Merit

Telmisartan.

40 mg: Each tablet contains Telmisartan 40 mg.
80 mg: Each tablet contains Telmisartan 80 mg.

Pharmacotherapeutic group: Angiotensin II Receptor Blocker.
Pharmacology: Pharmacodynamics: Telmisartan is an orally active and specific angiotensin II receptor subtype 1 (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 administered to healthy volunteers 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.
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 plasma concentration-time curve (AUCO-∞) 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 on AUC is not expected to cause a reduction in the therapeutic efficacy. There is no linear relationship between dose 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 and glycoprotein. The mean steady-state apparent volume of distribution (Vdss) is approximately 500 litres.
Biotransformation: Telmisartan is metabolized by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown to the conjugate.
Elimination: Telmisartan is characterized 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 the 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 (Cltot) is high (approximately 1,000 mL/min) compared with hepatic blood flow (about 1,500 mL/min).
Special Populations: Pediatric population: The pharmacokinetics of two doses of telmisartan were assessed as a secondary objective in hypertensive patients (n=57) aged 6 to <18 years after taking telmisartan 1 mg/kg or 2 mg/kg over a four-week treatment period. Pharmacokinetic objectives included the determination of the steady-state of telmisartan in children and adolescents, and investigation of age differences. Although the study was too small for a meaningful assessment of the pharmacokinetics of children under 12 years of age. The results are generally consistent with the findings in adults and confirm the non-linearity of telmisartan, particularly for C_max.
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.
Older people: The pharmacokinetics do not differ between the older people 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 in adults.
Cardiovascular prevention: Reduction of cardiovascular morbidity in adults with: i) Manifest atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral arterial disease) or ii) Type 2 diabetes mellitus with documented target organ damage.

Posology: Treatment of essential hypertension: The usual 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.
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.
No posology adjustment is required for patients with mild to moderate renal impairment.
Patients with hepatic impairment: Telmisartan is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, the posology should not exceed 40 mg once daily.
Older people: No dose adjustment is necessary for older people.
Paediatric population: The safety and efficacy of Telmisartan in children and adolescents aged below 18 have not been established.
Method of administration: Telmisartan tablets are for once daily oral administration and should be taken with liquid, with or without food.

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.
Second and third trimester of pregnancy.
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/1.73m²).

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy.

Pregnancy: Angiotensin II receptor antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA 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 AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
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.
Intravascular hypovolaemia: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions 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.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Other conditions with stimulation of the renin-angiotensin-aldosterone system: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria or rarely acute renal failure.
Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Telmisartan/Hydrochlorothiazide 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, 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 are: Diabetes mellitus, renal impairment, age (>70 years).
Combination with one or more 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, dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of 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.
Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ethnic differences: As observed for ACE 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.
Hepatic impairment: Telmisartan is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic impairment since telmisartan is mostly eliminated in 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.
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.
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 Telmisartan.

Pregnancy: The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy.
There are no adequate data from the use of Telmisartan in pregnant women.
Studies in animals have shown reproductive toxicity.
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 increase 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 antagonists have occurred from the second trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) the 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.
Lactation: Because no information is available regarding the use of Telmisartan during breast-feeding, Telmisartan is not recommended and alternative treatments with better established safety profiles during the breast-feeding are preferable, especially while nursing a newborn infant.

Tabulated summary of adverse reactions: Adverse reactions have been ranked under heading 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 outcome.
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: Depression, insomnia; 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: Hypotension, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: Uncommon: Dyspnea, cough; Very rare: Interstitial lung disease.
Gastrointestinal disorders: Uncommon: Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting; Rare: Stomach discomfort, dry mouth.
Hepato-biliary disorders: Rare: Hepatic function abnormal/liver disorder.
Skin and subcutaneous tissue disorders: Uncommon: Hyperhidrosis, pruritus, rash; Rare: Angioedema (also with fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption.
Musculoskeletal and connective tissue disorders: Uncommon: Myalgia, back pain (e.g., sciatica), muscle spasms; Rare: Arthralgia, pain in extremity, tendon pain (tendonitis-like symptoms).
Renal and urinary disorders: Uncommon: Renal impairment including acute renal failure.
General disorders and administrative 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 creatinine 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: 1. 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.
2. Hypotension: The adverse effect 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.
3. 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.
4. Hepatic function abnormal/liver disorder: Most cases of hepatic function abnormal/liver disorder from post-marketing experience occurred in patients in Japan, who are more likely to experience these adverse reactions.

Dual blocked of the renin-angiotensin-aldosterone system (RAAS): 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.
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. 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 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 previously 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 the precautions 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., spironolactone, 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.
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 the 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 inhibits cyclo-oxygenase may result in further deterioration of renal function, including possible 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 AUC_0-24 and C_max 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 a risk of hypotension when initiating therapy with telmisartan.
Other antihypertensive agents: The blood pressure lowering effect of telmisartan can be increased by concomitant use of other antihypertensive medicinal products.
Based from their pharmacological properties it can be expected that the following medicinal products may potentiate the hypertensive effects of all the antihypertensives including telmisartan: Baclofen, amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics, or antidepressants.
Corticosteroid (systemic route): Reduction of the antihypertensive effect.

Store at temperatures not exceeding 30°C.

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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