Arbitel n

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARBITEL H (ARBITEL H)

Composition:

Active substances: telmisartan, hydrochlorothiazide;

One tablet contains telmisartan 40 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 25 mg;

Excipients for the 40 mg/12.5 mg and 80 mg/12.5 mg dosages: mannitol (E 421); meglumine; sodium hydroxide; povidone (K-30); crospovidone (type A); lactose monohydrate; microcrystalline cellulose; iron oxide red (E 172); corn starch; magnesium stearate;

Excipients for the 80 mg/25 mg dosage: mannitol (E 421); meglumine; sodium hydroxide; povidone (K-30); crospovidone (type A); lactose monohydrate; microcrystalline cellulose; iron oxide yellow (E 172); corn starch; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets 40 mg/12.5 mg: bilayer, biconvex, oval, uncoated tablets. The telmisartan layer is white or almost white, possibly containing red specks, with engraving «TH», and the hydrochlorothiazide layer is red or reddish-pink;

Tablets 80 mg/12.5 mg: bilayer, biconvex, oval, uncoated tablets. The telmisartan layer is white or almost white, possibly containing red specks, with engraving «TH3», and the hydrochlorothiazide layer is red or reddish-pink;

Tablets 80 mg/25 mg: bilayer, biconvex, oval, uncoated tablets. The telmisartan layer is white or almost white, possibly containing yellow specks, with engraving «TH1», and the hydrochlorothiazide layer is light yellow or yellow.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics.

ATC code C09D A07.

Pharmacological Properties

Pharmacodynamics

Arbitel H is a combination of an angiotensin II receptor blocker (telmisartan) and a thiazide diuretic (hydrochlorothiazide). The combination of these components provides an additive antihypertensive effect, reducing arterial pressure to a greater extent than either component alone. When administered once daily within the therapeutic dose range, Arbitel H tablets produce effective and gradual reduction of arterial pressure.

Mechanism of Action

Telmisartan is effective when administered orally; it is a specific blocker of angiotensin II subtype 1 (AT1) receptors. With very high affinity for these receptors, telmisartan displaces angiotensin II from its binding sites on AT1-receptors. It exhibits no partial agonist activity at AT1-receptors. Telmisartan selectively binds to AT1-receptors, and this binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other less-characterized AT-receptors. Telmisartan does not inhibit human plasma renin and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kinase II), the enzyme also responsible for bradykinin degradation. Therefore, potentiation of bradykinin-mediated adverse effects is not expected.

In healthy volunteers, telmisartan at a dose of 80 mg almost completely inhibits the hypertensive effect of angiotensin II in humans. The inhibitory effect lasts over 24 hours and persists up to 48 hours.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazide diuretics affect electrolyte reabsorption mechanisms in renal tubules, thereby directly increasing excretion of sodium and chloride in approximately equivalent amounts. Due to the diuretic effect of hydrochlorothiazide, plasma volume decreases, plasma renin activity increases, and aldosterone secretion rises, resulting in increased urinary excretion of potassium and bicarbonates and a reduction in serum potassium levels. Possibly, through blockade of the renin-angiotensin-aldosterone system (RAAS), concomitant administration of telmisartan may counteract the potassium loss associated with these diuretics. After hydrochlorothiazide administration, diuresis begins within 2 hours, peak effect occurs approximately 4 hours later, and the duration of action lasts about 6–12 hours.

Pharmacodynamic Effects

After the first dose of telmisartan, antihypertensive activity gradually develops over 3 hours. Maximum reduction in arterial pressure is typically achieved within 4–8 weeks after initiation of treatment and is maintained during long-term therapy. The antihypertensive effect remains consistent over 24 hours after dosing, including the last 4 hours before the next dose. This is confirmed by the ratio of telmisartan concentration just before the next dose to Cmax, which is 80% after administration of 40 and 80 mg telmisartan in clinical studies. In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of other classes of antihypertensive agents (as demonstrated in studies comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, and lisinopril).

Upon abrupt discontinuation of telmisartan therapy, arterial pressure gradually returns to pre-treatment levels over several days, without evidence of rebound syndrome.

In clinical trials comparing two antihypertensive treatment regimens, dry cough occurred significantly less frequently in patients receiving telmisartan than in those receiving angiotensin-converting enzyme (ACE) inhibitors.

The effect of the fixed-dose combination of telmisartan/hydrochlorothiazide on mortality and cardiovascular morbidity is unknown.

Non-melanoma skin cancer

Epidemiological data have demonstrated an association between cumulative hydrochlorothiazide dose and non-melanoma skin cancer.

Pharmacokinetics

Co-administration of hydrochlorothiazide and telmisartan does not affect the pharmacokinetics of either component in healthy volunteers.

Absorption

Telmisartan. After oral administration, peak plasma concentration of telmisartan is reached within 0.5–1.5 hours. Absolute bioavailability of telmisartan at doses of 40 mg and 160 mg is 42% and 58%, respectively. Food slightly reduces telmisartan bioavailability, with a reduction in the area under the concentration-time curve (AUC) ranging from approximately 6% (40 mg dose) to 19% (160 mg dose). Plasma concentrations 3 hours after administration are similar regardless of whether telmisartan is taken with or without food. The minor reduction in AUC is not considered to result in a decrease in therapeutic efficacy. Telmisartan does not accumulate significantly in plasma with repeated dosing.

Hydrochlorothiazide. After oral administration of Arbitel H, peak plasma concentration of hydrochlorothiazide is reached within 1–3 hours. Due to the cumulative renal excretion of hydrochlorothiazide, absolute bioavailability is approximately 60%.

Distribution

Telmisartan. Telmisartan is highly bound to plasma proteins (>99.5%), primarily to albumin and alpha-1-acid glycoprotein. The volume of distribution is approximately 500 L, indicating extensive tissue binding.

Hydrochlorothiazide. Hydrochlorothiazide is bound to plasma proteins by 68%, and its volume of distribution is 0.8±0.3 L/kg.

Metabolism

Telmisartan is metabolized via conjugation to form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite identified in humans. After administration of a single dose of 14C-labeled telmisartan, the glucuronide accounts for approximately 11% of measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in telmisartan metabolism.

Hydrochlorothiazide is not metabolized in humans.

Elimination

Telmisartan. After intravenous or oral administration of 14C-labeled telmisartan, the majority of the dose (>97%) is excreted in feces via biliary excretion. Only a negligible amount is found in urine. Total plasma clearance of telmisartan after oral administration is >1500 mL/min. The terminal elimination half-life exceeds 20 hours.

Hydrochlorothiazide is excreted almost entirely unchanged in urine. Approximately 60% of an oral dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. Terminal elimination half-life is 10–15 hours.

Linearity / Non-linearity

Telmisartan. The pharmacokinetics of orally administered telmisartan are non-linear over the dose range of 20–160 mg, with greater-than-proportional increases in plasma concentrations (Cmax and AUC) as dose increases. Telmisartan does not accumulate significantly in plasma with repeated dosing.

Hydrochlorothiazide exhibits linear pharmacokinetics.

Special Patient Populations

Elderly patients. The pharmacokinetics of telmisartan do not differ between elderly and younger patients.

Sex. Plasma concentrations of telmisartan are generally 2–3 times higher in women than in men. However, clinical trial data show no significant increase in blood pressure reduction or incidence of orthostatic hypotension in women. Dose adjustment is not required. Women tend to have higher plasma concentrations of hydrochlorothiazide than men, but this has no clinical significance.

Patients with renal impairment. Lower plasma concentrations were observed in patients with dialysis-dependent renal failure. In patients with renal impairment, telmisartan is highly bound to plasma proteins and is not removed by dialysis. Elimination half-life remains unchanged in patients with renal dysfunction. In patients with renal impairment, the elimination rate of hydrochlorothiazide is reduced. In a typical study, in patients with a mean creatinine clearance of 90 mL/min, the half-life of hydrochlorothiazide increased. In patients with absent or non-functioning kidneys, the half-life is approximately 34 hours.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability to nearly 100%. The elimination half-life in these patients is unchanged.

Clinical characteristics

Indications

Essential hypertension

Arbitel H, tablets, in fixed-dose combination (40 mg telmisartan / 12.5 mg hydrochlorothiazide) is indicated for use in adult patients when treatment with telmisartan as monotherapy does not provide adequate blood pressure control.

Arbitel H, tablets, in fixed-dose combination (80 mg telmisartan / 25 mg hydrochlorothiazide) is indicated for use in adult patients when treatment with telmisartan / hydrochlorothiazide 80 mg / 12.5 mg does not provide adequate blood pressure control, or in adult patients whose blood pressure has been stabilized with telmisartan and hydrochlorothiazide as individual agents at the corresponding doses.

Contraindications

• Hypersensitivity to any of the active substances or to any of the excipients of the medicinal product.
• Hypersensitivity to other sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide derivative).
• Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Cholestatic and biliary obstructive disorders.
• Severe hepatic impairment.
• Severe renal impairment (creatinine clearance < 30 mL/min), anuria.
• Refractory hypokalemia / hyponatremia, hypercalcemia.
• Breastfeeding period.
• Symptomatic hyperuricemia (gout).
• Pediatric population (under 18 years of age).

Concomitant use of Arbitel H and aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamics").

Interaction with other medicinal products and other types of interactions

Lithium. Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and angiotensin-converting enzyme (ACE) inhibitors. Rare cases of interaction have been reported with angiotensin II receptor blockers (including telmisartan / hydrochlorothiazide). Concomitant use of lithium and Arbitel H is not recommended (see section "Contraindications"). If combination therapy is necessary, careful monitoring of serum lithium levels is recommended during concomitant use.

Medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid and its derivatives). When these medicinal products are used concomitantly with telmisartan / hydrochlorothiazide combination, monitoring of plasma potassium levels is recommended, as these agents may potentiate the effect of hydrochlorothiazide on plasma potassium levels (see section "Special precautions for use").

Iodinated contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high doses of iodinated contrast agents. Patients require rehydration prior to administration of iodinated agents.

Medicinal products that may increase potassium levels and cause hyperkalemia (e.g., ACE inhibitors, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, cyclosporine, or other medicinal products such as sodium heparin). When these medicinal products are used concomitantly with telmisartan / hydrochlorothiazide combination, monitoring of plasma potassium levels is recommended. Based on experience with other agents that inhibit the renin-angiotensin-aldosterone system (RAAS), concomitant use of these medicinal products is not recommended, as it may lead to increased serum potassium levels (see section "Special precautions for use").

Medicinal products causing disturbances in serum potassium levels. Periodic monitoring of serum potassium levels and ECG monitoring are recommended when Arbitel H is used concomitantly with the following medicinal products that may cause disturbances in serum potassium levels (e.g., with digoxin glycosides, antiarrhythmics) and medicinal products that may provoke ventricular fibrillation, including certain antiarrhythmics, and hypokalemia as a triggering factor for ventricular fibrillation:

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Others (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids).

Digoxin glycosides. Hypokalemia or hypomagnesemia induced by thiazides may predispose to digoxin-induced cardiac arrhythmias (see section "Special precautions for use").

Digoxin. When telmisartan was co-administered with digoxin, increases in mean peak (49%) and trough (20%) plasma digoxin concentrations were observed. Digoxin levels should be monitored at the beginning of therapy, during dose adjustments, and upon discontinuation of telmisartan therapy to maintain digoxin levels within the therapeutic range.

Other antihypertensive agents. Telmisartan may enhance the hypotensive effect of other antihypertensive agents.

Clinical data have shown that dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to use of a single RAAS-acting agent (see sections "Special precautions for use", "Contraindications", and "Pharmacodynamics").

Antidiabetic agents (oral agents and insulin). Dose adjustment of the antidiabetic agent may be required (see section "Special precautions for use").

Metformin. Metformin should be used with caution due to the risk of lactic acidosis caused by possible renal impairment associated with hydrochlorothiazide use.

Cholestyramine and colestipol resins. Absorption of hydrochlorothiazide is reduced in the presence of ion-exchange resins.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (including acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics and angiotensin II receptor antagonists. In some patients with renal impairment (including dehydrated patients or elderly patients with impaired renal function), concomitant use of angiotensin II receptor blockers and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be used with caution, particularly in elderly patients. Adequate hydration should be ensured after initiation of combination therapy, and renal function should be closely monitored periodically during treatment.

In one study, concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in the area under the plasma concentration-time curve (AUC0–24) and maximum plasma concentration (Cmax) of ramipril and ramiprilat. The clinical significance of this observation remains unknown.

Vasoactive amines (e.g., norepinephrine). The effect of vasoactive amines may be reduced.

Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine). The effect of non-depolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Medicinal products used to treat gout (e.g., probenecid, sulfinpyrazone, allopurinol). Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Calcium salts. Thiazide diuretics may increase serum calcium levels due to reduced excretion. When calcium supplements or calcium-retaining agents (e.g., vitamin D therapy) are prescribed, serum calcium levels should be monitored and the dose adjusted accordingly.

Beta-blockers and diazoxide. The hyperglycemic effects of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic medicinal products (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics by increasing gastrointestinal motility and gastric emptying.

Amantadine. Thiazides may increase the risk of adverse effects associated with amantadine.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate). Thiazides may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Based on pharmacological properties, baclofen and amifostine are expected to enhance the hypotensive effect of all antihypertensive agents, including telmisartan. Additionally, orthostatic hypotension may be exacerbated by alcohol, barbiturates, narcotics, or antidepressants.

Salicylates. When high doses of salicylates are used, hydrochlorothiazide may potentiate their toxic effects on the central nervous system (CNS).

Methyldopa. Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine. Concomitant use of cyclosporine may exacerbate hyperuricemia and increase the risk of complications such as gout.

Effect of medicinal products on laboratory test results. Due to their effect on calcium metabolism, thiazides may affect the assessment of parathyroid gland function (see section "Special precautions for use").

Carbamazepine. Clinical and biological monitoring is required due to the risk of symptomatic hyponatremia.

Amphotericin B (parenteral), corticosteroids, ACTH, and stimulant laxatives. Hydrochlorothiazide may exacerbate electrolyte imbalances, particularly hypokalemia.

Special precautions for use

Pregnancy. Angiotensin II receptor antagonists should not be initiated during pregnancy. Women of childbearing potential who are planning pregnancy should be switched to alternative antihypertensive agents with established safety profiles for use in pregnancy. If pregnancy is diagnosed, angiotensin II receptor blockers should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Hepatic impairment. Arbitele N should not be administered to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency (see section "Contraindications"), as telmisartan is primarily excreted via bile. Hepatic clearance of telmisartan is expected to be reduced in these patients.

Arbitele N should be used with caution in patients with hepatic dysfunction or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic encephalopathy. There is no clinical experience with the use of the telmisartan/hydrochlorothiazide combination in patients with hepatic insufficiency.

Renovascular hypertension. There is an increased risk of severe hypotension and renal failure when drugs affecting the renin-angiotensin-aldosterone system (RAAS) are administered to patients with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney.

Renal impairment and kidney transplantation. Arbitele N is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications"). There is no experience with the use of the telmisartan/hydrochlorothiazide combination in patients with severe renal impairment or with a recently transplanted kidney. Limited experience exists with the use of the drug in patients with mild to moderate renal impairment; therefore, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. Azotemia associated with thiazide diuretics may occur in patients with renal dysfunction.

Telmisartan is not removed from the blood by hemofiltration and is not dialyzable.

Reduced intravascular volume and/or sodium depletion. Symptomatic hypotension, particularly after the first dose, may occur in patients with reduced fluid and/or sodium volume due to diuretic therapy, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected prior to administration of Arbitele N.

Cases of hyponatremia associated with neurological symptoms (nausea, progressive disorientation, apathy) have been reported with hydrochlorothiazide use.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure).

Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision and with continuous careful 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.

Other conditions requiring RAAS activity. In patients whose vascular tone and renal function depend primarily on RAAS activity (e.g., patients with congestive heart failure or severe renal disease, including renal artery stenosis), treatment with other drugs affecting the RAAS may be associated with acute hypotension, hyperazotemia, oliguria, or rarely, acute renal failure (see section "Adverse reactions").

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via RAAS blockade; therefore, use of Arbitele N is not recommended in this patient group.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, particular caution is required when treating patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Metabolic and endocrine effects. Thiazide therapy may reduce glucose tolerance, while hypoglycemia may occur in diabetic patients receiving insulin or antidiabetic therapy along with telmisartan. Therefore, blood glucose levels should be monitored in these patients; dose adjustments of insulin or hypoglycemic agents may be necessary. Latent diabetes mellitus may become apparent during thiazide therapy.

Elevated cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, with the use of formulations containing 12.5 mg hydrochlorothiazide, minimal or no increase in cholesterol and triglycerides has been observed. Hyperuricemia or overt gout may occur in some patients receiving thiazide therapy.

Electrolyte imbalance. All patients receiving diuretic therapy should have periodic determination of serum electrolytes. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting (see section "Adverse reactions").

• Hypokalemia. Although hypokalemia may develop during thiazide diuretic therapy, concomitant treatment with telmisartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with liver cirrhosis, those with marked diuresis, those receiving inadequate oral electrolyte supplementation, and those receiving concomitant corticosteroid or ACTH therapy (see section "Interaction with other medicinal products and other forms of interaction").
• Hyperkalemia. Conversely, due to angiotensin II receptor (AT1) antagonism caused by telmisartan – a component of Arbitele N – hyperkalemia may occur. However, clinically significant hyperkalemia due to Arbitele N has not been documented. Risk factors for hyperkalemia include renal impairment and/or heart failure and diabetes mellitus. Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be used cautiously when administered concomitantly with Arbitele N (see section "Interaction with other medicinal products and other forms of interaction").
• Hypochloremic alkalosis. Chloride deficiency is usually mild and generally does not require treatment.
• Hypercalcemia. Thiazides may reduce urinary calcium excretion and may cause slight increases in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before parathyroid function tests are performed.
• Hypomagnesemia. Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").

Race. As with other angiotensin II receptor blockers, telmisartan is less effective in lowering blood pressure in black patients, presumably due to the higher prevalence of low-renin hypertension in this patient population.

Ischemic heart disease. As with any other antihypertensive agent, significant lowering of blood pressure in patients with ischemic heart disease or myocardial ischemia may lead to myocardial infarction or stroke.

General information. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with a history of allergy or bronchial asthma, and even more likely in patients with such conditions in their medical history. Exacerbation or activation of systemic lupus erythematosus has been observed with thiazide diuretics, including hydrochlorothiazide.

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section "Adverse reactions"). If photosensitivity reactions occur during treatment, drug use should be discontinued. If re-administration of the diuretic is considered necessary, protection of exposed skin areas from sunlight or artificial UV radiation is recommended.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Hydrochlorothiazide and sulfonamides may cause hypersensitivity reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma.

Symptoms include sudden onset of decreased visual acuity or eye pain and usually occur from several hours to weeks after initiation of treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Treatment with hydrochlorothiazide should be discontinued as soon as possible. Emergency medical or surgical treatment may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer. Two epidemiological studies based on the Danish National Cancer Registry showed an increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) with increasing cumulative doses of hydrochlorothiazide (see section "Adverse reactions"). The photosensitizing effect of hydrochlorothiazide may be a mechanism in the development of NMSC.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and should regularly examine their skin for new lesions and promptly report any suspicious skin changes. Preventive measures such as limiting exposure to sunlight and ultraviolet radiation are possible. Patients should be advised to use adequate protection against such exposure to minimize the risk of skin cancer. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. The use of hydrochlorothiazide should also be reconsidered in patients with a history of NMSC (see section "Adverse reactions").

Acute respiratory toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung function, and hypotension. If ARDS is suspected, Arbitele N should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be used in patients who have previously experienced ARDS after hydrochlorothiazide administration.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, Arbitele N should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Lactose. The medicinal product contains lactose monohydrate. Therefore, patients with hereditary fructose intolerance and/or hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Effects on laboratory test results:

• May decrease plasma protein-bound iodine levels;
• Treatment should be discontinued prior to laboratory testing to assess parathyroid function;
• May increase free bilirubin concentration in serum.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, it should be discontinued immediately and replaced with another medicinal product permitted for use (see sections "Contraindications" and "Special precautions for use").

There are no data on the use of the telmisartan/hydrochlorothiazide combination in pregnant women. Animal studies have shown reproductive toxicity.

Epidemiological evidence regarding teratogenic risk after ACE inhibitor use during the first trimester of pregnancy is inconclusive; however, a small increased risk cannot be excluded. Although controlled epidemiological data on the risk of angiotensin II receptor blockers are lacking, similar risks are possible for this class of medicinal products. Women of childbearing potential who are planning pregnancy should be switched to alternative antihypertensive agents with established safety profiles for use in pregnancy. If pregnancy is diagnosed, angiotensin II receptor blockers should be discontinued immediately and alternative therapy initiated if necessary.

Treatment with angiotensin II receptor blockers during the second and third trimesters of pregnancy causes fetotoxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor blockers were used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull condition is recommended. Newborns whose mothers took angiotensin II receptor blockers should be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal studies are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may impair placental-fetal blood flow and lead to intrauterine and neonatal effects such as jaundice, electrolyte imbalance in the fetus, and thrombocytopenia.

Hydrochlorothiazide should not be used for edema or hypertension related to pregnancy, or for pre-eclampsia, due to the risk of reduced plasma volume and placental hypoperfusion without positive effect on disease course.

Hydrochlorothiazide should not be used in pregnant women with severe hypertension, except in rare cases where no other treatment is possible.

Breastfeeding

Due to lack of information on the use of the telmisartan/hydrochlorothiazide combination during breastfeeding, the use of the medicinal product during lactation is not recommended; alternative therapy with medicinal products with better-established safety profiles should be preferred, especially when breastfeeding newborns or preterm infants.

Hydrochlorothiazide passes into breast milk in small amounts. Thiazides in high doses, causing intense diuresis, may suppress breast milk production. The use of Arbitele N during breastfeeding is contraindicated.

Fertility

Fertility studies in humans using fixed-dose combinations or individual components have not been conducted.

Preclinical studies did not reveal effects of telmisartan and hydrochlorothiazide on male or female fertility.

Effect on ability to drive and use machines

Arbitele N may affect the ability to drive or operate machinery. Treatment with antihypertensive agents, including Arbitele N, may cause dizziness or syncope.

Patients experiencing these adverse effects should avoid potentially hazardous tasks such as driving or operating machinery.

Method of Administration and Dosage

Dosage

Arbitel N should be prescribed to patients whose blood pressure is not adequately controlled with telmisartan alone. Before switching to Arbitel N, the dose of each component should be determined. Direct substitution of monotherapy with fixed-dose combinations may be considered if clinically justified.

Arbitel N, 40 mg/12.5 mg tablets, can be administered once daily to patients whose blood pressure is not adequately controlled with Arbitel 40 mg tablets.

Arbitel N, 80 mg/12.5 mg tablets, can be administered once daily to patients whose blood pressure is not adequately controlled with Arbitel 80 mg tablets.

Arbitel N, 80 mg/25 mg tablets, can be administered once daily to patients if treatment with Arbitel N 80 mg/12.5 mg does not provide adequate blood pressure control, or to adult patients whose blood pressure has been stabilized with telmisartan or hydrochlorothiazide as monotherapies (see section "Indications").

Elderly patients. Dose adjustment is not required for elderly patients.

Renal impairment. Experience in treating patients with mild to moderate renal impairment is limited but does not indicate adverse effects; therefore, dose adjustment is not considered necessary. Periodic monitoring of renal function is recommended (see section "Special precautions for use").

Telmisartan is not removed from blood by hemofiltration and is not dialyzable.

Hepatic impairment. For patients with mild to moderate hepatic impairment, the daily dose of Arbitel N should not exceed 40 mg/12.5 mg. Arbitel N is contraindicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic impairment (see section "Special precautions for use").

Route of administration

Arbitel N should be taken orally once daily, swallowing the tablet whole with liquid, regardless of food intake.

Safety precautions prior to drug administration

Arbitel N should be stored in its sealed blister pack due to the hygroscopic properties of the tablets. Tablets should be removed from the blister immediately before administration.

Children

The safety and efficacy of the telmisartan/hydrochlorothiazide combination in children under 18 years of age have not been established. The use of Arbitel N in children is not recommended.

Overdose

Information regarding telmisartan overdose in humans is limited. The extent to which hydrochlorothiazide is removed by hemodialysis is unknown.

Symptoms. The most likely expected manifestations of telmisartan overdose are arterial hypotension and tachycardia; bradycardia, dizziness, vomiting, increased serum creatinine, and acute renal failure have also been observed. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients receiving digitalis glycosides or certain antiarrhythmic agents.

Treatment. Telmisartan is not removed by hemofiltration and is not dialyzable. Careful monitoring of the patient is required. Treatment for overdose symptoms should be symptomatic and supportive. Therapy depends on the time elapsed since tablet ingestion and the severity of symptoms. Supportive measures include induction of vomiting and/or gastric lavage. Administration of activated charcoal may be beneficial in treating overdose. Electrolyte and creatinine levels should be monitored. In case of arterial hypotension, the patient should be placed in a supine position and treated with saline and volume-expanding solutions.

Adverse Reactions

Safety profile characterization. The most common adverse reaction is dizziness. Serious angioedema may occur rarely (≥1/10,000 – <1/1,000).

Overall, the frequency of reported adverse reactions for telmisartan/hydrochlorothiazide is comparable to that of telmisartan alone in a randomized controlled trial involving 1,471 patients receiving either the combination of telmisartan and hydrochlorothiazide (835 patients) or telmisartan alone (636 patients). The number of adverse effects is not dose-dependent and has no correlation with sex, age, or race of patients.

Characterization of adverse reactions

Below are adverse reactions identified during clinical trials of the telmisartan/hydrochlorothiazide combination, observed more frequently than with placebo. Adverse reactions not observed during clinical trials but expected during treatment with telmisartan/hydrochlorothiazide, based on experience with telmisartan or hydrochlorothiazide used separately, are also listed below in separate sections.

Adverse reactions are listed by frequency: very common (≥1/10), common (≥1/100 – <1/10), uncommon (≥1/1,000 – <1/100), rare (≥1/10,000 – <1/1,000), very rare (<1/10,000), not known (cannot be estimated from available data). Adverse reactions are listed in order of decreasing severity.

Infections and infestations:

rare – bronchitis, pharyngitis, sinusitis.

Metabolism and nutrition disorders:

uncommon – hypokalaemia;

rare – hyperuricaemia, hyponatraemia.

Psychiatric disorders:

uncommon – anxiety;

rare – depression, insomnia, sleep disorders.

Nervous system disorders:

common – dizziness;

uncommon – syncope, paraesthesia.

Eye disorders:

rare – visual disturbance, transient blurred vision.

Ear and labyrinth disorders:

uncommon – vertigo.

Cardiac disorders:

uncommon – tachycardia, arrhythmia.

Vascular disorders:

uncommon – arterial hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

uncommon – dyspnoea;

rare – respiratory distress syndrome, pneumonitis, pulmonary oedema.

Gastrointestinal disorders:

uncommon – diarrhoea, dry mouth, flatulence;

rare – abdominal pain, constipation, dyspepsia, vomiting, gastritis.

Hepatobiliary disorders:

rare – liver function disorders / hepatic disorders².

Skin and subcutaneous tissue disorders:

rare – angioedema (including fatal cases), erythema, pruritus, rash, increased sweating, urticaria.

Musculoskeletal and connective tissue disorders:

uncommon – back pain, muscle cramps, myalgia;

rare – arthralgia, limb pain (leg pain), activation of systemic lupus erythematosus¹.

Reproductive system and breast disorders:

uncommon – erectile dysfunction.

General disorders and administration site conditions:

uncommon – chest pain;

rare – influenza-like symptoms, pain.

Investigations:

uncommon – increased blood uric acid;

rare – increased creatinine, increased blood creatine phosphokinase, increased liver enzymes.

Additional information on individual components

Adverse reactions observed with individual components may be potential adverse reactions during treatment with Arbetil N, even if they were not observed during clinical trials.

Telmisartan

Adverse reactions occurred with similar frequency in patients receiving placebo or telmisartan. Below are additional adverse reactions reported during clinical trials of telmisartan monotherapy in patients with arterial hypertension or in patients aged 50 years or older at high cardiovascular risk.

Infections and infestations:

uncommon – upper respiratory tract infection, urinary tract infection (including cystitis);

rare – sepsis, including fatal cases².

Blood and lymphatic system disorders:

uncommon – anaemia;

rare – eosinophilia, thrombocytopenia.

Immune system disorders:

rare – hypersensitivity, anaphylactic reactions.

Metabolism and nutrition disorders:

uncommon – hyperkalaemia;

rare – hypoglycaemia (in diabetic patients), hyponatraemia.

Psychiatric disorders:

uncommon – insomnia, depression;

rare – anxiety.

Nervous system disorders:

uncommon – syncope;

rare – somnolence.

Eye disorders:

rare – visual disturbances.

Ear and labyrinth disorders:

uncommon – vertigo.

Cardiac disorders:

uncommon – bradycardia;

rare – tachycardia.

Vascular disorders:

uncommon – arterial hypotension², orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

uncommon – dyspnoea, cough;

rare – interstitial lung disease¹,².

Gastrointestinal disorders:

uncommon – abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting;

rare – dry mouth, abdominal discomfort.

Hepatobiliary disorders:

rare – liver function disorders / hepatic disorders².

Skin and subcutaneous tissue disorders:

uncommon – pruritus, increased sweating, rash;

rare – angioedema (including fatal cases), eczema, erythema, urticaria, drug eruption, toxic dermatitis.

Musculoskeletal and connective tissue disorders:

uncommon – back pain, muscle cramps, myalgia;

rare – arthralgia, limb pain, tendon pain (symptoms similar to tendinitis).

Renal and urinary disorders:

uncommon – renal function impairment, including acute renal failure.

General disorders and administration site conditions:

uncommon – chest pain, asthenia (weakness);

rare – influenza-like symptoms.

Investigations:

uncommon – increased blood creatinine;

rare – decreased haemoglobin, increased blood uric acid, increased liver enzymes, increased blood creatine phosphokinase.

Hydrochlorothiazide

Hydrochlorothiazide may cause or worsen hypovolaemia, which may lead to electrolyte imbalance (see section "Special precautions").

Below are adverse reactions occurring with unknown frequency during monotherapy with hydrochlorothiazide.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)².

Blood and lymphatic system disorders:

rare – thrombocytopenia (sometimes with purpura);

not known – aplastic anaemia;

rare – haemolytic anaemia, bone marrow suppression, leucopenia, agranulocytosis.

Immune system disorders:

rare – hypersensitivity.

Metabolism and nutrition disorders:

very common – hypokalaemia, hyperlipidaemia;

common – hypomagnesaemia, hyperuricaemia, hyponatraemia, loss of appetite;

rare – hypercalcaemia, hyperglycaemia, loss of diabetes control;

very rare – hypochloraemic alkalosis.

Psychiatric disorders:

rare – depression, sleep disorders.

Nervous system disorders:

rare – headache, dizziness, paraesthesia.

Eye disorders:

rare – visual disturbances;

not known – acute angle-closure glaucoma, choroidal effusion.

Cardiac disorders:

rare – arrhythmia.

Vascular disorders:

common – orthostatic hypotension;

very rare – necrotic vasculitis.

Respiratory, thoracic and mediastinal disorders:

very rare – respiratory distress syndrome, pneumonitis, pulmonary oedema; acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders:

common – nausea, vomiting, diarrhoea;

rare – abdominal discomfort, constipation;

very rare – pancreatitis.

Hepatobiliary disorders:

rare – jaundice, cholestasis.

Skin and subcutaneous tissue disorders:

common – rash, urticaria;

rare – photosensitivity reactions;

very rare – lupus-like syndrome, toxic epidermal necrolysis;

not known – erythema multiforme.

Musculoskeletal and connective tissue disorders:

very rare – systemic lupus erythematosus;

not known – muscle cramps.

Renal and urinary disorders:

uncommon – acute renal failure;

very rare – glucosuria;

not known – renal failure.

Reproductive system and breast disorders:

common – erectile dysfunction.

General disorders and administration site conditions:

not known – asthenia (weakness), malaise.

¹ Based on post-marketing experience

² See section "Adverse Reactions. Description of selected adverse reactions"

Description of selected adverse reactions

Liver function disorders / hepatic disorders. Most cases of liver function disorders / hepatic disorders reported during the post-marketing period with telmisartan occurred in patients of Japanese nationality. These patients appear to be more susceptible to these adverse reactions.

Sepsis. In the PRoFESS study, cases of sepsis were observed more frequently in patients receiving telmisartan than in those receiving placebo. This may be due to chance or may indicate an unknown underlying process.

Interstitial lung disease. Cases of interstitial lung disease associated with telmisartan have been reported during post-marketing use. However, a causal relationship has not been established.

Cases of intestinal angioedema have been reported after administration of angiotensin II receptor blockers (see section "Special precautions").

Non-melanoma skin cancer

Based on available epidemiological data, there is a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer (see sections "Special precautions" and "Pharmacodynamics").

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of the reach of children.

Packaging. 7 tablets per blister; 4 and 8 blisters per cardboard box.

14 tablets per blister; 1, 2, 4, and 7 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and location of operations

Plot No. S.155 – S.159 and N1, Verna Industrial Estate, Phase III and Phase IV, Verna Salcette, In-403 722, India.