Leitlinien & Arzneimittelsicherheit

HOS-093378 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most commonly reported adverse reaction is dizziness. Serious angioedema may occur rarely (≥ 1/10 000 to < 1/1 000). The overall incidence of adverse reactions reported with telmisartan/HCTZ was comparable to those reported with telmisartan alone in randomised controlled trials involving 1 471 patients randomised to receive telmisartan plus HCTZ (835) or telmisartan alone (636). Dose-relationship of adverse reactions was not established and they showed no correlation with gender, age or race of the patients. Tabulated list of adverse reactions Adverse reactions reported in all clinical trials and occurring more frequently (p ≤ 0.05) with telmisartan plus HCTZ than with placebo are shown below according to system organ class. Adverse reactions known to occur with each component given singly but which have not been seen in clinical trials may occur during treatment with telmisartan/HCTZ. Adverse reactions previously reported with one of the individual components may be potential adverse reactions with MicardisPlus, even if not observed in clinical trials with this product. Adverse reactions have been ranked under headings of frequency using the following convention: 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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 10 Table 1: Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and from post-marketing experience MedDRA System Adverse Reactions Frequency Organ Class MicardisPlus Telmisartana Hydrochlorothiazide Infections and Sepsis including infestations fatal outcome rare2 Bronchitis rare Pharyngitis rare Sinusitis rare Upper respiratory tract infection uncommon Urinary tract infection uncommon Cystitis uncommon Neoplasms Non-melanoma skin benign, cancer (Basal cell malignant and carcin

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HOS-093384 · has-adverse-reaction-information · PDF-Seite 30

Summary of the safety profile The most commonly reported adverse reaction is dizziness. Serious angioedema may occur rarely (≥ 1/10 000 to < 1/1 000). The overall incidence and pattern of adverse reactions reported with MicardisPlus 80 mg/25 mg was comparable with MicardisPlus 80 mg/12.5 mg. A dose-relationship of adverse reactions was not established and they showed no correlation with gender, age or race of the patients. Tabulated list of adverse reactions Adverse reactions reported in all clinical trials and occurring more frequently (p ≤ 0.05) with telmisartan plus HCTZ than with placebo are shown below according to system organ class. Adverse reactions known to occur with each component given singly but which have not been seen in clinical trials may occur during treatment with telmisartan/HCTZ. Adverse reactions previously reported with one of the individual components may be potential adverse reactions with MicardisPlus, even if not observed in clinical trials with this product. Adverse reactions have been ranked under headings of frequency using the following convention: 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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 30 Table 1: Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and from post-marketing experience MedDRA System Adverse Reactions Frequency Organ Class MicardisPlus Telmisartana Hydrochlorothiazide Infections and Sepsis including infestations fatal outcome rare2 Bronchitis rare Pharyngitis rare Sinusitis rare Upper respiratory tract infection uncommon Urinary tract infection uncommon Cystitis uncommon Neoplasms Non-melanoma skin benign, cancer (Basal cell malignant and carcinoma and unspecified (incl. Squamous cell cysts and polyps) carcinoma) not

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HOS-093380 · has-contraindication-information · PDF-Seite 23

• Hypersensitivity to any of the active substances or to any of the excipients listed in section 6.1. • Hypersensitivity to other sulphonamide-derived substances (since HCTZ is a sulphonamide- derived medicinal product). • Second and third trimesters of pregnancy (see sections 4.4 and 4.6). • Cholestasis and biliary obstructive disorders. • Severe hepatic impairment. • Severe renal impairment (creatinine clearance < 30 mL/min, anuria. • Refractory hypokalaemia, hypercalcaemia. The concomitant use of telmisartan/HCTZ with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.5 and 5.1).

HOS-093374 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to any of the active substances or to any of the excipients listed in section 6.1. • Hypersensitivity to other sulphonamide-derived substances (since HCTZ is a sulphonamide- derived medicinal product). • Second and third trimesters of pregnancy (see sections 4.4 and 4.6). • Cholestasis and biliary obstructive disorders. • Severe hepatic impairment. • Severe renal impairment (creatinine clearance < 30 mL/min, anuria. • Refractory hypokalaemia, hypercalcaemia. The concomitant use of telmisartan/HCTZ with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.5 and 5.1).

HOS-093379 · has-indication-information · PDF-Seite 22

Treatment of essential hypertension. MicardisPlus fixed dose combination (80 mg telmisartan/25 mg hydrochlorothiazide (HCTZ)) is indicated in adults whose blood pressure is not adequately controlled on MicardisPlus 80 mg/12.5 mg (80 mg telmisartan/12.5 mg HCTZ) or adults who have been previously stabilised on telmisartan and HCTZ given separately.

HOS-093373 · has-indication-information · PDF-Seite 2

Treatment of essential hypertension. MicardisPlus fixed dose combination (40 mg telmisartan/12.5 mg hydrochlorothiazide (HCTZ) and 80 mg telmisartan/12.5 mg HCTZ) is indicated in adults whose blood pressure is not adequately controlled on telmisartan alone.

HOS-093382 · has-interaction-information · PDF-Seite 27

Lithium Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have also been reported with angiotensin II receptor blockers (including telmisartan/HCTZ). Co- administration of lithium and telmisartan/HCTZ is not recommended (see section 4.4). If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use. Medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and derivatives) If these substances are to be prescribed with the HCTZ-telmisartan combination, monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect of HCTZ on serum potassium (see section 4.4). Iodinated contrast products In the event of dehydration caused by diuretics, there is an increased risk of acute functional renal failure, particularly during use of high doses of iodinated contrast products. Rehydration before administration of the iodinated product is required. Medicinal products that may increase potassium levels or induce hyperkalaemia (e.g. ACE inhibitors, potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporin or other medicinal products such as heparin sodium) If these medicinal products are to be prescribed with the HCTZ-telmisartan combination, monitoring of potassium plasma levels is advised. Based on the experience with the use of other medicinal products that blunt the renin-angiotensin system, concomitant use of the above medicinal products may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Medicinal products affected by serum potassium disturbances Periodic monitoring of serum potassium and ECG is recommended when telmisartan/HCTZ is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes. - class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide) - class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide) - some antipsychotics (e.g. thio

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HOS-093376 · has-interaction-information · PDF-Seite 7

Lithium Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have also been reported with angiotensin II receptor blockers (including telmisartan/HCTZ). Co- administration of lithium and telmisartan/HCTZ is not recommended (see section 4.4). If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use. Medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and derivatives) If these substances are to be prescribed with the HCTZ-telmisartan combination, monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect of HCTZ on serum potassium (see section 4.4). Iodinated contrast products In the event of dehydration caused by diuretics, there is an increased risk of acute functional renal failure, particularly during use of high doses of iodinated contrast products. Rehydration before administration of the iodinated product is required. Medicinal products that may increase potassium levels or induce hyperkalaemia (e.g. ACE inhibitors, potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporin or other medicinal products such as heparin sodium) If these medicinal products are to be prescribed with the HCTZ-telmisartan combination, monitoring of potassium plasma levels is advised. Based on the experience with the use of other medicinal products that blunt the renin-angiotensin system, concomitant use of the above medicinal products may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4). Medicinal products affected by serum potassium disturbances Periodic monitoring of serum potassium and ECG is recommended when telmisartan/HCTZ is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes. - class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide) - class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide) - some antipsychotics (e.g. thio

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HOS-093383 · has-pregnancy-information · PDF-Seite 29

Pregnancy The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor blockers is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). There are no adequate data from the use of telmisartan/HCTZ in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor blockers, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to angiotensin II receptor blocker therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to angiotensin II receptor blockers have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor blockers should be closely observed for hypotension (see sections 4.3 and 4.4). There is limited experience with HCTZ during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of HCTZ its use during the second and third trimester may compromise foeto- placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used fo

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HOS-093377 · has-pregnancy-information · PDF-Seite 9

Pregnancy The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor blockers is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). There are no adequate data from the use of telmisartan/HCTZ in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor blockers, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to angiotensin II receptor blocker therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to angiotensin II receptor blockers have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor blockers should be closely observed for hypotension (see sections 4.3 and 4.4). There is limited experience with HCTZ during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of HCTZ its use during the second and third trimester may compromise foeto- placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

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HOS-093375 · has-warning-information · PDF-Seite 3

Pregnancy Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continued angiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be 3 stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Hepatic impairment Telmisartan/HCTZ must not be given to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated in the bile. These patients can be expected to have reduced hepatic clearance for telmisartan. In addition, telmisartan/HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with telmisartan/HCTZ in patients with hepatic impairment. Renovascular hypertension There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. Renal impairment and kidney transplantation Telmisartan/HCTZ must not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3). There is no experience regarding the administration of telmisartan/HCTZ in patients with recent kidney transplantation. Experience with telmisartan/HCTZ is modest in the patients with mild to moderate renal impairment, therefore periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. Telmisartan is not removed from blood by haemofiltration and is not dialysable. Volume and/or sodium depleted patients Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions, especially volume and/or sodium depletion, should be corrected before the administration of MicardisPlus. I

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HOS-093381 · has-warning-information · PDF-Seite 23

Pregnancy Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continued angiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Hepatic impairment Telmisartan/HCTZ must not be given to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated in the bile. These patients can be expected to have reduced hepatic clearance for telmisartan. In addition, telmisartan/HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with telmisartan/HCTZ in patients with hepatic impairment. 23 Renovascular hypertension There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. Renal impairment and kidney transplantation Telmisartan/HCTZ must not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3). There is no experience regarding the administration of telmisartan/HCTZ in patients with recent kidney transplantation. Experience with telmisartan/HCTZ is modest in the patients with mild to moderate renal impairment, therefore periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. Telmisartan is not removed from blood by haemofiltration and is not dialysable. Volume and/or sodium depleted patients Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions, especially volume and/or sodium depletion, should be corrected before the administration of MicardisPlus.

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