TOLURA 40mg tablets medication leaflet

Tolura 40 mg tablets

Each tablet contains 40 mg telmisartan.

Each tablet contains 149.8 mg sorbitol (E420) and 57 mg lactose.

For the full list of excipients, see section 6.1.

Tablet.

40 mg: white to almost white, biconvex, oval tablets

Treatment of essential hypertension in adults.

Cardiovascular prevention

Reduction of cardiovascular morbidity in adults with:

- manifest atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, orperipheral arterial disease) or

- type 2 diabetes mellitus with documented target organ damage.

Treatment of essential hypertension

The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can beincreased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combinationwith thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additiveblood pressure lowering effect with telmisartan. When considering raising the dose, it must be bornein mind that the maximum antihypertensive effect is generally attained four to eight weeks after thestart of treatment (see section 5.1).

Cardiovascular prevention

The recommended dose is 80 mg once daily. It is not known whether doses lower than 80 mg oftelmisartan are effective in reducing cardiovascular morbidity.

When initiating telmisartan therapy for the reduction of cardiovascular morbidity, close monitoring ofblood pressure is recommended, and if appropriate adjustment of medications that lower bloodpressure may be necessary.

Limited experience is available in patients with severe renal impairment or haemodialysis. A lowerstarting dose of 20 mg is recommended in these patients (see section 4.4). No posology adjustment isrequired for patients with mild to moderate renal impairment.

Tolura is contraindicated in patients with severe hepatic impairment (see section 4.3).

In patients with mild to moderate hepatic impairment the posology should not exceed 40 mg oncedaily (see section 4.4).

No dose adjustment is necessary for elderly patients.

The safety and efficacy of Tolura in children and adolescents aged below 18 years have not beenestablished.

Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology canbe made.

Telmisartan tablets are for once-daily oral administration and should be taken with liquid, with orwithout food.

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

Tolura tablets cannot be divided, therefore they are not suitable for patients who require a dose of 20mg of telmisartan for the treatment of hypertension or for patients with severe renal impairment orhaemodialysis. For these patients, an equivalent product with the same active ingredient is available.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Second and third trimester of pregnancy (see sections 4.4 and 4.6)

- Biliary obstructive disorders

- Severe hepatic impairment

The concomitant use of Tolura with aliskiren-containing products is contraindicated in patients withdiabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continuedangiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy shouldbe changed to alternative antihypertensive treatments which have an established safety profile for usein pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists shouldbe stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and4.6).

Tolura is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepaticimpairment (see section 4.3) since telmisartan is mostly eliminated with the bile. These patients can beexpected to have reduced hepatic clearance for telmisartan. Tolura should be used only with caution inpatients with mild to moderate hepatic impairment.

Intestinal angioedema

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

Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinalangioedema is diagnosed, telmisartan should be discontinued and appropriate monitoring should beinitiated until complete resolution of symptoms has occurred.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateralrenal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinalproducts that affect the renin-angiotensin-aldosterone system.

When Tolura is used in patients with impaired renal function, periodic monitoring of potassium andcreatinine serum levels is recommended. There is no experience regarding the administration of Tolurain patients with recent kidney transplantation.

Intravascular hypovolaemia

Symptomatic hypotension, especially after the first dose of Tolura, may occur in patients who arevolume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, orvomiting. Such conditions should be corrected before the administration of Tolura. Volume and/orsodium depletion should be corrected prior to administration of Tolura.

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers oraliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (includingacute 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 specialistsupervision 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 withdiabetic 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 renaldisease, including renal artery stenosis), treatment with medicinal products that affect this system suchas telmisartan has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acuterenal failure (see section 4.8).

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal productsacting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is notrecommended.

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

Diabetic patients treated with insulin or antidiabetics

In these patients hypoglycaemia may occur under telmisartan treatment. Therefore, in these patients anapproptiate blood glucose monitoring should be considered; a dose adjustment of insulin orantidiabetics may be required, when indicated.

The use of medicinal products that affect the renin-angiotensin-aldosterone system may causehyperkalaemia.

In the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantlytreated with other medicinal products that may increase potassium levels, and/or in patients withintercurrent events, hyperkalaemia may be fatal.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated.

The main risk factors for hyperkalaemia to be considered are:

- Diabetes mellitus, renal impairment, age (>70 years).

- Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Medicinal products or therapeutic classes ofmedicinal products that may provoke hyperkalaemia are salt substitutes containing potassium,potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidalanti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.

- Intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolicacidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectiousdiseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extend trauma).

Close monitoring of serum potassium in at risk patients is recommended (see section 4.5).

Sorbitol

This medicine contains 149.8 mg sorbitol in each tablet.

The additive effect of concomitantly administered products containing sorbitol (or fructose) anddietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of othermedicinal products for oral use administered concomitantly.

Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

Tolura tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take Tolura.

Ethnic differences

As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin IIreceptor antagonists are apparently less effective in lowering blood pressure in black people than innon-blacks, possibly because of higher prevalence of low-renin states in the black hypertensivepopulation.

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

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

As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan mayprovoke hyperkalaemia (see section 4.4). The risk may increase in case of treatment combination withother medicinal products that may also provoke hyperkalaemia (salt substitutes containing potassium,potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,immunosuppressives (cyclosporin or tacrolimus), and trimethoprim).

The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case ofthe above-mentioned treatment combinations. The risk is particularly high in combination withpotassium sparing-diuretics, and when combined with salt substitutes containing potassium. Acombination with ACE inhibitors or NSAIDs, for example, presents a lesser risk provided thatprecautions for use are strictly followed.

Potassium sparing diuretics or potassium supplements

Angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss.

Potassium sparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassiumsupplements, or potassium-containing salt substitutes may lead to a significant increase in serumpotassium. If concomitant use is indicated because of documented hypokalaemia they should be usedwith caution and with frequent monitoring of serum potassium.

Reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors, and withangiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary,careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Non-steroidal anti-inflammatory medicinal products

NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients withcompromised renal function), the co-administration of angiotensin II receptor antagonists and agentsthat inhibit cyclo-oxygenase may result in further deterioration of renal function, including possibleacute renal failure, which is usually reversible. Therefore, the combination should be administeredwith caution, especially in the elderly. Patients should be adequately hydrated and considerationshould be given to monitoring of renal function after initiation of concomitant therapy and periodicallythereafter.

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.

Diuretics (thiazide or loop diuretics)

Prior treatment with high dose diuretics such as furosemide (loop diuretic) and hydrochlorothiazide(thiazide diuretic) may result in volume depletion and in a risk of hypotension when initiating therapywith telmisartan.

To be taken into account with concomitant use

Other antihypertensive agents

The blood pressure lowering effect of telmisartan can be increased by concomitant use of otherantihypertensive medicinal products.

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 associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting agent (seesections pct. 4.3, pct. 4.4 and 5.1).

Based on their pharmacological properties it can be expected that the following medicinal productsmay potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen,amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcoticsor antidepressants.

Corticosteroids (systemic route)

Reduction of the antihypertensive effect.

The use of angiotensin II receptor antagonists is not recommended during the first trimester ofpregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated duringthe second and third trimesters of pregnancy (see sections 4.3 and 4.4).

There are no adequate data from the use of Tolura in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin IIreceptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin IIreceptor antagonist therapy is considered essential, patients planning pregnancy should be changed toalternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stoppedimmediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is knownto induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossificationretardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to angiotensin II receptor antagonists have occurred from the second trimester ofpregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed forhypotension (see sections 4.3 and 4.4).

Because no information is available regarding the use of Tolura during breast-feeding, Tolura is notrecommended and alternative treatments with better established safety profiles during breast-feedingare preferable, especially while nursing a newborn or preterm infant.

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

When driving vehicles or operating machinery it should be taken into account that dizziness ordrowsiness may occasionally occur when taking antihypertensive therapy such as Tolura.

Serious adverse drug reactions include anaphylactic reaction and angioedema which may occur rarely(≥1/10,000 to <1/1,000), and acute renal failure.

The overall incidence of adverse reactions reported with telmisartan was usually comparable toplacebo (41.4 % vs 43.9 %) in controlled trials in patients treated for hypertension. The incidence ofadverse reactions was not dose related and showed no correlation with gender, age or race of thepatients. The safety profile of telmisartan in patients treated for the reduction of cardiovascularmorbidity was consistent with that obtained in hypertensive patients.

The adverse reactions listed below have been accumulated from controlled clinical trials in patientstreated for hypertension and from post-marketing reports. The listing also takes into account seriousadverse reactions and adverse reactions leading to discontinuation reported in three clinical long-termstudies including 21642 patients treated with telmisartan for the reduction of cardiovascular morbidityfor up to six years.

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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations Uncommon: Urinary tract infection including cystitis, upper respiratory tract infectionincluding pharyngitis and sinusitis

Rare: Sepsis including fatal outcome1

Blood and the lymphatic system disorders

Uncommon: Anaemia

Rare: Eosinophilia, thrombocytopenia

Rare: Anaphylactic reaction, hypersensitivity

Uncommon: Hyperkalaemia

Rare: Hypoglycaemia (in diabetic patients)

Uncommon: Insomnia, depression

Rare: Anxiety

Uncommon: Syncope

Rare: Somnolence

Rare: Visual disturbance

Ear and labyrinth disorders

Uncommon: Vertigo

Uncommon: Bradycardia

Rare: Tachycardia

Uncommon: Hypotension2, orthostatic hypotension

Uncommon: Dyspnoea, cough

Very rare: Interstitial lung disease4

Uncommon: Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting

Rare: Dry mouth, stomach discomfort, dysgeusia

Hepato-biliary disorders

Rare: Hepatic function abnormal/liver disorder3

Uncommon: Pruritus, hyperhidrosis, rash

Rare: Angioedema (also with fatal outcome), eczema, erythema, urticaria, drugeruption, toxic skin eruption

Muscoloskeletal and connective tissue disorders

Uncommon: Back pain (e.g. sciatica), muscle spasms, myalgia,

Rare: Arthralgia, pain in extremity, tendon pain (tendinitis like symptoms)

Uncommon: Renal impairment including acute renal failure

Uncommon: Chest pain, asthenia (weakness)

Rare: Influenza-like illness

Uncommon: Blood creatinine increased

Rare: Haemoglobin decreased, blood uric acid increased, hepatic enzymeincreased, blood creatine phosphokinase increased1, 2, 3, 4: for further descriptions, please see sub-section “Description of selected adverse reactions”

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

This adverse reaction was reported as common in patients with controlled blood pressure who weretreated with telmisartan for the reduction of cardiovascular morbidity on top of standard care.

Hepatic function abnormal/liver disorder

Most cases of hepatic function abnormal/liver disorder from post-marketing experience occurred in

Japanese patients. Japanese patients are more likely to experience these adverse reactions.

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

Intestinal angioedema

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited information available with regard to overdose in humans.

Symptoms: The most prominent manifestations of telmisartan overdose were hypotension andtachycardia; bradycardia, dizziness, increase in serum creatinine, and acute renal failure have alsobeen reported.

Treatment: Telmisartan is not removed by haemodialysis. The patient should be closely monitored,and the treatment should be symptomatic and supportive. Management depends on the time sinceingestion and the severity of the symptoms. Suggested measures include induction of emesis and/orgastric lavage. Activated charcoal may be useful in the treatment of overdosage. Serum electrolytesand creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in asupine position, with salt and volume replacement given quickly.

Pharmacotherapeutic group: Angiotensin II Antagonists, plain, ATC code: C09CA07.

Telmisartan is an orally active and specific angiotensin II receptor (type AT1) antagonist. Telmisartandisplaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, whichis responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonistactivity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting. Telmisartan does not show affinity for other receptors, including AT2 and other lesscharacterised AT receptors. The functional role of these receptors is not known, nor is the effect oftheir possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasmaaldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin orblock ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), theenzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects.

In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked bloodpressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to48 hours.

Treatment of essential hypertension

After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start oftreatment and is sustained during long-term therapy.

The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hoursbefore the next dose as shown by ambulatory blood pressure measurements. This is confirmed bytrough to peak ratios consistently above 80 % seen after doses of 40 and 80 mg of telmisartan inplacebo controlled clinical studies. There is an apparent trend to a dose relationship to a time torecovery of baseline systolic blood pressure (SBP). In this respect data concerning diastolic bloodpressure (DBP) are inconsistent.

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure withoutaffecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to itshypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparableto that of agents representative of other classes of antihypertensive medicinal products (demonstratedin clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, andlisinopril).

Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatmentvalues over a period of several days without evidence of rebound hypertension.

The incidence of dry cough was significantly lower in patients treated with telmisartan than in thosegiven angiotensin converting enzyme inhibitors in clinical trials directly comparing the twoantihypertensive treatments.

Cardiovascular prevention

ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint

Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril oncardiovascular outcomes in 25620 patients aged 55 years or older with a history of coronary arterydisease, stroke, TIA, peripheral arterial disease, or type 2 diabetes mellitus accompanied by evidenceof end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria),which is a population at risk for cardiovascular events.

Patients were randomized to one of the three following treatment groups: telmisartan 80 mg (n =8542), ramipril 10 mg (n = 8576), or the combination of telmisartan 80 mg plus ramipril 10 mg (n =8502), and followed for a mean observation time of 4.5 years.

Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint ofcardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization forcongestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7 %)and ramipril (16.5 %) groups. The hazard ratio for telmisartan vs. ramipril was 1.01 (97.5 % CI 0.93 -1.10, p (non-inferiority) = 0.0019 at a margin of 1.13). The all-cause mortality rate was 11.6 % and11.8 % among telmisartan and ramipril treated patients, respectively.

Telmisartan was found to be similarly effective to ramipril in the pre-specified secondary endpoint ofcardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.99 (97.5 % CI 0.90 -1.08), p (non-inferiority) = 0.0004], the primary endpoint in the reference study HOPE (The Heart

Outcomes Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo.

TRANSCEND randomized ACE-I intolerant patients with otherwise similar inclusion criteria as

ONTARGET to telmisartan 80 mg (n=2954) or placebo (n=2972), both given on top of standard care.

The mean duration of follow up was 4 years and 8 months. No statistically significant difference in theincidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction,non-fatal stroke, or hospitalization for congestive heart failure) was found [15.7 % in the telmisartanand 17.0 % in the placebo groups with a hazard ratio of 0.92 (95 % CI 0.81 - 1.05, p = 0.22)]. Therewas evidence for a benefit of telmisartan compared to placebo in the pre-specified secondarycomposite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke[0.87 (95 % CI 0.76 - 1.00, p = 0.048)]. There was no evidence for benefit on cardiovascular mortality(hazard ratio 1.03, 95 % CI 0.85 - 1.24).

Cough and angioedema were less frequently reported in patients treated with telmisartan than inpatients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.

Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. CVmortality and all cause mortality were numerically higher with the combination. In addition, there wasa significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in thecombination arm. Therefore the use of a combination of telmisartan and ramipril is not recommendedin this population.

In the “Prevention Regimen For Effectively avoiding Second Strokes” (PRoFESS) trial in patients 50years and older, who recently experienced stroke, an increased incidence of sepsis was noted fortelmisartan compared with placebo, 0,70 % vs. 0,49 % RR 1,43 (95 % confidence interval 1,00 -2,06) the incidence of fatal sepsis cases was increased for patients taking telmisartan (0,33 %) vs.patients taking placebo (0,16 %) RR 2,07 (95 % confidence interval 1,14 - 3,76). The observedincreased occurrence rate of sepsis associated with the use of telmisartan may be either a chancefinding or related to a mechanism not currently known.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs

Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with anangiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovasculardisease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-Dwas a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes andmortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension ascompared to monotherapy was observed. Given their similar pharmacodynamic properties, theseresults are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitoror an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidneydisease, cardiovascular disease, or both. The study was terminated early because of an increased riskof adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in thealiskiren group than in the placebo group and adverse events and serious adverse events of interest(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskirengroup than in the placebo group.

The safety and efficacy of telmisartan in children and adolescents aged below 18 years have not beenestablished.

The blood pressure lowering effects of two doses of telmisartan were assessed in 76 hypertensive,largely overweight patients aged 6 to < 18 years (body weight ≥ 20 kg and ≤ 120 kg, mean 74.6 kg),after taking telmisartan 1 mg/kg (n = 29 treated) or 2 mg/kg (n = 31 treated) over a four-weektreatment period. By inclusion the presence of secondary hypertension was not investigated. In someof the investigated patients the doses used were higher than those recommended in the treatment ofhypertension in the adult population, reaching a daily dose comparable to160 mg, which was tested inadults. After adjustment for age group effects mean SBP changes from baseline (primary objective)were -14.5 (1.7) mmHg in the telmisartan 2 mg/kg group, -9.7 (1.7) mmHg in the telmisartan 1 mg/kggroup, and -6.0 (2.4) in the placebo group. The adjusted DBP changes from baseline were -8.4 (1.5)mmHg, -4.5 (1.6) mmHg and -3.5 (2.1) mmHg respectively. The change was dose dependent. Thesafety data from this study in patients aged 6 to < 18 years appeared generally similar to that observedin adults. The safety of long term treatment of telmisartan in children and adolescents was notevaluated.

An increase in eosinophils reported in this patient population has not been recorded in adults. Itsclinical significance and relevance is unknown.

These clinical data do not allow to make conclusions on the efficacy and safety of telmisartan inhypertensive paediatric population.

Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolutebioavailability for telmisartan is about 50 %. When telmisartan is taken with food, the reduction in thearea under the plasma concentration-time curve (AUC0-∞) of telmisartan varies from approximately6 % (40 mg dose) to approximately 19 % (160 mg dose). By 3 hours after administration, plasmaconcentrations are similar whether telmisartan is taken fasting or with food.

The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. There isno linear relationship between doses and plasma levels. Cmax and to a lesser extent AUC increasedisproportionately at doses above 40 mg.

Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acidglycoprotein. The mean steady state apparent volume of distribution (Vdss) is approximately 500 l.

Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. Nopharmacological activity has been shown for the conjugate.

Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal eliminationhalf-life of >20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, the areaunder the plasma concentration-time curve (AUC), increase disproportionately with dose. There is noevidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasmaconcentrations were higher in females than in males, without relevant influence on efficacy.

After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the faeces,mainly as unchanged compound. Cumulative urinary excretion is <1 % of dose. Total plasmaclearance (Cltot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about1,500 ml/min).

The pharmacokinetics of two doses of telmisartan were assessed as a secondary objective inhypertensive patients (n = 57) aged 6 to < 18 years after taking telmisartan 1 mg/kg or 2 mg/kg over afour-week treatment period. Pharmacokinetic objectives included the determination of the steady-stateof telmisartan in children and adolescents, and investigation of age-related differences. Although thestudy was too small for a meaningful assessment of the pharmacokinetics of children under 12 years ofage, the results are generally consistent with the findings in adults and confirm the non-linearity oftelmisartan, particularly for Cmax.

Differences in plasma concentrations were observed, with Cmax and AUC being approximately 3- and2-fold higher, respectively, in females compared to males.

The pharmacokinetics of telmisartan do not differ between the elderly and those younger than65 years.

In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations wasobserved. However, lower plasma concentrations were observed in patients with renal insufficiencyundergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient patients andcannot be removed by dialysis. The elimination half-life is not changed in patients with renalimpairment.

Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolutebioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepaticimpairment.

In preclinical safety studies, doses producing exposure comparable to that in the clinical therapeuticrange caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit), changes in renalhaemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassiumin normotensive animals. In dogs, renal tubular dilation and atrophy were observed. Gastric mucosalinjury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically-mediated undesirable effects, known from preclinical studies with both angiotensin converting enzymeinhibitors and angiotensin II receptor antagonists, were prevented by oral saline supplementation.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the renaljuxtaglomerular cells were observed. These changes, also a class effect of angiotensin convertingenzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinicalsignificance.

No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan aneffect on the postnatal development of the offsprings such as lower body weight and delayed eyeopening was observed.

There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and noevidence of carcinogenicity in rats and mice.

Povidone (K30)

Meglumine

Sodium hydroxide

Lactose monohydrate

Sorbitol (E420)

Magnesium stearate

Not applicable.

3 years.

Do not store above 30°C.

Store in the original package in order to protect from light.

OPA/Al/PVC Al blister. Each blister contains 7 or 10 tablets.

Pack sizes: 14, 28, 30, 56, 84, 90, 98 and 100 tablets in a box.

Not all pack sizes may be marketed.

No special requirements.

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

14 tablets: EU/1/10/632/00828 tablets: EU/1/10/632/00930 tablets: EU/1/10/632/01056 tablets: EU/1/10/632/01184 tablets: EU/1/10/632/01290 tablets: EU/1/10/632/01398 tablets: EU/1/10/632/014100 tablets: EU/1/10/632/023

Date of first authorisation: 4 June 2010

Date of latest renewal: 19 March 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu