Tolura

Telmisartan.

Each tablet contains 40 mg telmisartan.
Each tablet contains 80 mg telmisartan.
Excipients/Inactive Ingredients: Povidone, meglumine, sodium hydroxide, lactose monohydrate, sorbitol and magnesium stearate.

Pharmacotherapeutic Group: Angiotensin II Antagonists, plain. ATC Code: C09CA07.
Pharmacology: Pharmacodynamics: Mechanism of action: Telmisartan is an orally active and specific angiotensin II receptor (type AT₁) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity 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 less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme 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 blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatment and is sustained during long-term therapy.
Paediatric population: The safety and efficacy of telmisartan in children and adolescents aged below 18 years have not been established.
Pharmacokinetics: Absorption: Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50 %. When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC_0-∞) of telmisartan varies from approximately 6 % (40 mg dose) to approximately 19 % (160 mg dose). By 3 hours after administration, plasma concentrations are similar whether telmisartan is taken fasting or with food.
Linearity/non-linearity: The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. There is no linear relationship between doses and plasma levels. C_max and to a lesser extent AUC increase disproportionately at doses above 40 mg.
Distribution: Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (V_dss) is approximately 500 l.
Biotransformation: Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Elimination: Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (C_max) and, to a smaller extent, the area under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma concentrations 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 plasma clearance (Cl_tot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about 1,500 ml/min).
Special Populations: Gender: Differences in plasma concentrations were observed, with C_max and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years.
Renal impairment: In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations was observed. However, lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient patients and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepatic impairment.

Hypertension: Treatment of essential hypertension.
Cardiovascular risk reduction: Telmisartan is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors.
High risk of cardiovascular events can be evidenced by history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. Telmisartan can be used in additional to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy).
Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves.
Use of telmisartan with an ACE inhibitor is not recommended.

Adults: Treatment of essential hypertension: The recommended dose is 40 mg once daily. In cases where the target blood pressure is not achieved, telmisartan dose 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-eight weeks after the start of treatment.
In patients with severe hypertension treatment with telmisartan at doses up to 160 mg alone and in combination with hydrochlorothiazide 12.5-25 mg daily was well tolerated and effective.
Cardiovascular prevention: The recommended dose of telmisartan 80mg once a day and can be administered with or without food. It is not known whether doses lower than 80mg of telmisartan are effective in reducing the risk of cardiovascular morbidity and mortality.
When initiating telmisartan therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate adjustment of medications that lower blood pressure may be necessary.
Telmisartan may be taken with or without food.
Renal impairment: No posology adjustment is required for patients with renal impairment, including those on haemodialysis.
Telmisartan is not removed from blood by hemofiltration.
Hepatic impairment: In patients with mild to moderate hepatic impairment the posology should not exceed 40 mg once daily.
Elderly: No dosing adjustment is necessary.
Children and adolescents: The safety and efficacy of telmisartan for use in children below 18 years have not been established.

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 haemodialysis. 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 overdosage. 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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Second and third trimester of pregnancy (see Precautions and Use in Pregnancy & Lactation).
Biliary obstructive disorders.
Severe hepatic impairment.
The concomitant use of Tolura with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see Pharmacology: Pharmacodynamics under Actions and Interactions).

Hepatic impairment: Tolura is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic impairment (see Contraindications) since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan. Tolura 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 Tolura 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 Tolura in patients with recent kidney transplantation.
Intravascular hypovolaemia: Symptomatic hypotension, especially after the first dose of Tolura, 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 Tolura. Volume and/or sodium depletion should be corrected prior to administration of Tolura.
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 Pharmacology: Pharmacodynamics under Actions and Interactions).
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 Adverse Reactions).
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 approptiate 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, immunosuppressives (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 ischemia, rhabdomyolysis, extend trauma).
Close monitoring of serum potassium in at risk patients is recommended (see Interactions).
Sorbitol: Tolura tablets contain sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take Tolura.
Lactose: Tolura tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Tolura.
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.
Other: 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.
Other ingredients: Sorbitol: Tolura tablets contain sorbitol. Patients with rare hereditary problems of fructose intolerance should not take Tolura.
Lactose: Tolura tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Tolura.
Effects on ability to drive and use machines: When driving vehicles or operating machinery it should be taken into account that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy such as Tolura.
Use in 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 Contraindications and Use in Pregnancy & Lactation).

Use in 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 Contraindications and text as follows).
Pregnancy: The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see Precautions). The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy (see Contraindications and Precautions).
There are no adequate data from the use of Tolura in pregnant women.
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).
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 Contraindications and Precautions).
Breast-feeding: Because no information is available regarding the use of Tolura during breast-feeding, Tolura is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Summary of the safety profile: Serious adverse drug reactions include anaphylactic reaction and angioedema which may occur rarely and acute renal failure.
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.
Tabulated summary of adverse reactions: 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 infection including pharyngitis and sinusitis. 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).
Psychiatric disorders: Uncommon: Insomnia, depression. Rare: Anxiety.
Nervous system disorders: Uncommon: Syncope. Rare: Somnolence.
Eye disorders: Rare: Visual disturbance.
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: Dry mouth, stomach discomfort, dysgeusia.
Hepato-biliary disorders: Rare: Hepatic function abnormal/liver disorder³.
Skin and subcutaneous tissue disorders: Uncommon: Pruritus, hyperhidrosis, rash. Rare: Angioedema (also with fatal outcome), eczema, erythema, urticaria, drug eruption, 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).
Renal and urinary disorders: Uncommon: Renal impairment including acute renal failure.
General disorders and administration site conditions: Uncommon: Chest pain, asthenia (weakness). Rare: Influenza-like illness.
Investigations: Uncommon: Blood creatinine increased. Rare: Haemoglobin decreased, blood uric acid increased, hepatic enzyme increased, blood creatine phosphokinase increased.
1, 2, 3, 4: for further descriptions, see Description of selected adverse reactions as follows.
Description of selected adverse reactions: Sepsis: An increased incidence of sepsis was observed with telmisartan. The event may be a chance finding or related to a mechanism currently not known.
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.

Digoxin: 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 Precautions). 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, immunosuppressives (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.
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.
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 Pharmacology: Pharmacodynamics under Actions, Contraindications and Precautions).
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.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30 °C.
Store in the original package in order to protect from light.

Angiotensin II Antagonists

C09CA07 - telmisartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.

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