Micardis

Interactions with herbal products have not been established.

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 antihypertensive therapy.

When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of telmisartan varies from approximately 6% (40 mg) to approximately 19% (160 mg), and the reduction in C_max varies from approximately 26% (40 mg) to 56% (160 mg). However, three hours after administration, plasma concentrations are similar whether telmisartan is taken with or without food.

Interactions with laboratory tests have not been established.

The antihypertensive effect is present within 2 weeks and maximal reduction is generally attained after four weeks. If additional blood pressure reduction is required, a thiazide diuretic may be added.

MICARDIS should be taken consistently with or without food.

The recommended dose of MICARDIS (telmisartan) is 80 mg once daily.

No initial dosing adjustment is necessary for elderly patients or for patients with renal impairment, but greater sensitivity in some older individuals cannot be ruled out. Markedly reduced telmisartan plasma levels were observed in patients on hemodialysis.

For patients with hepatic impairment a starting dose of 40 mg is recommended (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

MICARDIS should be taken at the same time each day, preferably in the morning. However, if a dose is missed during the day, the next dose should be continued at the usual time. Do not double dose.

Rare: visual disturbance.

cerebrovascular disorder, purpura.

Rare: hepatic function abnormal/liver disorder.

Rare: hypersensitivity. Unknown: anaphylactic reaction.

abdomen enlarged, allergy, cyst nos, fall, fever, leg pain, rigors, syncope.

myocardial infarction.

arrhythmia, tachycardia.

hypertonia, migraine-aggravated, muscle contraction-involuntary.

Uncommon: upper respiratory tract infections, urinary tract infections. Not known: sepsis including fatal outcome.

Common: edema, palpitation. Uncommon: bradycardia, orthostatic hypotension, hypotension. Rare: tachycardia.

dysuria, hematuria, micturition disorder, urinary tract infection.

Infrequently, a decrease in hemoglobin has been observed which occurs more often during treatment with telmisartan than with placebo.

The adverse drug events listed below have been accumulated from 27 clinical trials including 5788 hypertensive patients treated with telmisartan. Adverse events have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000).

Very common: headache. Common: dizziness, insomnia. Uncommon: vertigo.

anemia.

vision abnormal.

vaginitis.

Uncommon: anemia. Rare: thrombocytopenia. Unknown: eosinophilia.

Common: skin disorders like rash. Uncommon: pruritus. Rare: erythema, drug eruption, angioedema, eczema, toxic skin eruption. Unknown: urticaria.

hypotension, hypotension-postural, leg edema.

Unknown: blood creatinine increased. Rare: blood uric acid increased, hepatic enzymes increased, blood creatinine phosphokinase increased, haemoglobin decreased.

nervousness.

Clinically significant changes in hemoglobin and hematocrit (<10g/dL and <30%, respectively) were rarely observed with MICARDIS treatment and did not differ from rates in placebo-treated patients. No patients discontinued therapy due to anemia.

In placebo-controlled trials, marked increases in serum cholesterol were reported in a total of 6 telmisartan-treated patients (0.4%) and no placebo patients. Two of these patients were followed over time, in both cases cholesterol values reverted to baseline levels.

Serum elevations in cholesterol were reported as adverse events in 11 of 3445 patients (0.3%) in all clinical trials. There were no reported cases of hypercholesterolemia in telmisartan-treated patients in placebo-controlled trials.

Since the introduction of telmisartan in the market, cases of anxiety, dizziness, vision troubled, vertigo, abdominal distension, abdominal pain, retching, hyperhidrosis, arthralgia, myalgia, muscle spasm, back pain, asthenia, pain in extremity, fatigue, chest pain, blood creatinine increased, erythema, pruritus, syncope/faint, insomnia, depression, stomach discomfort, vomiting, hypotension (including orthostatic hypotension), bradycardia, tachycardia, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, hyperkalemia, dyspnoea, anaemia, eosinophilia, thrombocytopenia, and weakness have been reported. The frequency of these effects is unknown. As with other angiotensin II antagonists, rare cases of angioedema, pruritus, rash and urticaria have been reported.

Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

In addition, since the introduction of telmisartan in the market, cases with increased blood creatinine phosphokinase (CPK) have been reported.

In placebo-controlled clinical trials involving 1041 patients treated with MICARDIS monotherapy, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS.

bronchospasm, epistaxis, pneumonia, bronchitis.

Uncommon: hyperkalemia.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Side effects were reported in clinical trials with telmisartan in the indication hypertension or in patients 50 years or older at high risk of cardiovascular events.

MICARDIS (telmisartan) has been evaluated for safety in 27 clinical trials involving 7968 patients. Of these 7968 patients, 5788 patients were treated with MICARDIS monotherapy including 1058 patients treated for ≥1 year and 1395 patients treated in placebo-controlled trials.

In 3400 patients, discontinuation of therapy due to adverse events was required in 2.8% of MICARDIS patients and 6.1% of placebo patients. The following potentially serious adverse events have been reported rarely with telmisartan in controlled clinical trials: syncope and hypotension. In placebo-controlled trials, no serious adverse event was reported with a frequency of greater than 0.1% in MICARDIS-treated patients.

arthritis, arthritis aggravated, arthrosis, bursitis, fascitis plantar, tendinitis.

The incidence of adverse events was not dose-related and did not correlate with the gender, age, or race of patients.

Common: anxiety, nervousness. Uncommon: depression.

diabetes mellitus, hypokalaemia.

Common: arthralgia, muscle spasms (cramps in legs) or pain in extremity (leg pain), myalgia, arthritis, arthrosis. Uncommon: tendon pain (tendonitis like symptoms), back pain.

abscess, infection, bacterial, moniliasis genital, otitis media.

Increases in BUN (≥11.2 mg/dL) and creatinine (≥0.5 mg/dL) were observed in 1.5% and 0.6% of MICARDIS-treated patients; the corresponding incidence was 0.3% each for placebo-treated patients. These increases occurred primarily with MICARDIS in combination with hydrochlorothiazide. One telmisartan treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen.

An increase in serum uric acid (≥2.7 mg/dL) was reported in 1.7% of patients treated with MICARDIS and in 0.0% of patients treated with placebo. Clinically significant hyperuricemia (>10 mEq/L) was observed in 2.3% of patients with MICARDIS, with 0.4% reported in patients at baseline. Increases in serum uric acid were primarily observed in patients who received MICARDIS in combination with hydrochlorothiazide. No patient was discontinued from treatment due to hyperuricemia.

anorexia, appetite increased, flatulence, gastrointestinal disorder nos, gastroenteritis, gastroesophageal reflux, melena, mouth dry, abdominal pain.

Uncommon: syncope (faint).

sweating increased.

rash, skin dry.

Common: abdominal pain, diarrhoea, dyspepsia, nausea, constipation, gastritis. Uncommon: dry mouth, flatulence, vomiting. Rare: stomach discomfort.

Common: upper respiratory tract infections including pharyngitis and sinusitis, bronchitis, coughing, dyspnea, rhinitis.

In addition, the following adverse events, with no established causality, were reported at an incidence <1% in placebo-controlled clinical trials.

Common: chest pain, influenza-like symptoms, symptoms of infection (e.g. urinary tract infection including cystitis), fatigue, conjunctivitis. Uncommon: hyperhidrosis, asthenia (weakness).

Marked laboratory changes in serum potassium (≥+/−1.4 mEq/L) occurred rarely and with a lower frequency in MICARDIS-treated patients (0.3%, 0.1%, respectively) than in placebo patients (0.6%, 0.3%, respectively). Clinically significant changes in potassium (that exceeded 3 mEq/L) were found in 0.6% of MICARDIS-treated patients, with 0.5% of these reported at baseline. The corresponding rates for placebo-treated patients were 0.6% and 0.8%.

Clinically significant elevations in AST and ALT (>3 times the upper limit of normal) occurred in 0.1% and 0.5% respectively of patients treated with MICARDIS compared to 0.8% and 1.7% of patients receiving placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function.

Uncommon: renal impairment including acute renal failure.

MICARDIS is not recommended for use in children below 18 years due to limited data on safety and efficacy.

No dosing adjustment is necessary. It should be recognized, however, that greater sensitivity in some older individuals can not be ruled out.

Each white, oblong-shaped, uncoated tablet, marked with the Boehringer Ingelheim logo on one side, and on the other side, with 52H, contains: telmisartan 80 mg. Nonmedicinal ingredients: magnesium stearate, meglumine, povidone, sodium hydroxide and sorbitol. Individually blister sealed in cartons of 28 as 4 cards containing 7 tablets each.

Each white, oblong-shaped, uncoated tablet, marked with the Boehringer Ingelheim logo on one side, and on the other side, with 51H, contains: telmisartan 40 mg. Nonmedicinal ingredients: magnesium stearate, meglumine, povidone, sodium hydroxide and sorbitol. Individually blister sealed in cartons of 28 as 4 cards containing 7 tablets each.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals (such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure). Dual blockade of the renin-angiotensin-aldosterone system (e.g. concomitant use of an angiotensin II receptor antagonist with an ACE-inhibitor) has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. Upon treatment with such combination, renal function should be closely monitored.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely acute renal failure and/or death. There is no experience with long term use of MICARDIS (telmisartan) in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated. In susceptible patients, concomitant diuretic use may further increase the risk. Use of telmisartan should include appropriate assessment of renal function in these types of patients.

There is no experience regarding the administration of MICARDIS (telmisartan) in patients with a recent kidney transplant.

Of the total number of patients receiving MICARDIS (telmisartan) in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall age related differences were seen in the adverse effect profile, but greater sensitivity in some older patients cannot be ruled out.

For specific monitoring and laboratory tests, see Warnings and Precautions (Cardiovascular, Endocrine and Metabolism, Hepatic/Biliary/Pancreatic and Renal) and Drug Interactions.

In patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting, symptomatic hypotension may occur after initiation of therapy with MICARDIS. Such conditions, especially volume and/or sodium depletion, should be corrected prior to administration of MICARDIS. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

The use of a dual renin-angiotensin-aldosterone system (RAAS) blockade may lead to increased occurrence of hypotension when given as add-on therapy in patients with controlled blood pressure.

As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency have reduced clearance of telmisartan. Three to four fold increases in C_max and AUC were observed in patients with liver impairment as compared to healthy subjects. MICARDIS (telmisartan) should be used with caution in these patients (see Dosage and Administration).

MICARDIS is not recommended for use in children below 18 years due to limited data on safety and efficacy.

Drugs such as MICARDIS that affect the renin-angiotensin-aldosterone system can cause hyperkalemia. Monitoring of serum potassium in patients at risk is recommended. Based on experience with the use of drugs that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to a greater risk of an increase in serum potassium.

The use of a dual renin-angiotensin-aldosterone system (RAAS) blockade may lead to increased occurrence of hyperkalemia when given as add-on therapy in patients with controlled blood pressure.

Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, MICARDIS (telmisartan) should be discontinued as soon as possible.

The use of angiotensin receptor (AT₁) blockers (ARBs) is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARB, similar risks may exist for this class of drugs. 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 antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

The use of ARBs 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).

Infants with a history of in utero exposure to ARBs should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as a means of reversing hypotension and/or substituting for disordered renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

It is not known if telmisartan can be removed from the body by hemodialysis.

Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day with saline supplementation. In rabbits, fetotoxicity (total resorptions) associated with maternal toxicity (reduced body weight gain, mortality) was observed at the highest dose level (45 mg/kg/day). In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 50 mg/kg/day in late gestation and during lactation were observed to produce adverse effects in rat fetuses and neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Significant levels of telmisartan were present in rat milk and rat fetuses’ blood during late gestation.

It is not known whether telmisartan is excreted in human milk but significant levels have been found in the milk of lactating rats. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

There is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction.

In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100%. A lower starting dose should be considered (see Warnings and Precautions and Dosage and Administration).

The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years (see Dosage and Administration).

Telmisartan is >99.5% bound to plasma protein, mainly albumin and a1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with therapeutic doses. The volume of distribution for telmisartan is approximately 500 liters, indicating additional tissue binding sites.

When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of telmisartan varies from approximately 6% (40 mg) to approximately 19% (160 mg), and the reduction in C_max varies from approximately 26% (40 mg) to 56% (160 mg). However, three hours after administration, plasma concentrations are similar whether telmisartan is taken with or without food.

Following oral administration, telmisartan is well absorbed, with a mean absolute bioavailability of about 50%. Mean peak concentrations of telmisartan are reached in 0.5-1 hour after dosing.

The pharmacokinetic profile is characterized by greater than proportional increases of plasma concentrations (C_max and AUC) with increasing doses greater than 40 mg. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours, and does not accumulate in plasma upon repeated once-daily dosing.

Telmisartan is an orally active angiotensin II AT₁ receptor antagonist. By selectively blocking the binding of angiotensin II to the AT₁ receptors telmisartan blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁ receptors, and has essentially no affinity for the AT₂ receptors. AT₂ receptors have been found in many tissues, but to date they have not been associated with cardiovascular homeostasis. In vitro binding studies indicate that telmisartan has no relevant affinity for other receptors nor does it inhibit human plasma renin.

Telmisartan does not inhibit angiotensin converting enzyme, also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis.

In hypertensive patients blockade of angiotensin II AT₁ receptors results in two to three fold increase in plasma renin and angiotensin II plasma concentrations. Long term effects of increased AT₂ receptor stimulation by angiotensin II are unknown.

Total plasma clearance of telmisartan is >800 mL/min. Half-life and total clearance appear to be independent of dose. Biliary excretion is the main route of elimination of telmisartan and its metabolite. Following intravenous and oral administration of C¹⁴ labelled telmisartan 0.91% and 0.49% of administered dose were found in the urine as glucuronide, respectively. Most of the oral and intravenous dose, >97%, was excreted in feces as the parent compound.

Women have a lower telmisartan clearance and have a greater systolic blood pressure response at trough than men.

Renal excretion of telmisartan is negligible. No dosage adjustment is necessary in patients with renal insufficiency. In patients on hemodialysis both C_max and AUC of telmisartan were markedly reduced as compared to healthy volunteers. Telmisartan is not removed by hemodialysis (see Warnings and Precautions and Dosage and Administration).

Plasma concentrations of telmisartan are generally 2-3 fold higher in females than in males. No dosage adjustment is necessary.

Telmisartan is metabolized by conjugation with glucuronic acid to form an acylglucuronide of telmisartan. This glucuronide is the only metabolite which has been identified in human plasma and urine. Following both oral dosing and intravenous administration of radiolabeled telmisartan, the parent compound represented approximately 85% and the glucuronide approximately 11% of total radioactivity in plasma. No pharmacological activity has been shown for the glucuronide conjugate.

The CYP 450 isoenzymes are not responsible for telmisartan metabolism.

No studies were conducted to evaluate the influence of genetic polymorphisms on the pharmacokinetics or pharmacodynamics of telmisartan.

In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak with approximately 40% inhibition persisting for 24 hours.

In hypertensive patients with normal renal function, no clinically significant effects on renal plasma flow, filtration fraction, or glomerular filtration rate were observed. In multiple dose studies in hypertensive patients, telmisartan had no adverse effect on renal function as measured by serum creatinine or blood urea nitrogen.

The antihypertensive effects of telmisartan were demonstrated in six placebo-controlled clinical trials, in a total of 1773 patients, 1031 of whom were treated with MICARDIS (telmisartan). Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose and there was a gradual increase in the antihypertensive effect during continued treatment for up to 12 weeks, with most of the increase occurring during the first month. Onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. The antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. The magnitude of blood pressure reduction from baseline, after placebo subtraction, was on average (SBP/DBP) −11.3/−7.3 mmHg for MICARDIS 40 mg once daily, and −13.7/−8.1 mmHg for MICARDIS 80 mg once daily. Upon abrupt cessation of treatment with MICARDIS, blood pressure gradually returned to baseline values over a period of several days. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year.

For those patients treated with telmisartan 80 mg once daily who required additional blood pressure reduction, addition of a low dose of hydrochlorothiazide (12.5 mg) resulted in incremental blood pressure reductions of −9.4/−7.0 mmHg.

The antihypertensive effect of once-daily telmisartan (40-80 mg) was similar to that of once-daily amlodipine (5-10 mg), atenolol (50-100 mg), enalapril (5-20 mg) and lisinopril (10-40 mg).

There was essentially no change in heart rate in telmisartan-treated patients in controlled trials.

In clinical trials with post-dose in-clinic monitoring no excessive blood pressure lowering peak effect was observed even after the first dose, and the incidence of symptomatic orthostasis was very low (0.04%). With automated ambulatory blood pressure monitoring, the 24-hour trough-to-peak ratio for telmisartan was determined to be at least 80% for both systolic and diastolic blood pressure.

The antihypertensive effect of telmisartan is not influenced by patient age, weight or body mass index. Blood pressure in hypertensive black patients (usually a low renin population) is significantly reduced by telmisartan (compared to placebo), but less so than in non-black patients.

Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.

In case of rare hereditary condition of fructose intolerance, the use of MICARDIS is contraindicated. MICARDIS contains 338 mg of sorbitol per maximum recommended daily dose.