case of bradycardia unresponsive to therapy, implantation of an artificial pacemaker is indicated. Vital functions, serum electrolyte levels, and serum creatinine should be closely monitored.
Symptoms of hydrochlorothiazide overdose include increased diuresis, suppression of consciousness (up to coma), seizures, paresis, cardiac arrhythmias, and renal failure.
Atropine administration is indicated for treatment of bradycardia or pronounced vagal reactions.
Hypokalemia may potentiate arrhythmias in patients receiving digoxin.
Adverse reactions
The adverse reactions listed below, reported during treatment with lisinopril and (or) hydrochlorothiazide, are categorized by frequency 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), and frequency not known (cannot be estimated from available data).
Among adverse reactions, cough, dizziness, arterial hypotension, and headache were most commonly observed (occurring in 1−10% of patients). According to clinical trial data, adverse reactions were generally mild, transient in nature, and in most cases did not require discontinuation of therapy.
Lisinopril
| Frequency of adverse reactions |
|||||
| Organ system |
Common |
Uncommon |
Rare |
Very rare |
Frequency not known |
| Blood and lymphatic system disorders |
decreased hemoglobin levels, decreased hematocrit |
bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section "Special precautions"), hemolytic anemia, lymphadenopathy, autoimmune disorders |
|||
| Immune system disorders |
anaphylactic/ anaphylactoid reaction |
||||
| Endocrine disorders |
syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
||||
| Metabolism and nutrition disorders |
hypoglycemia |
||||
| Psychiatric disorders |
mood lability, symptoms of depression |
confusion |
hallucinations |
||
| Nervous system disorders |
dizziness, headache, syncope |
paraesthesia, vertigo, taste disturbances, sleep disorders |
disorders of smell |
||
| Cardiac disorders |
myocardial infarction or cerebrovascular accident, possibly due to excessive reduction in blood pressure in high-risk patients (see section "Special precautions"), palpitations, tachycardia |
||||
| Vascular disorders |
orthostatic effects (including orthostatic hypotension) |
Raynaud's syndrome |
flushing |
||
| Respiratory, thoracic and mediastinal disorders |
cough (see section "Special precautions") |
rhinitis |
bronchospasm, sinusitis, allergic alveolitis and/or eosinophilic pneumonia |
||
| Gastrointestinal disorders |
diarrhea, vomiting |
nausea, abdominal pain, dyspepsia |
dry mouth |
pancreatitis, angioneurotic edema of the intestine |
|
| Hepatobiliary disorders |
hepatitis (hepatocellular or cholestatic), jaundice, hepatic failure* (see section "Special precautions") |
||||
| Skin and subcutaneous tissue disorders |
rash, pruritus |
hypersensitivity/ angioedema of the face, extremities, lips, tongue, glottis and/or larynx (see section "Special precautions"), urticaria, alopecia, psoriasis |
increased sweating, bullous eruption (pemphigus), toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma** |
||
| Renal and urinary disorders |
renal function impairment |
uremia, acute renal failure |
oliguria, anuria |
||
| Reproductive system and breast disorders |
impotence |
gynecomastia |
|||
| General disorders |
asthenic syndrome, fatigue |
||||
| Investigations |
increased liver enzyme and bilirubin levels, increased urea, increased serum creatinine, hyperkalemia |
hyponatremia |
|||
*In rare cases, hepatitis has been reported, which subsequently progressed to liver failure. If jaundice or a marked increase in liver enzyme activity occurs during treatment with the combination of lisinopril and hydrochlorothiazide, the drug should be discontinued; the patient must remain under close medical supervision.
**A syndrome has been reported, characterized by one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia (arthritis), increased levels of antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis, rash, photosensitivity, or other skin reactions.
Hydrochlorothiazide
| Frequency of adverse reactions |
||
| Organ system |
Uncommon |
Frequency unknown |
| Infections and infestations |
Sialadenitis |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
|
| Blood and lymphatic system disorders |
Leukopenia, neutropenia (agranulocytosis), thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression |
|
| Metabolism and nutrition disorders |
Anorexia; hyperglycemia; glucosuria; hyperuricemia, electrolyte imbalance (including hyponatremia and hypokalemia, hypochloremic alkalosis, hypomagnesemia), increased cholesterol and triglyceride concentrations, gout |
|
| Psychiatric disorders |
Restlessness, depression, sleep disorders |
|
| Nervous system disorders |
Decreased appetite, paresthesia, pre-syncopal state |
|
| Eye disorders |
Xanthopsia, transient decrease in visual acuity, choroidal effusion, acute myopia, acute angle-closure glaucoma |
|
| Ear and labyrinth disorders |
Dizziness |
|
| Cardiac disorders |
Orthostatic hypotension |
|
| Vascular disorders |
Necrotizing angiitis (vasculitis, cutaneous vasculitis) |
|
| Respiratory, thoracic and mediastinal disorders |
Acute respiratory distress syndrome (ARDS) (see section "Special warnings and precautions for use") |
Respiratory distress syndrome (including pneumonitis and pulmonary edema) |
| Gastrointestinal disorders |
Irritation of gastric mucosa, diarrhea, constipation, pancreatitis |
|
| Hepatobiliary disorders |
Jaundice (jaundice due to intrahepatic cholestasis) |
|
| Skin and subcutaneous tissue disorders |
Photosensitivity reactions, rash, systemic lupus erythematosus, lupus-like skin reactions, exacerbation of systemic lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis |
|
| Musculoskeletal and connective tissue disorders |
Muscle spasm, muscle weakness |
|
| Renal and urinary disorders |
Renal function impairment, interstitial nephritis |
|
| General disorders |
Fever, weakness |
|
Description of some adverse reactions
Non-melanoma skin cancer (NMSC): based on available data from epidemiological studies, an association has been described between the cumulative dose of hydrochlorothiazide and NMSC (see sections "Pharmacological properties" and "Instructions for use").
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.
Shelf life.
2 years.
Storage conditions.
Store at a temperature not exceeding 25 °C.
Keep out of the reach of children.
Packaging.
10 tablets in a blister. 1 (10×1) or 3 (10×3) blisters in a cardboard package.
Prescription status.
Prescription only.
Manufacturer.
Gedeon Richter Polska Sp. z o.o.
Manufacturer's address and place of business.
ul. ks. J. Poniatowskiego 5, Grodzisk Mazowiecki, 05-825, Poland.
Manufacturer.
JSC "Gedeon Richter".
Manufacturer's address and place of business.
H-1103 Budapest, Demrédi u. 19-21, Hungary.
Marketing Authorization Holder.
JSC "Gedeon Richter".
Address of the Marketing Authorization Holder.
H-1103 Budapest, Demrédi u. 19-21, Hungary.