4.1. Therapeutic indications

Hypertension

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, or peripheral arterial disease) or

- type 2 diabetes mellitus with documented target organ damage

4.2. Posology and method of administration

Posology

Treatment of essential hypertension

The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of 20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can be increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the start 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 of telmisartan are effective in reducing cardiovascular morbidity.

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

Special populations

Patients with renal impairment

Limited experience is available in patients with severe renal impairment or haemodialysis. A lower starting dose of 20 mg is recommended in these patients (see section 4.4). No posology adjustment is required for patients with mild to moderate renal impairment. Telmisartan is not removed from blood by hemofiltration and is not dialyzable.

Patients with hepatic impairment

Telmisartan 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 once daily (see section 4.4).

Elderly patients

No dose adjustment is necessary for elderly patients.

Paediatric population

The safety and efficacy of telmisartan in children and adolescents aged below 18 years have not been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Telmisartan tablets are for once-daily oral administration and should be swallowed whole with liquid, with or without food.

Precautions to be taken before handling or administering the medicinal product.

Telmisartan 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 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 telmisartan 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

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 intestinal angioedema is diagnosed, Telmisartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist 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 antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Hepatic impairment

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

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

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

Volume- and/or sodium-depleted patients

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

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 such as telmisartan 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 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.

Diabetic patients treated with insulin or antidiabetics

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

Hyperkalaemia

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

In the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent 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 of medicinal products that may provoke hyperkalaemia are 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, immunosuppressive agents (cyclosporin or tacrolimus), and trimethoprim.

• Intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischaemia, rhabdomyolysis, extend trauma).

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

Ethnic differences

As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin II receptor antagonists are apparently less effective in lowering blood pressure in black people 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.

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

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.

As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may provoke hyperkalaemia (see section 4.4). The risk may increase in case of treatment combination with other 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, immunosuppressive agents (cyclosporin or tacrolimus), and trimethoprim).

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

Concomitant use not recommended

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, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with angiotensin 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 with compromised renal function), the co-administration of angiotensin II receptor antagonists 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.

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 therapy with 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 other antihypertensive 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 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).

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.

Corticosteroids (systemic route)

Reduction of the antihypertensive effect.

4.6. Fertility, pregnancy and lactation

Pregnancy

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists 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 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 antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist 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 antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

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

Should exposure to angiotensin II receptor antagonists 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 antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding

Because no information is available regarding the use of telmisartan during breast-feeding, Telmisartan Brown & Burk tablets are not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a new born or preterm infant.

Fertility

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

4.7. Effects on ability to drive and use machines

When driving vehicles or operating machinery it should be taken into account that syncope or vertigo may occasionally occur when taking antihypertensive therapy such as Telmisartan.

4.8. Undesirable effects

Summary of the safety profile

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 to placebo (41.4 % vs 43.9 %) in controlled trials in patients treated for hypertension. The incidence of adverse reactions was not dose related and showed no correlation with gender, age or race of the patients. The safety profile of telmisartan in patients treated for the reduction of cardiovascular morbidity was consistent with that obtained in hypertensive patients.

The adverse reactions listed below have been accumulated from controlled clinical trials in patients treated for hypertension and from post-marketing reports. The listing also takes into account serious adverse reactions and adverse reactions leading to discontinuation reported in three clinical long-term studies including 21,642 patients treated with telmisartan for the reduction of cardiovascular morbidity for up to six years.

Tabulated summary of adverse reactions

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: Upper respiratory tract infection including pharyngitis and sinusitis, urinary tract infection including cystitis

Rare: Sepsis including fatal outcome1

Blood and the lymphatic system disorders

Uncommon: Anaemia

Rare: Eosinophilia, thrombocytopenia

Immune system disorders

Rare: Anaphylactic reaction, hypersensitivity

Metabolism and nutrition disorders

Uncommon: Hyperkalaemia

Rare: Hypoglycaemia (in diabetic patients), hyponatraemia

Psychiatric disorders

Uncommon: Depression, insomnia

Rare: Anxiety

Nervous system disorders

Uncommon: Syncope, dizziness

Rare: Somnolence

Eye disorders

Rare: Visual impairment

Ear and labyrinth disorders

Uncommon: Vertigo

Cardiac disorders

Uncommon: Bradycardia

Rare: Tachycardia

Vascular disorders

Uncommon: Hypotension2, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea, cough

Very rare: Interstitial lung disease4

Gastrointestinal disorders

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

Rare: abdominal discomfort, dry mouth, dysgeusia

Hepato-biliary disorders

Rare: Hepatic function abnormal/liver disorder3

Skin and subcutaneous tissue disorders

Uncommon: Hyperhidrosis, pruritus, rash

Rare: Angioedema (including fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption

Muscoloskeletal and connective tissue disorders

Uncommon: Myalgia, back pain (e.g. sciatica), muscle spasms

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

Renal and urinary disorders

Uncommon: Renal impairment (including acute kidney injury)

General disorders and administration site conditions

Uncommon: Chest pain, asthenia (weakness)

Rare: Influenza-like illness

Investigations

Uncommon: Blood creatinine increased

Rare: Blood uric acid increased, hepatic enzyme increased, blood creatine phosphokinase increased, haemoglobin decreased

1,2,3,4,: for further descriptions, please see sub-section “Description of selected adverse reactions”

Description of selected adverse reactions

Intestinal angioedema

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

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 also section 5.1).

Hypotension

This adverse reaction was reported as common in patients with controlled blood pressure who were treated 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.

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.

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 at 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 with regard to overdose in humans.

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

Treatment: Telmisartan is not removed by haemofiltration and is not dialyzable. 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 over dosage. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacement given quickly.