Telmisartan

Telmisartan

40mg Tablet

80mg Tablet

Drug Category: Anti-hypertensive drug

Indications:

Treatment of essential hypertension. Prevention of cardiovascular morbidity and mortality in patients 55 years or older at high risk of cardiovascular disease (see Pharmacological properties).

Dosage and Administration:

Adults

Treatment of essential hypertension

The recommended dose is 40mg once daily. Some patients may already benefit at a daily dose of 20mg. In cases where the target blood pressure is not achieved, telmisartan dose can be increased to maximum of 80mg 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 anti-hypertensive effect is generally attained four – eight weeks after the start of treatment. In patients with sever hypertension treatment with telmisartan at doses up to 160mg alone and in combination with hydrochlorothiazide 12.5 – 25mg daily was well tolerated and effective.

Prevention of cardiovascular morbidity and mortality

The recommended dose is 80mg once daily. It is not known whether doses lover than 80mg of telmisartan are effective in preventing cardiovascular morbidity and mortality.

When initiating telmisartan therapy for the prevention of cardiovascular morbidity and mortality, monitoring adjustment of medications that lover 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 hemodialysis. Telmisartan is not removed from blood by hemofiltration.

Hepatic impairment

In patients with mild to moderate hepatic impairment the posology should not exceed 40mg 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.

Contraindications:

• Hypersensitivity to the active ingredient or any of the excipients
• Second and third trimesters of pregnancy
• Lactation
• Biliary obstruction disorders
• Severe hepatic impairment

In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to “special warnings and precautions”) the use of the product is contraindicated.

Special warnings and precautions:

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 anti-hypertensive 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.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patient 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 transplant

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

Intravascular volume depletion

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, diarrhea or vomiting. Such conditions, especially volume and/or sodium depletion, should be corrected before the administration of telmisartan.

Dual blockade of the renin-angiotensin-aldosterone system

As a consequence of inhibiting renin-angiotensin-aldosterone system changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should therefore be limited to individually defined cases with close monitoring of renal function.

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 anti-hypertensive medicinal products acting through inhibition of 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 form aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Hyperkalemia

During treatment with medicinal products that affect the renin-angiotensin-aldosterone system hyperkalemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended.

Based on experience with the use of medicinal products that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salts substitute containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with telmisartan.

Hepatic impairment

Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduce clearance. Telmisartan should be used with caution in these patients.

Sorbitol

This product contains 338mg of sorbitol per maximum recommended daily dose. Patients with the rare hereditary condition of fructose intolerance should not take this medicine.

Other

As observed for angiotensin converting enzyme inhibitors, angiotensin receptor blockers including telmisartan 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.

As with any anti-hypertensive agent, excessive reduction of blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.

Interactions:

Telmisartan may increase the hypotensive effect of other anti-hypertensive agents. Other interactions of clinical significance have not been identified.

Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.

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.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors.

Cases have also been reported with angiotensin II receptor antagonists including telmisartan.Therefore, serum lithium level monitoring is advisable during concomitant use.

Treatments with NSAIDs (i.e. ASA at anti-inflammatory dosage regimens, COX-2 inhibitors and not-selective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and telmisartan should be adequately hydrated and be monitored for renal function at the beginning of combined treatment.

A reduced effect of anti-hypertensive drugs like telmisartan by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.

Fertility, pregnancy and lactation:

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.

Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.

Angiotensin II receptor antagonists exposure 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, hyperkalemia).

Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.

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.

Telmisartan is contraindicated during lactation since it is not known whether it is excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk.

Fertility

No studies on fertility in humans have been performed. In preclinical studies, an effect of telmisartan on male and female fertility was not observed.

Effects on ability to drive and use machines:

No studies on the effect on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it should be taken into account that dizziness or drowsiness may occasionally occur when taking anti-hypertensive therapy.

Side effects:

The overall incidence of adverse events reported with telmisartan (41.4%) was usually comparable to placebo (43.9%) in controlled clinical trials in patients treated for hypertension. The incidence of adverse events 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 prevention of cardiovascular morbidity and mortality was consistent with that obtained in hypertensive patients.

The adverse drug 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 events and adverse events leading to discontinuation reported in three clinical long-term studies including 21642 patients treated with telmisartan for prevention of cardiovascular morbidity and mortality for up to six years.

Infections and infestation:

Urinary tract infections (including cystitis), upper respiratory tract infections, sepsis included fatal outcome

Blood and lymphatic system disorders:

Anemia, eosinophilia, thrombocytopenia

Immune system disorders:

Anphylactice reaction, hypersensitivity

Metabolism and nutrition disorders:

Hyperkalemia, hypoglycemia (in diabetic patients)

Psychiatric disorders:

Anxiety, insomnia, depression

Nervous system disorders:

Syncope (faint)

Eye disorders:

Visual disturbance

Ear and labyrinth disorders:

Vertigo

Cardiac disorders:

Bradycardia, tachycardia

Vascular disorders:

Hypotension, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders:

Dyspnea

Gastrointestinal disorders:

Abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence, stomach discomfort, vomiting

Hepatobiliary disorders:

Hepatic function abnormal / liver disorder*

*Most cases of hepatic function abnormal / liver disorder from post-marketing experience with telmisartan occurred in patients in Japan, who are more likely to experience these adverse reactions.

Skin and subcutaneous tissue disorders:

Pruritus, hyperhidrosis, rash, angioedema (with fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption

Musculoskeletal, connective tissue and bone disorders:

Arthralgia, back pain, muscle spasms (cramps in legs) pain in extremity (leg pain), myalgia, tendon pain (tendinitis like symptoms)

Renal and urinary tract disorders:

Renal impairment including acute renal failure

(see also under Special precautions and warnings)

General disorders and administration site conditions:

Chest pain, influenza-like illness, asthenia (weakness)

Investigations:

Hemoglobin decreased, blood uric acid increased, blood creatinine increased, hepatic enzymes increased, blood creatine phosphokinase (CPK) increased.

Overdose:

Limited information is available with regard to overdose in humans. The most prominent manifestations of telmisartan overdose were hypotension and tachycardia, bradycardia also occurred. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Pharmacological properties:

Telmisartan is an orally effective 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 characterized AT receptors. The functional role of these receptors is not known, nor is the effect of their possible over-stimulation 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 man, an 80mg 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.

Treatment of essential hypertension

After the first dose of telmisartan, the anti-hypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy.

The anti-hypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the nest dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies.

There is an apparent trend to a dose relationship to a time to recovery of baseline SBP. In this respective data concerning DBP are inconsistent.

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The anti-hypertensive efficacy of telmisartan has been compared to anti-hypertensive drugs such as amlodipine, atenolol, enalapril, hydrochlorothiaze, losartan, lisinopril, ramipril and valsartan.

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

Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy.

Telmisartan treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.

The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trails directly comparing the two anti-hypertensive treatments.

Prevention of cardiovascular morbidity and mortality

ONTARGET (ONgoin 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 outcomes in 25620 patients aged 55 years or older with history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high risk patients.

Patients were randomized to one of the three following treatment groups: telmisartan 80mg (n=8542), ramipril 10mg (n=8576), or the combination of telmisartan 80mg plus ramipril 10mg (n=8502), and followed for a mean observation time of 4.5 years. The population studied was 73% male, 74% Caucasian, 14% Asian and 43% were 65 years of age or older. Hypertension was present in nearly 83% of randomized patients: 69% of patients had a history of hypertension at randomization and an additional 14% had actual blood pressure readings above 140/90mmHg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76%), statins (62%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%).

The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure.

Adherence to treatment was better for telmisartan than for ramipril or the combination of telmisartan and ramipril, although the study population had been pre-screened for tolerance to treatment with an ACE-inhibitor. The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.

Telmisartan has similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the telmisartan (16.7%), ramipril (16.5%) and telmisartan plus ramipril combination (16.3%) arms.

The hazard ration for telmisartan vs. ramipril was 1.01 (97.5% CI 0.93 – 1.10, p (non-inferiority) = 0.0019). The treatment effect was found to persist following corrections for difference in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.

Telmisartan was also found to e similarly effective to ramipril in several pre-specified secondary endpoints, including a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, the primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which has investigated the effect of ramipril vs. placebo. The hazard ratio of telmisartan vs. ramipril for this endpoint in ONTARGET was 0.99 (97.5% CI 0.90 – 1.08, p (non-inferiority) = 0.0004).

Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. In addition, there was a significantly higher incidence of hyperkalemia, renal failure, hypotension and syncope in the combination arm. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.

Pediatric population

The blood pressure lowering effects of two doses of telmisartan were assessed in hypertensive patients aged 6 to <18 years (n=76) after taking telmisartan 1mg/kg (n=30 treated) or 2mg/kg (31 treated) over four-week treatment period. After adjustment for age group effects and baseline SBP values an average placebo-corrected SBP change from baseline (primary objective) of 8.5mmHg was observed in the telmisartan 2mg/kg group, and a -3.6mmHg SBP change was found in the telmisartan 1mg/kg group. The adjusted and placebo-corrected DBP changes from baseline were 4.5mmHg and -4.8mmHg in the telmisartan 1mg/kg and 2mg/kg groups, respectively. The change was dose dependent. The safety profile appeared generally comparable to that observed in adults.

Pharmacokinetics:

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) of telmisartan varies from approximately 6% (40mg dose) to approximately 19% (160mg dose). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food.

The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.

Gender differences in plasma concentration were observed, C_max and AUC being approximately 3-and 2-fold higher, respectively, in females compared to males without relevant influence of efficacy. Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 glycoprotein. The mean steady state apparent volume of distribution (V_SS) I approximately 500L.

Telmisartan is metabolized by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.

Telmisartan is characterized by biexponential decay pharmacokinetics with a terminal elimination half-life of >20hours. The maximum plasma concentration (C_max) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan.

After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the feces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose.

Total plasma clearance (Cl_tot) is high (approximately 900ml/min compared with hepatic blood flow (about 1500mg/min)

Elderly patients

The pharmacokinetics of telmisartan do not differ between younger and elderly patients.

Patients with renal impairment

Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.

Patients with hepatic impairment

Pharmacokinetics 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.

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 1mg/kg or 2mg/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-related 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 finding in adults and confirm the non-linearity of telmisartan, particularly for C_max.

Toxicology:

In preclinical safety studies doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, hemoglobin, hematocrit) and changes in renal hemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically mediated side effects, known from preclinical studies with both angiotensin converting enzyme inhibitors and angiotensin II antagonists, were prevented by oral saline supplementation.

In both species increase plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of ACE-inhibitors and other angiotensin II antagonists, do not appear to have clinical significance.

Animal studies indicated some hazardous potential of telmisartan to the postnatal development of the offspring: lower body-weight, delayed eye opening, higher mortality.

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

Storage Condition:

Store at temperature not exceeding 30^oC.