Isicard® n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IZICARD® H (IZICARD® H)

Composition:

Active substances: telmisartan, hydrochlorothiazide;

One tablet contains telmisartan 40 mg and hydrochlorothiazide 12.5 mg,

or

one tablet contains telmisartan 80 mg and hydrochlorothiazide 12.5 mg,

or

one tablet contains telmisartan 80 mg and hydrochlorothiazide 25 mg;

Excipients: mannite (E 421), povidone, sodium hydroxide, meglumine, magnesium stearate, sodium starch glycolate (type A), iron oxide red (E 172) – present in tablets with dosage 40 mg/12.5 mg and 80 mg/12.5 mg, or iron oxide yellow (E 172) – present in tablets with dosage 80 mg/25 mg.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets 40 mg/12.5 mg: bilayer tablets of elongated shape, uncoated; one layer white or almost white with imprint «C31» and the other layer red. The layer from white to almost white contains specks of red color;

Tablets 80 mg/12.5 mg: bilayer tablets of elongated shape, uncoated; one layer white or almost white with imprint «C32» and the other layer red. The layer from white to almost white contains specks of red color;

Tablets 80 mg/25 mg: bilayer tablets of elongated shape, uncoated; one layer white or almost white with imprint «C33» and the other layer yellow. The layer from white to almost white contains specks of yellow color.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics.

ATC code C09D A07.

Pharmacological Properties.

Pharmacodynamics.

IZIKARD® H is a combination medicinal product containing an angiotensin II receptor antagonist (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, IZIKARD® H produces effective and gradual reduction of arterial pressure.

Telmisartan is a specific antagonist of angiotensin II receptors (AT1 subtype). Due to its very high affinity for these receptors, telmisartan displaces angiotensin II from its binding sites on AT1 receptors. It does not exhibit any 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 (ACE, kininase II, an enzyme that also degrades bradykinin). Therefore, potentiation of bradykinin-mediated adverse effects is not expected.

At a dose of 80 mg, the drug almost completely inhibits the hypertensive effect of angiotensin II in humans. The effect lasts more than 24 hours and may persist up to 48 hours.

After the first dose of telmisartan, antihypertensive activity gradually develops within 3 hours. Maximum reduction in arterial pressure is 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 drug administration, including the last 4 hours before the next dose. This is confirmed by blood pressure measurements at peak effect and immediately before the next dose (the trough-to-peak ratio exceeds 80% after doses of 40 mg and 80 mg of telmisartan in placebo-controlled clinical trials).

In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting heart rate. The antihypertensive efficacy of telmisartan is comparable to that of other classes of antihypertensive agents (demonstrated in clinical trials 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, with no evidence of a withdrawal syndrome.

In clinical trials comparing two antihypertensive treatment regimens, the incidence of dry cough was significantly lower in patients receiving telmisartan compared to those receiving ACE inhibitors.

In the "Prevention Regimen for Effectively Avoiding Second Strokes" (PRoFESS) study in patients aged 50 years or older who had recently experienced a stroke, sepsis occurred more frequently in patients receiving telmisartan compared to placebo: 0.70% vs. 0.49%, respectively [RR 1.43 (95% confidence interval (CI) 1.00–2.06)]; fatal sepsis was more frequent in patients receiving telmisartan (0.33%) compared to those receiving placebo (0.16%) [RR 2.07 (95% CI 1.14–3.76)].

The observed increased incidence of sepsis with telmisartan use may be coincidental or due to a mechanism not yet established.

Hydrochlorothiazide is a thiazide diuretic, a sulfonamide derivative. The antihypertensive mechanism 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 increases, leading to increased urinary excretion of potassium and bicarbonate and a reduction in serum potassium levels. The concomitant administration of telmisartan, through blockade of the renin-angiotensin-aldosterone system (RAAS), may counteract the potassium loss associated with these diuretics. After administration of hydrochlorothiazide, diuresis begins within 2 hours, peak effect occurs approximately 4 hours later, and the duration of action lasts approximately 6–12 hours. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.

Based on available epidemiological data, a cumulative dose-dependent association has been established between hydrochlorothiazide use and the risk of non-melanoma skin cancer (NMSC)—basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In one study, 71,533 cases of BCC and 8,629 cases of SCC were identified from samples of 1,430,833 and 172,462 individuals, respectively. The odds ratio for BCC with high cumulative doses of hydrochlorothiazide—starting from 50,000 mg (≈5–6 years of daily 25 mg use)—was 1.29 (95% confidence interval (CI) 1.23–1.35), and for SCC it was 3.98 (CI 3.68–4.31). A clear dose-response relationship was observed for both BCC and SCC. Another study indicated a possible association between lip cancer (LC, a variant of SCC) and hydrochlorothiazide use: 633 cases of LC were compared with a control group of 63,067 individuals using a risk-set sampling strategy. The odds ratio for LC with long-term hydrochlorothiazide use compared to the general population was 2.1 (CI 1.7–2.6). At a cumulative dose of 25,000 mg (≈3 years of daily 25 mg use), the odds ratio increased to 3.9 (CI 3.0–4.9), and at the highest cumulative doses of 100,000 mg (≈10–12 years of daily 25 mg use), it increased to 7.7 (CI 5.7–10.5) (see also section "Special Warnings and Precautions for Use").

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

Pharmacokinetics.

Concomitant administration of hydrochlorothiazide and telmisartan does not affect the pharmacokinetics of either drug in healthy individuals.

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 intake slightly reduces telmisartan bioavailability, with a reduction in the area under the concentration-time curve (AUC) ranging from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). Three hours after administration, plasma concentrations are similar regardless of whether telmisartan is taken fasting or with food. The minor reduction in AUC is not considered to result in a decrease in therapeutic efficacy. The pharmacokinetics of orally administered telmisartan are nonlinear with increasing doses from 20 mg to 160 mg, with plasma concentrations (Cmax and AUC) increasing disproportionately. Telmisartan does not accumulate significantly in plasma with repeated dosing.

Hydrochlorothiazide. After oral administration of IZIKARD® H, peak plasma concentration of hydrochlorothiazide is reached within 1–3 hours. Due to combined 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.

Hydrochlorothiazide. Hydrochlorothiazide is 68% bound to plasma proteins, with a volume of distribution of 0.83–1.14 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 accounted for approximately 11% of the measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in telmisartan metabolism.

Hydrochlorothiazide is not metabolized in the human body.

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 exceeds 1500 mL/min. The terminal elimination half-life is more than 20 hours.

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

Special Patient Populations.

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

*Gender. Plasma concentrations of telmisartan are generally 2–3 times higher in women than in men. However, clinical trial data show no clinically significant increase in blood pressure reduction or in the 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. Renal excretion does not affect telmisartan elimination. Due to limited experience in patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min, average approximately 50 mL/min), dose adjustment is not required in these patients. Telmisartan is not removed by hemodialysis. In patients with renal insufficiency, the elimination rate of hydrochlorothiazide is reduced. In typical studies, in patients with a mean creatinine clearance of 90 mL/min, the elimination half-life of hydrochlorothiazide increases. In patients with anephria or absent 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 remains unchanged.

Clinical characteristics.

Indications.

Arterial hypertension.

IZIKARD® H in fixed-dose combination is indicated for use when telmisartan monotherapy does not provide adequate blood pressure control.

Contraindications.

Hypersensitivity to the active substances or to any of the components of the medicinal product.

Hypersensitivity to other sulfonamide derivatives.

Cholestatic and biliary obstructive disorders.

Severe hepatic impairment.

Concomitant use of IZIKARD® H and aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).

Anuria, severe renal impairment (creatinine clearance < 30 mL/min).

Refractory hypokalemia/hyponatremia, hypercalcemia.

Symptomatic hyperuricemia (gout).

Pregnancy or periods during which a woman plans to become pregnant.

Breastfeeding.

Pediatric population (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

Lithium.

Concomitant use of lithium with ACE inhibitors has been reported to cause reversible increases in serum lithium concentrations and lithium toxicity. Cases of such interactions have also been reported with angiotensin II receptor antagonists (ARBs). Concomitant use of lithium and IZIKARD® H is not recommended. If combination therapy is considered necessary, serum lithium levels should be carefully monitored.

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 derivatives).

When these medicinal products are used concomitantly with the telmisartan/hydrochlorothiazide combination, monitoring of plasma potassium levels is recommended. These medicinal products may potentiate the effect of hydrochlorothiazide on plasma potassium levels.

Medicinal products that may increase sodium levels and cause hyperkalemia.

Like other medicinal products affecting the renin-angiotensin-aldosterone system (RAAS), telmisartan may cause hyperkalemia. This risk may increase when combined with other medicinal products that may also provoke hyperkalemia (potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim).

The frequency of hyperkalemia depends on associated risk factors. The risk increases with the use of the above-mentioned therapeutic combinations. This risk is particularly high when combined with potassium-sparing diuretics and potassium-containing salt substitutes. Combinations, for example, with ACE inhibitors or NSAIDs, pose a lower risk provided strict adherence to usage precautions.

When using these medicinal products concomitantly with the telmisartan/hydrochlorothiazide combination, monitoring of plasma potassium levels is recommended. Based on experience with other RAAS-inhibiting medicinal products, concomitant use of these medicinal products may lead to increased serum potassium levels and is therefore not recommended.

Medicinal products causing disturbances in serum potassium levels.

When using IZIKARD® H with medicinal products that cause disturbances in serum potassium levels (e.g., digoxin glycosides, antiarrhythmic agents) and medicinal products that provoke ventricular arrhythmias (including certain antiarrhythmic agents) or hypokalemia, which is a triggering factor for ventricular arrhythmias:

• 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, levopromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• others (e.g., bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Periodic monitoring of serum potassium levels and ECG is recommended.

Digoxin glycosides.

Hypokalemia or hypomagnesemia caused by thiazides predisposes to digoxin-induced cardiac arrhythmias.

Digoxin.

When telmisartan is used concomitantly with digoxin, increases in mean peak plasma concentration (49%) and trough concentration (20%) of digoxin have been observed. Digoxin levels should be monitored at the beginning of therapy, during dose adjustments, and upon discontinuation of telmisartan therapy to maintain levels within the therapeutic range.

Other antihypertensive medicinal products.

Telmisartan may enhance the hypotensive effect of other antihypertensive agents. Clinical data have shown that dual blockade of the RAAS with combinations of ACE inhibitors, ARBs, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure) compared to use of a single RAAS-acting agent.

Antidiabetic medicinal products (oral agents and insulin).

Dosage adjustment of antidiabetic medicinal products may be required.

Metformin.

Metformin should be used with caution due to the risk of lactic acidosis when used concomitantly with hydrochlorothiazide.

Cholestyramine and colestipol resins.

Absorption of hydrochlorothiazide is reduced in the presence of anion-exchange resins.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

NSAIDs (specifically: acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics and the antihypertensive effect of ARBs. In dehydrated patients or elderly patients with impaired renal function, concomitant use of ARBs and agents that inhibit cyclooxygenase may lead to worsening of renal function, potentially resulting in acute renal failure, which is usually reversible. Such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured at the start of combination therapy and periodically throughout treatment, and renal function should be closely monitored.

Ramipril.

In a clinical study, co-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 finding has not been established.

Vasoactive amines (e.g., noradrenaline).

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 enhanced by hydrochlorothiazide.

Medicinal products used to treat gout (e.g., probenecid, sulfinpyrazone, allopurinol).

Dosage 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. If calcium supplementation is necessary, 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 medicinal products (e.g., cyclophosphamide, methotrexate).

Thiazides may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Due to 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 enhance their toxic effects on the central nervous system.

Metildopa.

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

Cyclosporine.

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

Effect of medicinal products on laboratory test results.

Due to effects on calcium metabolism, thiazides may influence the assessment of parathyroid gland function.

Carbamazepine.

Due to the risk of symptomatic hyponatremia, clinical and biological monitoring is required.

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.

Amphotericin B (parenteral), corticosteroids, ACTH, and stimulant laxatives.

Hydrochlorothiazide potentiates electrolyte imbalance, particularly hypokalemia.

Special precautions for use.

Pregnancy.

Therapy with ARAs II should not be initiated during pregnancy. Female patients of childbearing potential who are planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is detected, ARAs II should be discontinued immediately and alternative therapy should be started if necessary.

Liver dysfunction.

IZIKARD® H should not be administered to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency, as telmisartan is primarily excreted via bile. Reduced hepatic clearance of telmisartan is expected in such patients. IZIKARD® H should be used with caution in patients with impaired liver function or progressive liver disease, as these drugs may cause intrahepatic cholestasis, and even minor disturbances in fluid and electrolyte balance may lead to hepatic encephalopathy. There is no clinical experience with this combination of active substances in the treatment of patients with hepatic insufficiency.

Intestinal angioedema.

Cases of intestinal angioedema have been reported in patients receiving 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, telmisartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms.

Renovascular hypertension.

There is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney when treated with drugs affecting the RAAS.

Renal impairment and kidney transplantation.

IZIKARD® H should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min). There is no experience with this combination of active substances in patients with severe renal impairment or with recently transplanted kidneys. Due to limited experience with this combination in patients with mild to moderate renal impairment, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. Azotemia associated with thiazide diuretics may occur in patients with impaired renal function.

Reduced circulating blood volume (CBV) and/or hyponatremia.

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 before initiating IZIKARD® H.

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 reduced renal function (including acute renal failure).

Therefore, dual blockade of the RAAS by combining ACE inhibitors, ARAs II, or aliskiren is not recommended.

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision 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 stimulation.

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

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via RAAS blockade. Therefore, the use of IZIKARD® H is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

As with other vasodilators, special 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. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, with a product 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 serum electrolyte monitoring. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis), which may be exacerbated by concomitant diarrhea or vomiting. 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.

• Hypokalemia. Although hypokalemia may develop during thiazide diuretic therapy, concomitant telmisartan therapy may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with hepatic cirrhosis, those with marked diuresis, those receiving inadequate oral electrolyte supplementation, and those receiving concomitant corticosteroid or ACTH therapy.
• Hyperkalemia. Conversely, due to angiotensin II receptor (AT1) antagonism by telmisartan, a component of IZIKARD® H, hyperkalemia may occur. However, clinically significant hyperkalemia with this combination of active substances 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 with IZIKARD® H.
• Hyponatremia and hypochloremic alkalosis. There is no evidence that IZIKARD® H reduces or prevents diuretic-induced hyponatremia. Chloride deficiency is usually mild and generally does not require treatment. Hyponatremia due to hemodilution may occur in edematous patients during warm seasons.
• Hypercalcemia. Thiazides may reduce urinary calcium excretion and cause transient, 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 testing.
• Hypomagnesemia. Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia.

Race.

As with other ARAs II, telmisartan is likely less effective in reducing blood pressure in black patients due to the prevalent low-renin state in this population with hypertension.

Others.

As with any other antihypertensive agent, excessive blood pressure reduction 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, particularly in those with such conditions in their medical history. Exacerbation or activation of systemic lupus erythematosus has been observed with thiazide diuretics, including hydrochlorothiazide.

Photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during treatment, drug discontinuation is recommended. If re-administration is necessary, protection of exposed skin from sunlight or artificial ultraviolet radiation is advised.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma.

Drugs 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 sudden onset of decreased visual acuity or eye pain and typically occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Hydrochlorothiazide therapy 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.

Acute respiratory toxicity.

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients with a history of ARDS after hydrochlorothiazide use.

Non-melanoma skin cancer (NMSC).

An increased risk of NMSC with cumulative hydrochlorothiazide dose has been studied in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and should be regularly examined for new skin lesions. Any self-detected skin changes should be reported to a physician immediately.

To minimize the risk of NMSC, preventive measures such as limiting sun and ultraviolet exposure, or using appropriate skin protection if exposure is unavoidable, should be considered. Suspicious skin lesions should be promptly evaluated as potentially malignant, including histological examination of biopsies. The continued use of hydrochlorothiazide should be reconsidered in patients with a history of NMSC (see also section "Adverse reactions").

Effects on laboratory test results:

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

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

This medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, therapy should be discontinued immediately and replaced with a permitted alternative.

There are no data on the use of IZIKARD® H in pregnant women.

Epidemiological evidence on teratogenic risk after ARA II use in the first trimester is inconclusive; however, a small increased risk cannot be excluded.

Until ARA II therapy is considered appropriate, patients planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, ARA II therapy should be discontinued immediately and alternative therapy initiated if necessary.

ARA II use during the second and third trimesters of pregnancy causes fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ARA II is used from the second trimester, ultrasound monitoring of fetal renal function and skull condition is recommended. Newborns of mothers treated with ARA II should be closely monitored for hypotension.

Experience with hydrochlorothiazide use during pregnancy is limited, especially during the first trimester.

Hydrochlorothiazide crosses the placental barrier. Due to its pharmacological mechanism, hydrochlorothiazide use during the second and third trimesters may impair fetoplacental perfusion 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 pregnancy-induced hypertension or late toxemia due to the risk of plasma volume reduction and placental hypoperfusion without beneficial effects on disease course.

Hydrochlorothiazide should not be used in pregnant women with significant hypertension except in rare cases where alternative treatment is not possible.

Breastfeeding.

Due to lack of information on the use of IZIKARD® H during breastfeeding, its use during this period is not recommended. Alternative therapy with better-established safety profiles should be preferred, especially when nursing newborns or preterm infants.

Hydrochlorothiazide passes into breast milk in small amounts. High-dose thiazides causing intense diuresis may suppress breast milk production. If IZIKARD® H is used during breastfeeding, the lowest possible doses should be administered.

Fertility.

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

Ability to affect reaction speed while driving or operating machinery.

When driving or operating machinery, it should be considered that dizziness or drowsiness may occur during therapy with IZIKARD® H.

Method of Administration and Dosage.

IZICARD® H is intended for long-term treatment.

Patients whose blood pressure is inadequately controlled with telmisartan as monotherapy may be switched to combination therapy with IZICARD® H. The recommended dose is 1 tablet per day.

IZICARD® H tablets can be taken independently of food intake; it is recommended to take them with sufficient fluid.

Patients currently receiving hydrochlorothiazide and telmisartan separately may be switched to IZICARD® H containing the same doses of the components. Prior to switching to fixed-dose combination therapy, individual dose titration of the components (i.e., telmisartan and hydrochlorothiazide) is recommended. In cases of clinical necessity, direct substitution of monotherapy with fixed-dose combination therapy may be considered.

Precautions Before Drug Administration.

IZICARD® H should be stored in its sealed blister pack due to the hygroscopic properties of the tablets. Tablets should be removed from the blister pack immediately before use.

Use in Special Patient Populations.

Patients with Renal Impairment.

Periodic monitoring of renal function is recommended.

Patients with Hepatic Impairment.

For patients with mild to moderate hepatic impairment, the daily dose of IZICARD® H should not exceed 40 mg/12.5 mg. IZICARD® H is contraindicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with hepatic dysfunction.

Elderly Patients.

No dose adjustment is required for elderly patients.

Children.

The drug is not to be used in pediatric practice.

Overdose.

Information regarding telmisartan overdose 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 reported. Overdose with hydrochlorothiazide is associated with decreased serum electrolyte levels (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly when concomitant digoxin or certain antiarrhythmic drugs are used.

Treatment.

Telmisartan is not removed by hemodialysis. Close monitoring of the patient is required. Management of overdose symptoms should be symptomatic and supportive. Therapy depends on the time elapsed since tablet ingestion and the severity of symptoms. Recommended measures include induction of emesis and/or gastric lavage. Administration of activated charcoal may also be beneficial. Electrolyte levels and serum creatinine should be monitored. In case of arterial hypotension, the patient should be placed in a supine position with legs elevated, and treated with saline and plasma expanders as needed.

Adverse Reactions.

Safety profile overview.

The overall frequency of reported adverse reactions for medicinal products containing this combination of active substances can be compared to the number of reports for telmisartan alone in a randomized controlled study involving 1471 patients who received either a combination of telmisartan and hydrochlorothiazide (835 patients) or telmisartan alone (636 patients). The number of adverse effects was not dose-dependent and showed no correlation with gender, age, or race of patients.

The most commonly observed adverse reaction was dizziness.

Description of adverse reactions.

Listed below are adverse reactions identified during clinical trials of the combination of telmisartan and hydrochlorothiazide and observed more frequently than with placebo. Adverse reactions not observed during clinical trials but which may occur during treatment with this combination of active substances, based on experience with telmisartan or hydrochlorothiazide used individually, are also listed below.

Adverse reactions are listed by frequency of occurrence:

very common (≥ 1/10),
common (≥ 1/100 to < 1/10),
uncommon (≥ 1/1,000 to < 1/100),
rare (≥ 1/10,000 to < 1/1,000),
very rare (< 1/10,000),
not known (cannot be estimated from available data).

Adverse reactions were classified by system organ classes according to MedDRA terms.

Infections and infestations: rare – bronchitis, pharyngitis, sinusitis.

Immune system disorders: rare – exacerbation or activation of systemic lupus erythematosus.

Psychiatric disorders: uncommon – anxiety; rare – depression.

Nervous system disorders: common – dizziness; uncommon – syncope, paraesthesia; rare – insomnia, sleep disturbances.

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; very rare – acute respiratory distress syndrome (ARDS) (including pneumonitis and pulmonary oedema).

Gastrointestinal disorders: uncommon – diarrhoea, dry mouth, flatulence; rare – abdominal pain, constipation, dyspepsia, vomiting, gastritis.

Hepatobiliary disorders: rare – liver function abnormal/ hepatic disorder.

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, calf muscle cramps, leg pain.

Reproductive system and breast disorders: uncommon – impotence.

Metabolism and nutrition disorders: uncommon – hypokalaemia; rare – hyperuricaemia, hyponatraemia.

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 of the medicinal product.

Adverse reactions observed with individual components may be potential adverse reactions during treatment with this combination product, even if they did not occur during clinical trials.

Telmisartan.

Adverse reactions occurred with similar frequency among patients receiving telmisartan and those receiving placebo. Listed below are 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 cases.

Blood and lymphatic system disorders: uncommon – anaemia; rare – eosinophilia, thrombocytopenia.

Immune system disorders: rare – hypersensitivity, including anaphylactic reactions.

Metabolism and nutrition disorders: uncommon – hyperkalaemia; rare – hypokalaemia (in diabetic patients).

Cardiac disorders: uncommon – bradycardia.

Nervous system disorders: not known – somnolence.

Respiratory, thoracic and mediastinal disorders: uncommon – cough; very rare – interstitial lung disease.

Gastrointestinal disorders: rare – stomach discomfort.

Skin and subcutaneous tissue disorders: rare – eczema, drug eruption, toxic dermatitis.

Musculoskeletal and connective tissue disorders: rare – arthrosis, tendon pain.

Renal and urinary disorders: uncommon – renal failure (including acute renal failure).

General disorders and administration site conditions: uncommon – asthenia.

Investigations: rare – decreased haemoglobin.

Hydrochlorothiazide.

Hydrochlorothiazide may cause or exacerbate hypovolaemia, which may lead to electrolyte imbalance.

Listed below are adverse reactions occurring with unknown frequency during hydrochlorothiazide monotherapy.

Infections and infestations: not known – sialadenitis.

Blood and lymphatic system disorders: not known – aplastic anaemia, haemolytic anaemia, bone marrow depression, leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

Immune system disorders: not known – anaphylactic reactions, anaphylactic shock, hypersensitivity.

Endocrine disorders: not known – loss of diabetes control, decreased glucose tolerance, which may lead to manifestation of latent diabetes mellitus.

Metabolism and nutrition disorders: not known – anorexia, loss of appetite, electrolyte imbalance, hypercholesterolaemia, hyperglycaemia, hypovolaemia, hypomagnesaemia, hypercalcaemia, hypochloraemic alkalosis (which may induce hepatic encephalopathy or hepatic coma, particularly in patients with liver cirrhosis), hyperuricaemia (which may provoke gout attacks in patients with asymptomatic disease).

Psychiatric disorders: not known – restlessness, disorientation, somnolence, nervousness, mood changes.

Nervous system disorders: not known – mild dizziness, headache, convulsions, confusion.

Eye disorders: not known – xanthopsia, acute myopia, acute angle-closure glaucoma, choroidal effusion.

Vascular disorders: not known – necrotizing vasculitis.

Gastrointestinal disorders: not known – pancreatitis, stomach discomfort, thirst, nausea.

Hepatobiliary disorders: not known – hepatocellular jaundice, cholestatic jaundice, cholecystitis.

Skin and subcutaneous tissue disorders: not known – lupus-like syndrome, photosensitivity reactions, skin vasculitis, toxic epidermal necrolysis, purpura, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: not known – weakness.

Renal and urinary disorders: not known – interstitial nephritis, renal dysfunction, glucosuria, renal failure.

Reproductive system and breast disorders: not known – sexual disorders.

Benign, malignant and unspecified neoplasms (including cysts and polyps): not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

General disorders and administration site conditions: not known – heat exhaustion.

Investigations: not known – increased triglycerides.

Description of selected adverse reactions.

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

Sepsis. In the PRoFESS study, a higher incidence of sepsis was observed among patients receiving telmisartan compared to those receiving placebo. This may be due to chance or may reflect a mechanism currently not understood.

Non-melanoma skin cancer. Based on available epidemiological data, a cumulative dose-dependent association has been observed between hydrochlorothiazide use and non-melanoma skin cancer.

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

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

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging.

7 tablets in an aluminium blister, 2 or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Evertodjen Life Sciences Limited / Evertogen Life Sciences Limited.

Manufacturer's address and location of operations.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.