TELMISARTAN BIOGARAN 80 mg Cpr Plq/90

Tablet.

Oval, white, biconvex tablet with the logo "T1 " on one side.

Telmisartan.....................................................................................................................................................80 mg

For one tablet.

Excipients:

Hypertension

Treatment of essential hypertension in adults.

Cardiovascular prevention

Reduction of cardiovascular morbidity in adults presenting with:

• known atherothrombotic cardiovascular disease (history of coronary artery disease, stroke, or peripheral arterial disease) or

• type 2 diabetes with documented target organ damage.

Dosage

Treatment of essential hypertension

The usually effective dose is 40 mg once daily. In some patients, a daily dose of 20 mg may however be sufficient. In cases where blood pressure is not controlled at the usual dose, the telmisartan dose may be increased up to a maximum dose of 80 mg once daily. Before increasing the telmisartan dose, it should be taken into account that the maximum antihypertensive effect is generally reached between the fourth and eighth week after initiation of treatment (see section Pharmacodynamics). Telmisartan may also be combined with thiazide-type diuretics, such as hydrochlorothiazide, with which an additive antihypertensive effect has been demonstrated when combined with telmisartan.

Cardiovascular prevention

The recommended dose is 80 mg once daily. The efficacy of doses lower than 80 mg of telmisartan is not known in reducing cardiovascular morbidity. When initiating telmisartan treatment for reducing cardiovascular morbidity, close monitoring of blood pressure is recommended, and adjustment of blood pressure-lowering treatments may be necessary.

Special populations

Elderly patients

No dose adjustment is necessary in these patients.

 

Renal impairment

Experience is limited in patients with severe renal impairment or in patients on haemodialysis. In these patients, a lower initial dose of 20 mg is recommended (see section Warnings and precautions). No dose adjustment is necessary in cases of mild to moderate renal impairment. Telmisartan is not removed from the blood by haemofiltration and is not dialysable.

Hepatic impairment

TELMISARTAN BIOGARAN is contraindicated in patients with severe hepatic impairment (see section Contraindications).

In cases of mild to moderate hepatic impairment, the dose must not exceed 40 mg once daily (see section Warnings and precautions).

Paediatric population

The safety and efficacy of TELMISARTAN BIOGARAN in children and adolescents under the age of 18 years have not been established.

The data currently available are described in sections Pharmacodynamics and Pharmacokinetics but no dosage recommendation can be given.

Method of administration

Telmisartan tablets are administered orally once daily and must be swallowed whole with liquid, with or without food.

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition ;

• 2th and 3th trimesters of pregnancy (see sections Warnings and precautions and Fertility, pregnancy and breastfeeding) ;

• Biliary obstruction;

• Severe hepatic impairment;

• The combination of TELMISARTAN BIOGARAN with medicinal products containing aliskiren is contraindicated in patients with diabetes or renal impairment (GFR [glomerular filtration rate] < 60 mL/min/1,73 m²) (see sections Interactions and Pharmacodynamics).

Pregnancy

Angiotensin II receptor antagonists (ARB II) should not be initiated during pregnancy. Unless treatment with ARB II is considered essential, it is recommended that in patients planning a pregnancy the antihypertensive treatment be changed to a medicinal product with an established safety profile during pregnancy. In case of a diagnosis of pregnancy, treatment with ARB II must be stopped immediately and, if necessary, an alternative treatment will be initiated (see sections Contraindications and Fertility, pregnancy and breastfeeding).

Hepatic impairment

As telmisartan is eliminated predominantly via bile, TELMISARTAN BIOGARAN must not be administered to patients with cholestasis, biliary obstruction or severe hepatic impairment (see section Contraindications). Hepatic clearance of telmisartan is likely to be reduced in these patients. TELMISARTAN BIOGARAN must be administered with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension

When medicinal products acting on the renin-angiotensin-aldosterone system are administered to patients with bilateral renal artery stenosis or renal artery stenosis in a solitary functioning kidney, the risk of severe hypotension and renal insufficiency is increased.

Renal impairment and renal transplantation

When TELMISARTAN BIOGARAN is administered to patients with renal impairment, regular monitoring of serum potassium and serum creatinine levels is recommended. No data are available on the use of TELMISARTAN BIOGARAN in patients who have recently undergone renal transplantation.

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

Patients with hypovolaemia and/or sodium depletion

Symptomatic hypotension may occur, particularly after the first administration of TELMISARTAN BIOGARAN, in patients with hypovolaemia and/or sodium depletion, for example as a result of high-dose diuretic treatment, a low-sodium diet, diarrhoea or vomiting.

These conditions should be corrected before administration of TELMISARTAN BIOGARAN. Any hypovolaemia and/or sodium depletion should be corrected before initiation of treatment with TELMISARTAN BIOGARAN.

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

It is established that the combination of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists (ARB) or aliskiren increases the risk of hypotension, hyperkalaemia and impairment of renal function (including the risk of acute renal failure). Consequently, dual blockade of the RAAS with the combination of ACE inhibitors, ARBs or aliskiren is not recommended (see sections Interactions and Pharmacodynamics). Nevertheless, if such a combination is considered absolutely necessary, it should only be given under the supervision of a specialist with close and frequent monitoring of renal function, blood electrolytes and blood pressure. ACE inhibitors and ARBs should not be combined in patients with diabetic nephropathy.

Other conditions related to the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (for example patients with severe congestive heart failure, or with underlying renal disease, including renal artery stenosis), treatment with medicinal products acting on this system such as telmisartan has been associated with acute hypotension, hyperazotaemia, oliguria, or, more rarely, acute renal failure (see section Adverse effects).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive treatments acting through inhibition of the renin-angiotensin system. The use of telmisartan is therefore not recommended in these patients.

Mitral and aortic valve stenosis, hypertrophic obstructive cardiomyopathy 

As with other vasodilators, caution is required in patients with mitral or aortic stenosis or hypertrophic obstructive cardiomyopathy.

Diabetic patients treated with insulin or antidiabetic agents

In these patients, hypoglycaemia may occur during treatment with telmisartan. Therefore, appropriate monitoring of blood glucose should be considered in these patients; adjustment of the insulin or antidiabetic dose may be necessary depending on the results.

Hyperkalaemia

The use of medicinal products affecting the renin-angiotensin-aldosterone system may lead to hyperkalaemia.

In elderly patients, patients with renal impairment, diabetic patients, patients concomitantly treated with medicinal products likely to increase plasma potassium levels and/or in patients presenting with intercurrent events, hyperkalaemia may be fatal.

Before considering the concomitant use of medicinal products affecting the renin-angiotensin-aldosterone system, the benefit/risk ratio must be assessed.

The main risk factors to consider for hyperkalaemia are:

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

• Association with one or more medicinal products affecting the renin-angiotensin-aldosterone system and/or potassium supplementation therapy. Medicinal products or therapeutic classes of medicinal products likely to cause hyperkalaemia are potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX2 inhibitors), heparin, immunosuppressants (ciclosporin or tacrolimus) and trimethoprim.

• Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of renal function (for example infectious episodes), cell lysis (for example acute limb ischaemia, rhabdomyolysis, extensive trauma).

In patients at risk, close monitoring of serum potassium is recommended (see section Interactions).

Ethnic differences

As with angiotensin-converting enzyme inhibitors, telmisartan and other angiotensin II receptor antagonists appear to have less antihypertensive effect in Black patients than in other populations. This may be due to a higher prevalence of hypertensive patients with low renin levels in the Black population compared with other populations.

Ischaemic heart disease

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

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients treated with angiotensin II receptor antagonists (see section Adverse effects). 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 instituted until complete resolution of symptoms.

• Digoxin

Upon concomitant administration of telmisartan and digoxin, a median increase in maximum (49%) and minimum (20%) plasma concentration of digoxin was observed. Monitor digoxin levels at initiation, adjustment or discontinuation of telmisartan in order to maintain them within the therapeutic range.

As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may cause hyperkalaemia (see section Warnings and precautions). The risk may increase when combined with other medicinal products that can also cause hyperkalaemia (potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX2 inhibitors), heparin, immunosuppressants (ciclosporin or tacrolimus) and trimethoprim).

The occurrence of hyperkalaemia depends on associated risk factors. The drug combinations mentioned above increase the risk. The risk is particularly high with combinations with potassium-sparing diuretics and with concomitant use of potassium-containing salt substitutes. Combination with ACE inhibitors or NSAIDs, for example, presents a lower risk if precautions for use are strictly followed.

Combinations not recommended

• Potassium-sparing diuretics and potassium supplementation therapies

Angiotensin II receptor antagonists such as telmisartan attenuate diuretic-induced potassium loss. Potassium-sparing diuretics, for example spironolactone, eplerenone, triamterene or amiloride, potassium supplementation therapies or potassium-containing salt substitutes may significantly increase serum potassium. If the combination cannot be avoided due to documented hypokalaemia, its use should be cautious and serum potassium should be monitored frequently.

• Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been observed during concomitant treatment with lithium and angiotensin-converting enzyme inhibitors, as well as with angiotensin II receptor antagonists, including telmisartan. If the combination cannot be avoided, close monitoring of lithaemia is recommended.

Associations requiring precautions for use

• Non-steroidal anti-inflammatory drugs

NSAIDs (for example acetylsalicylic acid at anti-inflammatory doses, COX2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients whose renal function is impaired (for example dehydrated patients or elderly patients whose renal function is impaired), the combination of angiotensin II receptor antagonists and cyclo-oxygenase inhibitory agents may lead to further deterioration of renal function, including acute renal failure, usually reversible. Therefore, mainly in elderly patients, the combination should be used with caution.

Patients should be adequately hydrated and monitoring of renal function should be considered at the initiation of concomitant treatment and periodically thereafter.

In one study, co-administration of telmisartan and ramipril resulted in a 2,5-fold increase 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 lead to volume depletion and a risk of hypotension when initiating treatment with telmisartan.

Associations to be taken into account

• Other antihypertensive agents

The blood pressure-lowering effect of telmisartan may be enhanced by the concomitant use of other antihypertensive medicinal products.

Data from clinical trials have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and impaired renal function (including acute renal failure) compared with use of a single RAAS-acting medicinal product (see sections Contraindications, Warnings and precautions and Pharmacodynamics).

Given their pharmacological properties, baclofen and amifostine may potentiate the hypotensive effects of all antihypertensives, including telmisartan. In addition, alcohol, barbiturates, narcotics or antidepressants may potentiate the risk of orthostatic hypotension.

• Corticosteroids (systemic route)

Reduction of the antihypertensive effect.

Pregnancy

The use of angiotensin II receptor antagonists (ARA II) is not recommended during the 1er trimester of pregnancy (see section Warnings and precautions). The use of ARA II is contraindicated after the 2th and 3th trimesters of pregnancy (see sections Contraindications and Warnings and precautions).

There are no adequate data on the use of TELMISARTAN BIOGARAN in pregnant women. Animal studies have shown reproductive toxicity (see section Preclinical safety).

Available epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the 1er trimester of pregnancy do not allow conclusions to be drawn. However, a small increase in risk cannot be excluded. There are no controlled epidemiological data regarding the risk associated with ARA II, however similar risks may exist for this class. Unless treatment with ARA II is considered essential, it is recommended that in patients planning a pregnancy the antihypertensive treatment be changed to a medicinal product with an established safety profile during pregnancy. Upon diagnosis of pregnancy, treatment with ARA II should be stopped immediately and, if necessary, alternative antihypertensive treatment should be started.

Exposure to AIIRAs during the 2th and 3th trimesters of pregnancy is known to cause fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section Preclinical safety). In case of exposure from the 2th trimester of pregnancy, it is recommended to perform a fetal ultrasound to check renal function and the bones of the skull vault.

Newborns of mothers treated with ARA II should be monitored to detect possible hypotension (see sections Contraindications and Warnings and precautions).

Breast-feeding

As no information is available regarding the use of telmisartan during breast-feeding, its administration is not recommended. Alternative treatments with a better established safety profile during breast-feeding are preferable, particularly while breast-feeding a newborn or preterm infant.

Fertility

In preclinical studies, no effect of telmisartan on male and female fertility was observed.

Patients who drive vehicles or operate machinery should take into account that dizziness or vertigo may occur during treatment with antihypertensive agents such as TELMISARTAN BIOGARAN.

Summary of the safety profile

Serious adverse reactions include anaphylactic reactions and angioedema, which may occur at a rare frequency (≥ 1/10 000 to < 1/1000), and acute renal failure. The overall incidence of adverse reactions reported with telmisartan was generally comparable to that observed in the placebo group (41,4% vs 43,9%) in controlled clinical studies in patients treated for hypertension. The incidence of these adverse reactions was not dose-related and no correlation was found with sex, age or ethnic origin of patients. The safety profile of telmisartan in patients treated for reduction of cardiovascular morbidity was consistent with that seen in hypertensive patients.

The adverse reactions presented below come from controlled clinical studies in patients treated for hypertension and from post-marketing reports. The list also takes into account serious adverse reactions as well as adverse reactions leading to discontinuation of treatment, reported in three long-term clinical studies including 21 642 patients treated with telmisartan for reduction of cardiovascular morbidity over a period of up to 6 years.

Tabulated list of adverse reactions

Undesirable effects have been classified according to their frequency using the following classification:

• Very common (≥1/10) ;

• common (≥1/100 to <1/10) ;

• uncommon (≥1/1000 to <1/100) ;

• rare (≥1/10 000 to <1/1000) ;

• 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, cystitis, upper respiratory tract infection including pharyngitis and sinusitis
Rare	Sepsis including fatal outcome1
Blood and 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	Insomnia, depression
Rare	Anxiety
Nervous system disorders
Uncommon	Syncope, vertigo
Rare	Somnolence
Eye disorders
Rare	Impaired vision
Ear and labyrinth disorders
Uncommon	Vertigo
Cardiac disorders
Uncommon	Bradycardia
Rare	Tachycardia
Vascular disorders
Uncommon	Hypotension2, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon	Dyspnea, cough
Very rare	Interstitial lung disease4
Gastrointestinal disorders
Uncommon	Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting
Rare	Dry mouth, abdominal discomfort, dysgeusia
Hepatobiliary disorders
Rare	Abnormal liver function/ hepatic disorders3
Skin and subcutaneous tissue disorders
Uncommon	Pruritus, hyperhidrosis, rash
Rare	Angioedema (including fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption
Musculoskeletal and connective tissue disorders
Uncommon	Back pain (for example sciatica), muscle spasms, myalgia
Rare	Arthralgia, pain in extremities, tendon pain (tendinitis-like symptoms)
Renal and urinary disorders
Uncommon	Renal failure (including acute renal failure)
General disorders and administration site conditions
Uncommon	Chest pain, asthenia (weakness)
Rare	Flu-like syndrome
Investigations
Uncommon	Blood creatinine increased
Rare	Decreased haemoglobin, increased uric acid, elevation of liver enzymes, elevation of creatine phosphokinase (CPK)

1, 2, 3, 4: for a more detailed description, see the sub-section "Description of selected adverse reactions".

Description of selected adverse reactions

1. Sepsis

In the PRoFESS trial, a higher incidence of sepsis was observed in patients receiving telmisartan compared with patients receiving placebo. This event may be due to chance or linked to a mechanism currently unknown (see section 5. 1).

2. Hypotension

This adverse reaction was reported as frequent in patients whose blood pressure was controlled and who were treated with telmisartan for the reduction of cardiovascular morbidity in addition to standard treatments.

3. Abnormal hepatic function/hepatic disorders

Most cases of abnormal liver function/liver disorders reported after marketing authorisation occurred in Japanese patients. Japanese patients are more likely to experience these adverse reactions.

4. Interstitial lung disease

Cases of interstitial lung disease following the intake of telmisartan have been reported after marketing. However, a causal relationship has not been established.

Intestinal angioedema

Cases of intestinal angioedema have been reported following the use of angiotensin II receptor antagonists (see section Warnings and precautions).

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/  

The available information concerning overdose in humans is limited.

Symptoms

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

Management

Telmisartan is not eliminated by haemofiltration and is not dialysable. Close monitoring of the patient should be instituted, together with symptomatic and supportive treatment. Management should take into account the time elapsed since ingestion and the severity of symptoms. Administration of emetic medicinal products and/or gastric lavage may be considered. Activated charcoal may be useful in the treatment of overdose. Electrolyte balance and creatinine levels should be checked frequently. In case of hypotension, the patient should be placed in a supine position, and treatment with a saline plasma volume expander should be initiated rapidly.

Pharmacotherapeutic group: Angiotensin II receptor antagonists (ARA II), ATC code: C09CA07.

Mechanism of action

Telmisartan is a specific angiotensin II receptor (type AT1), active orally. Telmisartan has a very high affinity for the AT1 angiotensin II receptor. It displaces angiotensin II from its binding site on this receptor, which is responsible for the known effects of angiotensin II. It has no partial agonist effect on the AT1receptor. Telmisartan binds selectively to the AT1receptor. The receptor binding is long-lasting. Telmisartan has no affinity for other receptors, including the AT2 and other less well characterised AT receptors. The functional role of these receptors is not known, nor is the effect of a strong stimulation of these receptors by angiotensin II, whose levels are increased with telmisartan treatment. Plasma aldosterone levels are reduced with telmisartan treatment. Telmisartan does not inhibit human plasma renin and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme that also degrades bradykinin. There is therefore no reason to fear potentiation of bradykinin-related adverse reactions.

In humans, a dose of 80 mg of telmisartan almost completely inhibits the increase in blood pressure mediated by angiotensin II. The inhibitory effect is maintained for 24 hours, and remains measurable 48 hours after intake.

Clinical efficacy and safety

Treatment of essential hypertension

After the first intake of telmisartan, the antihypertensive effect develops gradually over the first 3 hours. Generally, the maximum reduction in blood pressure is obtained from 4 to 8 weeks after the start of treatment. It persists during long-term treatment.

Ambulatory blood pressure measurements show that the antihypertensive effect persists over 24 hours after administration, including during the last four hours before the next dose. The trough-to-peak ratio, consistently greater than 80 %, measured for doses of 40 and 80 mg in placebo-controlled clinical trials, confirms this. There appears to be a trend towards a relationship between dose and the time to return to baseline values with respect to systolic blood pressure (SBP). However, data obtained for diastolic blood pressure (DBP) do not confirm this possible relationship.

In hypertensive patients, telmisartan reduces systolic and diastolic blood pressure without modifying heart rate. Any diuretic and natriuretic effects of the medicinal product, which may contribute to its antihypertensive activity, remain to be confirmed. The antihypertensive effect of telmisartan is comparable to that observed with antihypertensive medicinal products of other classes (this efficacy was demonstrated in comparative clinical trials versus amlodipine, atenolol, enalapril, hydrochlorothiazide and lisinopril).

In case of abrupt interruption of telmisartan treatment, blood pressure gradually returns within a few days to its pre-treatment value, without rebound effect. In clinical trials comparing telmisartan with angiotensin-converting enzyme inhibitors, the incidence of dry cough was significantly lower in the groups of patients treated with telmisartan than in the groups of patients treated with angiotensin-converting enzyme inhibitors.

Cardiovascular prevention

The ONTARGET study (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular events in 25 620 patients aged 55 years or older with a history of coronary artery disease, stroke, transient ischemic attack, peripheral arterial disease or type 2 diabetes associated with documented target organ damage (for example retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a population at risk of cardiovascular events.

Patients were randomized to one of the following three treatment groups: telmisartan 80 mg (n = 8542), ramipril 10 mg (n = 8576), or the combination of telmisartan 80 mg and ramipril 10 mg (n = 8502), and were followed for a mean observation period of 4,5 years.

Telmisartan showed a similar effect to ramipril in reducing the composite primary endpoint comprising death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalization for congestive 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 versus ramipril was 1,01 (CI97,5 % [0,93 ; 1,10], p (non-inferiority) = 0,0019 with a non-inferiority margin of 1,13). The all-cause mortality rate was 11,6% and 11,8% in patients treated with telmisartan and ramipril, respectively.

Telmisartan was shown to have similar efficacy to ramipril on the pre-defined secondary endpoint comprising death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke [0,99 (CI97,5% [0,90 ; 1,08], p (non-inferiority) = 0,0004)], corresponding to the primary endpoint in the reference HOPE study (The Heart Outcomes Prevention Evaluation Study), which had studied the effect of ramipril versus placebo.

The TRANSCEND study randomized patients intolerant to ACE inhibitors, who otherwise had inclusion criteria similar to those of the ONTARGET study, to the telmisartan 80 mg (n = 2954) or placebo (n = 2972) groups; both treatments were given in addition to standard treatments. The mean duration of follow-up was 4 years and 8 months. No statistically significant difference in the incidence of the composite primary endpoint (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalization for congestive heart failure) was found [15,7 % in the telmisartan group and 17,0% in the placebo group with a hazard ratio of 0,92 (CI95 % [0,81 ; 1 ,05], p = 0,22)). A benefit of telmisartan versus placebo was shown on the pre-defined composite secondary endpoint comprising death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke [0,87 (CI95% [0,76 ; 1,00], p = 0,048)]. No benefit on cardiovascular mortality was demonstrated (hazard ratio 1,03, CI95% [0,85; 1 ,24]).

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

The combination of telmisartan and ramipril provided no additional benefit compared with ramipril or telmisartan alone. Cardiovascular mortality and overall mortality were numerically higher with the combination. In addition, the incidence of hyperkalaemia, renal impairment, hypotension and syncope was significantly higher in the group receiving the combination. Therefore, the use of the combination of telmisartan and ramipril is not recommended in this population.

In the "Prevention Regimen For Effectively avoiding Second Strokes" (PRoFESS) trial, conducted in patients aged 50 years and older who had recently experienced a stroke, a higher incidence of sepsis was observed in patients receiving telmisartan compared with patients receiving placebo, 0,70% versus 0,49% (RR 1,43 ; CI 95% [1,00 ; 2,06]); the incidence of fatal sepsis was higher in patients receiving telmisartan (0,33%) compared with that observed in patients receiving placebo (0,16%) (RR 2,07 ; CI95% [1,14; 3,76]). The higher incidence of sepsis associated with telmisartan may be due to chance or linked to a mechanism currently unknown.

The use of the combination of an angiotensin-converting enzyme (ACE) inhibitor with an angiotensin II receptor antagonist (ARB II) has been analysed in two large randomised controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes). 

The ONTARGET study was conducted in patients with a history of cardiovascular disease or cerebrovascular disease, or with type 2 diabetes with target organ damage. For more detailed information, see the section above "Cardiovascular prevention".

The VA NEPHRON-D study was conducted in patients with type 2 diabetes and diabetic nephropathy.

Compared with monotherapy, these studies did not demonstrate a significant beneficial effect on the course of renal and/or cardiovascular disease or on mortality, whereas an increased risk of hyperkalaemia, acute renal failure and/or hypotension was observed. These findings are also applicable to other ACE inhibitors and ARBs, given the similarity of their pharmacodynamic properties. ACE inhibitors and ARBs should therefore not be combined in patients with diabetic nephropathy.

The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was conducted with the aim of evaluating the benefit of adding aliskiren to standard treatment with an ACE inhibitor or an ARB II in patients with type 2 diabetes and chronic renal failure, with or without cardiovascular disorders. This study was stopped early due to an increased risk of adverse events. Deaths of cardiovascular origin and strokes were more frequent in the aliskiren group than in the placebo group; likewise, adverse events and certain serious adverse events of interest such as hyperkalaemia, hypotension and renal failure were reported more frequently in the aliskiren group than in the placebo group.

Paediatric population

The safety and efficacy of TELMISARTAN BIOGARAN in children and adolescents under the age of 18 years have not been established.

The antihypertensive effects of two doses of telmisartan were evaluated in 76 hypertensive patients, most of whom were overweight (weight ≥ 20 kg and ≤ 120 kg, mean weight 74,6 kg) and aged 6 to less than 18 years, after receiving 1 mg/kg (n = 29 treated patients) or 2 mg/kg (n = 31 treated patients) of telmisartan over a four-week treatment period. The presence of secondary hypertension was not investigated at inclusion. In some of these patients the doses administered were higher than those recommended for the treatment of hypertension in adults, reaching a daily dose equivalent to 160 mg (dose tested in adults). After adjustment for age group, changes from baseline in mean SBP (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/kg group and -6,0 (2,4) mmHg in the placebo group. Changes from baseline in adjusted DBP were -8,4 (1,5) mmHg, -4,5 (1,6) mmHg and -3,5 (2,1) mmHg, respectively. The change was dose-dependent. Safety data obtained in children aged 6 to less than 18 years in this study appeared generally similar to those observed in adults. The long-term safety of telmisartan treatment has not been evaluated in children and adolescents.

The increase in eosinophils reported in this patient population was not recorded in adults.

Its clinical importance and relevance are unknown.

These clinical data do not allow conclusions to be drawn regarding the efficacy and safety of telmisartan in the paediatric hypertensive population.

Absorption

Absorption of telmisartan is rapid, but the amount absorbed is variable. The mean absolute bioavailability of telmisartan is approximately 50%. When telmisartan is taken with food, the area under the plasma concentration-time curve (AUC 0-∞) varies by approximately 6% for a 40 mg dose to approximately 19% for a 160 mg dose. Three hours after administration, plasma concentrations are similar whether telmisartan was taken fasting or with a meal.

Distribution

Telmisartan is highly bound to plasma proteins (>99,5%), mainly to albumin and alpha-1 acid glycoprotein. The mean apparent steady-state volume of distribution (Vdss) is approximately 500 litres.

Biotransformation

Telmisartan is metabolised by glucuronide conjugation of the parent molecule. No pharmacological activity has been demonstrated for the conjugated derivative.

Elimination

The elimination kinetics of telmisartan are biexponential, with a terminal elimination half-life of more than 20 hours. The maximum plasma concentration (Cmax) and, to a lesser extent, the area under the plasma concentration-time curve (AUC), increase in a non-proportional manner with increasing dose. Daily administration of telmisartan at the recommended dose does not result in clinically notable accumulation. Plasma concentrations were found to be higher in women than in men, but this parameter has no influence on efficacy.

After oral (and intravenous) administration, telmisartan is almost exclusively eliminated via the faeces, essentially unchanged. Cumulative urinary elimination represents less than one percent of the dose. Total plasma clearance (Cltot) is high (approximately 1000 mL/min) compared with hepatic blood flow (approximately 1500 mL/min).

Linearity/non-linearity

The small decrease in AUC is not expected to cause a clinically significant reduction in therapeutic effect. There is no linear relationship between dose and plasma levels. The Cmax, and to a lesser extent the AUC, increase in a non-proportional manner from a dose of 40 mg.

Special populations

Paediatric population

The pharmacokinetics of two doses of telmisartan was evaluated as a secondary objective in hypertensive patients (n = 57) aged 6 to less than 18 years after taking 1 mg/kg or 2 mg/kg of telmisartan over a period of four weeks of treatment. The pharmacokinetic objectives included determining the steady state of telmisartan in children and adolescents, and studying age-related differences. Although the study is too small for a meaningful evaluation of pharmacokinetics in children under 12 years, the results are generally consistent with those obtained in adults and confirm the non-linearity of telmisartan, particularly for Cmax.

Gender

Differences in plasma concentrations were observed, with the values of the Cmax and the AUC being increased by approximately a factor of 3 and a factor of 2 respectively in women compared with men.

Elderly

The pharmacokinetics of telmisartan do not differ between elderly patients and patients under 65 years of age.

Renal impairment

In patients with mild to moderate renal impairment and in patients with severe renal impairment, a doubling of plasma concentrations was observed. However, in renally impaired patients undergoing dialysis, a decrease in plasma concentrations was observed. Telmisartan is highly protein-bound in renally impaired patients and cannot be removed by dialysis. The elimination half-life is not modified in patients with renal impairment.

Hepatic impairment

Pharmacokinetic studies conducted in patients with hepatic impairment showed an increase in absolute bioavailability of up to approximately 100%. The elimination half-life is not modified in patients with hepatic impairment.

In preclinical safety studies, doses producing exposure comparable to that observed within the range of therapeutic doses used clinically induced a decrease in erythrocyte parameters (erythrocyte count, haemoglobin and haematocrit), changes in renal haemodynamics (increased blood urea and serum creatinine), and an increase in serum potassium in normotensive animals. In dogs, dilation and atrophy of renal tubules were observed. In rats and dogs, lesions of the gastric mucosa (erosions, ulcers or inflammation) were also observed. These undesirable effects, related to the pharmacological activity and already observed in preclinical studies of angiotensin-converting enzyme inhibitors and other angiotensin II receptor antagonists, were prevented by oral sodium supplementation.

In both species, an increase in plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, which also correspond to a class effect of angiotensin-converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have a clinically significant impact.

No teratogenic effect has been clearly identified; however, at toxic doses of telmisartan, an effect on postnatal development of the offspring of the animals, such as a decrease in pup weight and delayed eye opening, was observed.

No significant mutagenic or clastogenic effect has been demonstrated in studies in vitro and no carcinogenic effect was observed in studies conducted in rats and mice.

No effect of telmisartan has been observed on male and female fertility.

3 years.

For the blister packs:

Store in the original outer packaging, protected from light.

For the bottles:

Store in the tightly closed bottle, protected from light.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400941977039 (Plq/30). CIP 3400941977329 (Plq/90).

Price:

3,75 euros (Plq/30). 10,85 euros (Plq/90).

Social security reimbursement at 65% (Blister/30, Blister/90).
Collection.