Ko-Diroton tablets 10 mg + 12.5 mg No. 30

Pharmacological properties

Pharmacodynamics. Co-Diroton is a fixed-dose combination of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide. Both components exhibit complementary and additive antihypertensive effects.

Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits ACE, which catalyzes the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II. 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 leads to a decrease in vasopressor activity and a decrease in aldosterone secretion. A further decrease may lead to an increase in plasma potassium.

Although the primary mechanism by which lisinopril lowers blood pressure is thought to be suppression of the angiotensin-aldosterone system, lisinopril lowers blood pressure even in patients with low-renin hypertension. ACE is identical to kininase II, the enzyme that degrades bradykinin. It remains to be determined whether elevated levels of bradykinin, a potent vasodilatory peptide, play any role in the therapeutic action of lisinopril.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It acts on the mechanism of electrolyte reabsorption in the distal renal tubule, increasing the excretion of sodium and chloride to approximately the same extent. Natriuresis may be accompanied by some loss of potassium and bicarbonate. The mechanism of the antihypertensive action of thiazides is unknown. Thiazides usually do not affect normal blood pressure.

Pharmacokinetics: Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either component. No clinically significant pharmacokinetic interactions have been observed between the two components when administered as a single tablet.

lisinopril

Absorption. After oral administration of lisinopril, Cmax in plasma is observed within approximately 7 hours. Based on urinary excretion data, the average absorption of lisinopril in the range of doses studied (5-80 mg) is approximately 25% with an interindividual variation of 6-60%. Absolute bioavailability is reduced by approximately 16% in patients with heart failure. The absorption of lisinopril is independent of food intake.

Distribution: Lisinopril is unlikely to bind to plasma proteins other than circulating ACE. Lisinopril is known to have poor blood-brain barrier penetration.

Elimination. Lisinopril is not metabolized and is excreted unchanged by the kidneys. With repeated administration, lisinopril has an effective T½ of 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 ml/min. The decrease in plasma concentrations indicates a prolonged terminal phase, which is not a consequence of drug accumulation. This terminal phase may indicate saturable binding to ACE and is not dose-proportional.

Heart failure: Patients with heart failure are more likely to be exposed to lisinopril than healthy volunteers (mean increase in area under the concentration-time curve (AUC) of 125%), but based on urinary excretion data, there is approximately 16% less absorption than in healthy volunteers.

Elderly patients have higher plasma AUC values (increased by approximately 60%) compared to younger volunteers.

Renal impairment: Impaired renal function reduces the elimination of lisinopril, which is excreted by the kidneys, but this becomes clinically significant only if the glomerular filtration rate is below 30 ml/min. In mild and moderate renal impairment (creatinine clearance ≥30-80 ml/min), the mean AUC was increased by only 13%, while in severe renal impairment (creatinine clearance ≥5-30 ml/min), the mean AUC was increased 4.5-fold.

Lisinopril can be removed from the body by dialysis. During 4 hours of hemodialysis, plasma concentrations of lisinopril decreased by an average of 60%, with dialysis clearance between 40 and 55 ml/min.

Hepatic impairment: Impaired hepatic function in patients with cirrhosis resulted in reduced absorption of lisinopril (approximately 30% as determined by urinary excretion) and increased exposure (approximately 50%) compared with healthy volunteers due to reduced clearance.

Hydrochlorothiazide. Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. In humans, about 70% of an orally administered therapeutic dose is absorbed mainly in the duodenum and upper small intestine. Food intake does not affect absorption, and C max is reached within 2-4 hours after administration. The volume of distribution is reported to be 0.8 to 3 l/kg. Hydrochlorothiazide is not metabolized, but is rapidly excreted by the kidneys. At least 61% of the dose is excreted unchanged within 24 hours. T ½ is 8-12 hours, and 95% of the absorbed hydrochlorothiazide is excreted by the kidneys. After oral administration of hydrochlorothiazide, diuresis begins after 2 hours, peaks after about 4 hours, and lasts for 6-12 hours. Hydrochlorothiazide crosses the placenta but does not cross the blood-brain barrier.

Indication

Treatment of patients with mild or moderate ag, which has a stable course against the background of therapy with individual drugs in the same doses.

Application

Adults. The fixed-dose combination is not suitable for initiating therapy. The fixed-dose combination can replace the combination of 10 mg or 20 mg lisinopril and 12.5 mg in patients who have been stabilised on the individual active substances at the same doses as the individual preparations. The usual dose is 1 tablet once daily. As with any other once-daily medicinal product, Co-Diroton should be taken at approximately the same time each day.

If the desired therapeutic effect is not achieved within 2-4 weeks of treatment, the dose can be increased to 2 tablets once a day.

Previous diuretic therapy. Symptomatic hypotension may develop after the first dose of Co-Diroton; this condition is more likely to develop in patients who are volume and/or salt depleted by previous diuretic therapy. Diuretic therapy should be discontinued 2-3 days before starting Co-Diroton therapy. If this is not possible, treatment should be initiated with the individual components at a lower dose (lisinopril at a dose of 5 mg).

Patients with renal insufficiency. Co-Diroton should not be used as initial therapy in patients with renal insufficiency.

In patients with mild or moderate renal impairment (creatinine clearance 30 and 80 ml/min), Co-Diroton should only be used after titration of the individual components. In this case, the recommended dose of lisinopril administered as a single agent is 5-10 mg.

Elderly patients. The efficacy and tolerability of lisinopril and hydrochlorothiazide when co-administered were similar in both elderly and younger patients with hypertension. Over the dose range of 20 mg to 80 mg, lisinopril was equally effective in elderly (65 years and older) and younger patients with hypertension. In elderly patients with hypertension, lisinopril monotherapy was as effective in lowering diastolic blood pressure as hydrochlorothiazide or atenolol monotherapy. If an elderly patient has decreased renal function, the initial dose of lisinopril should be adjusted. (See Patients with Renal Impairment).

Contraindication

Side effects

Adverse reactions have been reported with the use of individual components, which can potentially develop with the use of co-diroton.

Side effects caused by lisinopril and other ACE inhibitors

Blood and lymphatic system disorders: lymphadenopathy, anemia, agranulocytosis, bone marrow depression, hemolytic anemia, leukopenia, thrombocytopenia, neutropenia, autoimmune diseases.

Cardiovascular: palpitations, tachycardia, hypotension (including orthostatic hypotension), cerebrovascular accident, Raynaud's phenomenon, balance disorders, myocardial infarction or stroke, possibly due to severe hypotension in high-risk patients.

Mental disorders: mood changes, sleep disturbances, confusion, disorientation.

From the nervous system: dizziness, balance disorders, paresthesia, headache, taste disturbances, smell disturbances.

From the organs of hearing and balance: vertigo.

Respiratory, thoracic and mediastinal disorders: cough*, bronchospasm, shortness of breath, rhinitis, sinusitis, allergic alveolitis, eosinophilic pneumonia, upper respiratory tract infections.

Gastrointestinal: diarrhea, vomiting, nausea, dry mouth, glossitis, pancreatitis, angioedema of the intestine, abdominal pain, indigestion, decreased appetite, constipation.

From the hepatobiliary system: hepatitis, hepatocellular or cholestatic jaundice, hepatic failure **.

Skin and subcutaneous tissue disorders: rash, hypersensitivity, angioedema ***, symptom complex ****, alopecia, urticaria, itching, psoriasis, increased sweating, feeling of heat, skin hyperemia, skin disorders (pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pseudolymphoma of the skin).

Metabolism and nutrition disorders: hypoglycemia.

Musculoskeletal and connective tissue disorders: muscle spasm, muscle weakness.

On the part of the endocrine system: impaired secretion of antidiuretic hormone.

General complications: increased fatigue, asthenia, chest discomfort.

From the reproductive system and mammary glands: impotence, gynecomastia.

Laboratory indicators *****: increased activity of liver enzymes, increased concentration of creatinine in blood plasma, increased blood urea, decreased hemoglobin content, decreased hematocrit, and blood plasma bilirubin.

* Cough caused by ACE inhibitor therapy is characterized as persistent, nonproductive, and resolves upon drug withdrawal. This should be considered when performing differential diagnosis of cough.

** There have been very rare reports of patients in whom the undesirable development of hepatitis has led to liver failure. Patients who develop jaundice or a significant increase in liver enzymes during therapy should discontinue Co-Diroton and undergo an appropriate medical examination.

*** Isolated cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported (see Precautions).

**** A symptom complex has been reported, which may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), increased ESR, eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations.

***** A slight increase in plasma creatinine and urea concentrations has been observed. These phenomena are usually reversible upon discontinuation of the drug. A slight decrease in hemoglobin and hematocrit values has been reported. Bone marrow suppression, manifested by anemia and/or thrombocytopenia, has been reported. Hyper- or hypokalemia and hyponatremia have been observed. Isolated cases of increased liver enzymes and/or plasma bilirubin have been reported, but a relationship to the use of the drug containing lisinopril and hydrochlorothiazide has not been established.

Isolated cases of syncope and chest pain have been reported, but a relationship to the use of a drug containing lisinopril and hydrochlorothiazide has not been established.

There are reports of the development of neuropathy while taking ACE inhibitors.

Side effects caused by hydrochlorothiazide

Infections and infestations: sialadenitis.

Immune system disorders: hypersensitivity reactions, including anaphylactic reactions, shock.

Blood and lymphatic system disorders: leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow depression.

Metabolism and nutrition disorders: anorexia; hyperglycemia; glycosuria; hyperuricemia, which may provoke gouty attacks in patients with asymptomatic disease; electrolyte imbalance, including hyponatremia and hypokalemia; hypomagnesemia; hypercalcemia; increased blood lipid levels; gout; decreased glucose tolerance, which may cause manifestation of latent diabetes mellitus; hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma.

Mental disorders: anxiety, depression, mood swings, sleep disturbances, confusion, disorientation, drowsiness, nervousness.

From the nervous system: dizziness, headache, convulsions, paresthesia.

On the part of the organ of vision: xanthopsia, temporary visual impairment.

From the organs of hearing and balance: vertigo.

Cardiovascular system: arrhythmia, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: respiratory distress syndrome, including pneumonitis and pulmonary edema.

On the part of the digestive system: irritation of the gastric mucosa, constipation, dry mouth, thirst, nausea, vomiting.

From the hepatobiliary system: jaundice (jaundice due to intrahepatic cholestasis), pancreatitis, cholecystitis.

Skin and subcutaneous tissue disorders: vasculitis, necrotizing angiitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, photosensitivity reactions, rash, eczema, cutaneous lupus-like reactions, reactivation of cutaneous manifestations of systemic lupus erythematosus, urticaria, purpura.

Musculoskeletal and connective tissue disorders: muscle spasm and pain.

Renal and urinary disorders: renal failure, renal dysfunction and interstitial nephritis.

From the genitals: sexual disorders.

General complications: exhaustion.

Special instructions

Arterial hypotension and fluid and electrolyte imbalance

Symptomatic hypotension has also been reported in patients with heart failure with or without renal insufficiency. This condition is more likely to develop in patients with severe heart failure as a result of high doses of loop diuretics, hyponatremia or functional renal insufficiency. Patients at risk of developing symptomatic hypotension should be closely monitored at the beginning of therapy and during dose adjustment. In such patients, plasma electrolytes should be determined at regular intervals. Particular attention should be paid to the treatment of patients with ischemic heart disease or cerebrovascular disease, since an excessive decrease in blood pressure can lead to myocardial infarction or stroke.

If hypotension develops, the patient should be placed on his back and, if necessary, begin an intravenous infusion of saline. A transient hypotensive response is not a contraindication to continued therapy. After restoration of blood volume and blood pressure, therapy may be resumed at a reduced dose or the use of one of the components of the drug separately.

Patients should be under appropriate medical supervision to promptly detect clinical signs of fluid and salt imbalance (e.g. hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia), which may develop in the event of diarrhea or vomiting. In warm weather, patients with edema may develop hyponatremia due to blood thinning. If possible, hypovolemia and/or interstitial fluid depletion should be corrected before initiating treatment with lisinopril and the effect of the initial dose on blood pressure should be carefully monitored. In the event of acute myocardial infarction, lisinopril should not be used if treatment with vasodilators could worsen the patient's hemodynamic status (e.g., if systolic blood pressure is 100 mm Hg or lower) or in the event of cardiogenic shock.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

As with other ACE inhibitors, lisinopril should be used with caution in patients with left ventricular outflow tract obstruction. If the obstruction is hemodynamically significant, then the use of Co-Diroton is contraindicated (see Adverse Reactions).

Kidney dysfunction

Thiazides are not suitable for use in patients with renal insufficiency and are ineffective in patients with creatinine clearance of 30 ml/min or less (i.e. severe renal insufficiency). Co-Diroton should not be administered to patients with mild or moderate renal insufficiency (creatinine clearance 30 to 80 ml/min) unless titration of the individual components has established that the patient requires the doses of the combination tablet.

In cases of renal impairment (creatinine clearance 80 ml/min), the initial dose of lisinopril should be adjusted according to creatinine clearance (see Dosage and Administration) and clinical response to treatment. Continuous monitoring of serum potassium and creatinine is recommended in such patients. In patients with heart failure, hypotension occurring after initiation of ACE inhibitor therapy may lead to deterioration of renal function. AKI has been reported, which is usually reversible in such cases.

In some patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who received therapy with ACE inhibitors, an increase in blood urea and plasma creatinine concentrations was noted, usually reversible after discontinuation of therapy. The likelihood of developing this condition is higher in patients with renal insufficiency. If renovascular hypertension also occurs, there is an increased risk of developing severe hypotension and renal insufficiency. In such patients, treatment should be started with low doses under close medical supervision, and careful dose titration is required. Since diuretic treatment can lead to the development of the above-described situations, renal function should be monitored during the first few weeks of therapy with Co-Diroton.

In some patients with hypertension without a history of kidney disease, when lisinopril and a diuretic were used concomitantly, a slight transient increase in blood urea and plasma creatinine levels developed, as a rule. If this occurs during therapy with Co-Diroton, the combined drug should be discontinued. Therapy may be resumed at a reduced dosage or one of the components of the drug can be used separately.

Condition after kidney transplantation. Since there are no data on the use of lisinopril in patients after kidney transplantation, the use of the drug Co-Diroton in this group of patients is not recommended.

Patients on hemodialysis. The use of Co-Diroton is not indicated for patients on hemodialysis for renal failure.

Liver disease, hepatic failure. Very rarely, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is unclear. Patients who develop jaundice or marked elevations of liver enzymes while taking Co-Diroton should discontinue Co-Diroton and be placed under appropriate medical supervision.

Thiazides, including hydrochlorothiazide, should be used with caution in patients with impaired liver function or progressive liver disease, since the drug can cause intrahepatic cholestasis, and minimal changes in water-salt balance can provoke the development of hepatic coma (see Side effects).

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with drugs that cause hypotension, lisinopril may additionally block the formation of angiotensin II by compensatory renin release. If the development of hypotension is considered to be due to this mechanism, it can be eliminated by the introduction of large amounts of fluid.

Metabolic and endocrine effects: Concomitant administration of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) is known to increase blood glucose levels, which may increase the risk of hypoglycemia. This phenomenon is more likely to occur during the first weeks of combination therapy and in patients with renal impairment (see Interactions with other medicinal products and other forms of interaction).

Thiazide therapy may reduce glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be necessary. Thiazides may reduce urinary calcium excretion and cause transient and minor increases in plasma calcium. Marked hyperkalemia may be a sign of latent hyperparathyroidism. Thiazide diuretics should be discontinued prior to parathyroid function tests. Elevations in serum uric acid and TG may be associated with thiazide diuretic therapy.

Thiazide therapy may precipitate hyperuricemia and/or gout in some patients. However, lisinopril may increase urinary uric acid levels and thereby attenuate the hyperuricemic effect of hydrochlorothiazide.

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in isolated cases in patients treated with ACE inhibitors, including lisinopril. These events may occur at any time during treatment. In such cases, lisinopril should be discontinued immediately and appropriate monitoring should be instituted to ensure complete resolution of symptoms before discharge. Even in cases where only tongue swelling occurs without respiratory distress, prolonged observation may be necessary, as antihistamine and corticosteroid therapy may not be sufficient. Fatalities associated with angioedema (swelling of the larynx or tongue) have been reported very rarely. In cases where swelling of the tongue, glottis or larynx develops and is likely to cause airway obstruction, appropriate emergency treatment should be initiated immediately. This may include administration of adrenaline and/or maintenance of a patent airway. The patient should be closely monitored until symptoms have resolved. Angioedema can also affect the intestines and cause severe abdominal pain, nausea, vomiting and diarrhoea.

Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving ACE inhibitors (see Adverse Reactions).

Hypersensitivity reactions may occur in patients receiving thiazide diuretic therapy, with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with thiazides.

Race. The incidence of angioedema with ACE inhibitors is higher in African Americans than in non-African Americans. As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in African Americans than in non-African Americans, possibly because of the higher incidence of low-renin hypertension in these patients.

Desensitization: Patients receiving ACE inhibitors during desensitization therapy (e.g., hymenoptera venom) have developed anaphylactic reactions. In these same patients, this reaction was avoided by temporarily withholding ACE inhibitors, but it recurred upon accidental rechallenge.

Hyperkalemia. Some patients treated with ACE inhibitors, including lisinopril, have experienced increases in plasma potassium. The risk group for the development of hyperkalemia includes patients with renal insufficiency, diabetes mellitus, and those taking concomitant potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium, and those taking other drugs that may increase plasma potassium (e.g. heparin). If concomitant use of the above drugs is considered necessary, regular monitoring of plasma potassium is recommended.

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Neutropenia, agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors. Neutropenia and agranulocytosis resolve upon discontinuation of ACE inhibitors.

In patients with collagen vascular disease who are receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially in the presence of pre-existing renal impairment, lisinopril should be used with extreme caution. Some of these patients have developed serious infections, which in several cases have not responded to intensive antibacterial therapy. When prescribing lisinopril to such patients, regular monitoring of white blood cell counts should be performed and the patient should be advised to report any signs of infection.

Cough: Cough has been reported in patients taking ACE inhibitors. The cough is non-productive, persistent, and resolves after discontinuation of therapy. The fact that ACE inhibitors cause cough should be considered in the differential diagnosis of cough.

Lithium preparations. The combination of ACE inhibitors and lithium preparations should be avoided (see Interactions with other drugs).

Photosensitivity reactions. Cases of photosensitivity reactions have been reported during treatment with thiazide diuretics. If photosensitivity reactions occur during treatment, it is recommended to discontinue the drug. If the doctor considers that the drug should be re-administered, it is recommended to protect areas of the body exposed to sunlight or artificial UV radiation.

Laboratory indicators. The drug may affect the results of the following laboratory tests: hydrochlorothiazide in blood plasma may reduce the level of iodine bound to proteins (treatment with hydrochlorothiazide should be discontinued before laboratory tests to assess parathyroid function) and increase the concentration of free bilirubin in blood plasma.

Use during pregnancy and breastfeeding. The use of ACE inhibitors is not recommended in the first trimester of pregnancy (see Special precautions for use and contraindications). The use of ACE inhibitors is contraindicated in the second and third trimesters of pregnancy (see Side effects and Special precautions for use).

The available data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy have not been conclusive; however, a small increase in this risk cannot be excluded. 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. If pregnancy occurs, treatment with ACE inhibitors should be stopped immediately, and, if possible, alternative therapy should be started (see Adverse Reactions).

The use of ACE inhibitors during the second and third trimesters of pregnancy is known to induce human fetotoxic effects (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ACE inhibitors have been used during the third trimester of pregnancy, ultrasound monitoring of skull bones and renal function is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for possible hypotension (see Contraindications and Use).

The use of diuretics in healthy pregnant women is not recommended because the woman and fetus are exposed to unnecessary risks, including the possible development of fetal and neonatal jaundice, thrombocytopenia, and other adverse reactions similar to those observed in adult patients.

Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis, with some clinical benefit. Theoretically, it can be removed by exchange transfusion. There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.

The use of the drug Co-Diroton is contraindicated during breastfeeding (see Side effects). Lisinopril passes into the breast milk of rats. It is not known whether lisinopril passes into human breast milk, and hydrochlorothiazide also passes into it in an amount that, even in therapeutic doses, could affect the child.

Because of the potential for serious reactions in breastfed infants, a decision should be made whether to discontinue breast-feeding or to discontinue Co-Diroton, taking into account the need for the drug for the mother.

Children. The drug Co-Diroton is not intended for use in children. The safety and effectiveness of its use in children and adolescents (under the age of 18 years) have not been established.

Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Due to the development of adverse reactions, especially at the beginning of therapy, the drug Co-Diroton may slightly or moderately affect the reaction rate (see Side effects), so you should refrain from driving vehicles and / or working with other mechanisms. This risk increases if the drug Co-Diroton is combined with alcohol consumption.

Interactions

Diuretics. If a diuretic is added to lisinopril therapy, an additional antihypertensive effect will be obtained.

Symptomatic hypotension may develop after the first dose of Co-Diroton; this condition is more likely to occur in patients who are fluid and/or salt depleted due to prior diuretic therapy. Diuretic therapy should be discontinued prior to initiation of Co-Diroton therapy (see Precautions).

Potassium supplements, potassium-sparing salt substitutes containing potassium. The excretion of potassium from the body during the course of thiazide diuretics is usually attenuated by the potassium-sparing effect of lisinopril. The use of potassium supplements, potassium-sparing substances or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to a significant increase in plasma potassium. If the simultaneous use of Co-Diroton and the use of any of these substances is considered necessary, they should be used with caution and with frequent monitoring of plasma potassium (see Precautions).

Tricyclic antidepressants/antipsychotics/anesthetics: Concomitant use of certain anesthetics, tricyclic antidepressants or antipsychotics and ACE inhibitors may lead to an additional decrease in blood pressure (see Precautions).

Narcotics/antipsychotics: Orthostatic hypotension may develop when taking ACE inhibitors.

Barbiturates or narcotics: Increased orthostatic hypotension may occur.

NSAIDs. Long-term use of NSAIDs (selective COX-2 inhibitors, acetylsalicylic acid 3 g/day and non-selective NSAIDs) may reduce the hypotensive effect of both the ACE inhibitor and the thiazide. Concomitant use of NSAIDs and ACE inhibitors may worsen renal function. This effect is usually reversible. In rare cases, acute renal failure may develop, primarily in patients with impaired renal function, such as the elderly and in patients with dehydration.

In some patients, taking NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

Increases in plasma potassium levels have been reported with NSAIDs and ACE inhibitors, which may lead to renal dysfunction.

Sympathomimetics: Sympathomimetics may reduce the hypotensive effect of ACE inhibitors.

Other antihypertensive drugs. The antihypertensive effect of Co-Diroton may