4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

The fixed dose combination should be taken in patients whose blood pressure is not adequately controlled by telmisartan alone. Individual dose titration with each of the two components is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

• MicardisPlus 40 mg/12.5 mg may be administered once daily in patients whose blood pressure is not adequately controlled by Micardis 40 mg

• MicardisPlus 80 mg/12.5 mg may be administered once daily in patients whose blood pressure is not adequately controlled by Micardis 80 mg

Elderly

No dose adjustment is necessary for elderly patients.

Renal impairment

Experience in patients with mild to moderate renal impairment is modest but has not suggested adverse renal effects and dose adjustment is not considered necessary. Periodic monitoring of renal function is advised (see section 4.4). Due to the hydrochlorothiazide component, the fixed dose combination is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3).

Telmisartan is not removed from blood by haemofiltration and is not dialysable.

Hepatic impairment

In patients with mild to moderate hepatic impairment MicardisPlus should be administered with caution. For telmisartan, the posology should not exceed 40 mg once daily. The fixed dose combination is contraindicated in patients with severe hepatic impairment (see section 4.3). Thiazides should be used with caution in patients with impaired hepatic function (see section 4.4).

Paediatric population

The safety and efficacy of MicardisPlus has not been established in patients aged below 18 years. Use of MicardisPlus is not recommended in children and adolescents.

Method of administration

MicardisPlus tablets are for once-daily oral administration and should be swallowed whole with liquid. MicardisPlus can be taken with or without food.

Precautions to be taken before handling or administering the medicinal product

MicardisPlus should be kept in the sealed blister due to the hygroscopic property of the tablets. Tablets should be taken out of the blister shortly before administration (see section 6.6).

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

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.

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.

Isolated cases of hyponatraemia accompanied by neurological symptoms (nausea, progressive disorientation, apathy) have been observed with the use of HCTZ.

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

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section 4.8).

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan/HCTZ is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance, whereas hypoglycaemia may occur in diabetic patients under insulin or antidiabetic therapy and telmisartan treatment. Therefore, in these patients blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required, when indicated. Latent diabetes mellitus may become manifest during thiazide therapy.

An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy; however, at the 12.5 mg dose contained in the medicinal product, minimal or no effects were reported.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

- Hypokalaemia

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or Adrenocorticotropic hormone (ACTH) (see section 4.5).

- Hyperkalaemia

Conversely, due to the antagonism of the angiotensin II (AT1) receptors by the telmisartan component of the medicinal product, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not been documented with telmisartan/HCTZ, risk factors for the development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with telmisartan/HCTZ (see section 4.5).

- Hypochloraemic alkalosis

Chloride deficit is generally mild and usually does not require treatment.

- Hypercalcaemia

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

- Hypomagnesaemia

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see section 4.5).

Ethnic differences

As with all other angiotensin II receptor blockers, telmisartan is apparently less effective in lowering blood pressure in black patients than in non blacks, possibly because of higher prevalence of low renin states in the black hypertensive population.

Ischaemic heart disease

As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

General

Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics, including HCTZ.

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Choroidal Effusion, Acute Myopia and Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of HCTZ exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry (see section 4.8). Photosensitising actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, MicardisPlus should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor blockers (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. 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 has occurred.

Lactose

Each tablet contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sorbitol

MicardisPlus 40 mg/12.5 mg tablets

MicardisPlus 40 mg/12.5 mg tablets contain 169 mg sorbitol in each tablet.

MicardisPlus 80 mg/12.5 mg tablets

MicardisPlus 80 mg/12.5 mg tablets contain 338 mg sorbitol in each tablet. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Sodium

Each tablet contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)

- others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine IV.)

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of digitalis-induced arrhythmia (see section 4.4).

Digoxin

When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. When initiating, adjusting, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.

Other antihypertensive agents

Telmisartan may increase the hypotensive effect of other antihypertensive agents.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Antidiabetic medicinal products (oral agents and insulin)

Dose adjustment of the antidiabetic medicinal products may be required (see section 4.4).

Metformin

Metformin should be used with precaution: risk of lactic acidosis induced by a possible functional renal failure linked to HCTZ.

Cholestyramine and colestipol resins

Absorption of HCTZ is impaired in the presence of anionic exchange resins.

Non-steroidal anti-inflammatory medicinal products

NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dose regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effects of angiotensin II receptor blockers.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor blockers and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Pressor amines (e.g. noradrenaline)

The effect of pressor amines may be decreased.

Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine)

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by HCTZ.

Medicinal products used in the treatment for gout (e.g. probenecid, sulfinpyrazone and allopurinol)

Dose adjustment of uricosuric medications may be necessary as HCTZ may raise the level of serum uric acid. Increase in dose of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.

Calcium salts

Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dose adjusted accordingly.

Beta-blockers and diazoxide

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Amantadine

Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen, amifostine.

Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressants.

4.6. Fertility, pregnancy and lactation

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 for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breast-feeding

Because no information is available regarding the use of telmisartan/HCTZ during breast-feeding, telmisartan/HCTZ is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of telmisartan/HCTZ during breast-feeding is not recommended. If telmisartan/HCTZ is used during breast-feeding, doses should be kept as low as possible.

Fertility

No studies on fertility in humans with the fixed dose combination or with the individual components have been performed.

In preclinical studies, no effects of telmisartan and HCTZ on male and female fertility were observed.

4.7. Effects on ability to drive and use machines

MicardisPlus can have influence on the ability to drive and use machines. Dizziness, syncope or vertigo may occasionally occur when taking antihypertensive therapy such as telmisartan/HCTZ.

If patients experience these adverse events, they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8. Undesirable effects

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.

Table 1: Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and from post-marketing experience

MedDRA System Organ Class

Adverse Reactions

Frequency

MicardisPlus

Telmisartana

Hydrochlorothiazide

Infections and infestations

Sepsis including fatal outcome

rare2

Bronchitis

rare

Pharyngitis

rare

Sinusitis

rare

Upper respiratory tract infection

uncommon

Urinary tract infection

uncommon

Cystitis

uncommon

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

not known2

Blood and lymphatic system disorders

Anaemia

uncommon

Eosinophilia

rare

Thrombocytopenia

rare

rare

Thrombocytopenic purpura

rare

Aplastic anaemia

not known

Haemolytic anaemia

very rare

Bone marrow failure

very rare

Leukopenia

very rare

Agranulocytosis

very rare

Immune system disorders

Anaphylactic reaction

rare

Hypersensitivity

rare

very rare

Metabolism and nutrition disorders

Hypokalaemia

uncommon

very common

Hyperuricaemia

rare

common

Hyponatraemia

rare

rare

common

Hyperkalaemia

uncommon

Hypoglycaemia (in diabetic patients)

rare

Hypomagnesaemia

common

Hypercalcaemia

rare

Alkalosis hypochloraemic

very rare

Decreased appetite

common

Hyperlipidaemia

very common

Hyperglycaemia

rare

Diabetes mellitus inadequate control

rare

Psychiatric disorders

Anxiety

uncommon

rare

Depression

rare

uncommon

rare

Insomnia

rare

uncommon

Sleep disorders

rare

rare

Nervous system disorders

Dizziness

common

rare

Syncope

uncommon

uncommon

Paraesthesia

uncommon

rare

Somnolence

rare

Headache

rare

Eye disorders

Visual impairment

rare

rare

rare

Vision blurred

rare

Acute angle closure glaucoma

not known

Choroidal effusion

not known

Ear and labyrinth disorders

Vertigo

uncommon

uncommon

Cardiac disorders

Tachycardia

uncommon

rare

Arrhythmias

uncommon

rare

Bradycardia

uncommon

Vascular disorders

Hypotension

uncommon

uncommon

Orthostatic hypotension

uncommon

uncommon

common

Vasculitis necrotising

very rare

Respiratory, thoracic and mediastinal disorders

Dyspnoea

uncommon

uncommon

Respiratory distress

rare

very rare

Pneumonitis

rare

very rare

Pulmonaryoedema

rare

very rare

Cough

uncommon

Interstitial lung disease

very rare1,2

Acute respiratory distress syndrome (ARDS) (see section 4.4)

very rare

Gastrointestinal disorders

Diarrhoea

uncommon

uncommon

common

Dry mouth

uncommon

rare

Flatulence

uncommon

uncommon

Abdominal pain

rare

uncommon

Constipation

rare

rare

Dyspepsia

rare

uncommon

Vomiting

rare

uncommon

common

Gastritis

rare

Abdominal discomfort

rare

rare

Nausea

common

Pancreatitis

very rare

Hepatobiliary disorders

Abnormal hepatic function/liver disorder

rare2

rare2

Jaundice

rare

Cholestasis

rare

Skin and subcutaneous tissue disorders

Angioedema (including fatal outcome)

rare

rare

Erythema

rare

rare

Pruritus

rare

uncommon

Rash

rare

uncommon

common

Hyperhidrosis

rare

uncommon

Urticaria

rare

rare

common

Eczema

rare

Drug eruption

rare

Toxic skin eruption

rare

Lupus-like syndrome

very rare

Photosensitivity reaction

rare

Toxic epidermal necrolysis

very rare

Erythema multiforme

not known

Muscoloskeletal, connective tissue and bone disorders

Back pain

uncommon

uncommon

Muscle spasms (cramps in leg)

uncommon

uncommon

not known

Myalgia

uncommon

uncommon

Arthralgia

rare

rare

Pain in extremity (leg pain)

rare

rare

Tendon pain (tendonitis-like symptoms)

rare

Systemic lupus erythematosus

rare1

very rare

Renal and urinary disorders

Renal impairment

uncommon

not known

Acute renal failure

uncommon

uncommon

Glucosuria

rare

Reproductive system and breast disorders

Erectile dysfunction

uncommon

common

General disorders and administration site conditions

Chest pain

uncommon

uncommon

Influenza-like illness

rare

rare

Pain

rare

Asthenia (weakness)

uncommon

not known

Pyrexia

not known

Investigations

Blood uric acid increased

uncommon

rare

Blood creatinine increased

rare

uncommon

Blood creatine phosphokinase increased

rare

rare

Hepatic enzyme increased

rare

rare

Haemoglobin decreased

rare

1 Based on post-marketing experience

2 See subsections below for additional information

a Adverse reactions occurred with similar frequency in placebo and telmisartan treated patients. The overall incidence of adverse reactions reported with telmisartan (41.4%) was usually comparable to placebo (43.9%) in placebo controlled trials. The adverse reactions listed above have been accumulated from all clinical trials in patients treated with telmisartan for hypertension or in patients 50 years or older at high risk of cardiovascular events.

Description of selected adverse reactions

Hepatic function abnormal/liver disorder

Most cases of hepatic function abnormal/liver disorder from post-marketing experience with telmisartan occurred in Japanese patients. Japanese patients are more likely to experience these adverse reactions.

Sepsis

In the PRoFESS trial, an increased incidence of sepsis was observed with telmisartan compared with placebo. The event may be a chance finding or related to a mechanism currently not known (see section 5.1).

Interstitial lung disease

Cases of interstitial lung disease have been reported from post-marketing experience in temporal association with the intake of telmisartan. However, a causal relationship has not been established.

Non-melanoma skin cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

Intestinal angioedema

Cases of intestinal angioedema have been reported after the use of angiotensin II receptor blockers (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is limited information available for telmisartan with regard to overdose in humans. The degree to which HCTZ is removed by haemodialysis has not been established.

Symptoms

The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, vomiting, increase in serum creatinine, and acute renal failure have also been reported. Overdose with HCTZ is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

Treatment

Telmisartan is not removed by haemofiltration and is not dialysable. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.