These highlights do not include all the information needed to use MICARDIS safely and effectively. See full prescribing information for MICARDIS. MICARDIS (telmisartan) TabletsInitial U.S. Approval: 1998

When used in pregnancy, drugs that act directly on the renin-angiotensinsystem can cause injury and even death to the developing fetus.   When pregnancy is detected, MICARDIS tablets should bediscontinued as soon as possible. See Warnings and Precautions (5.1) .

MICARDIS is indicated for the treatment of hypertension.  It may be used alone or in combination with other antihypertensive agents [seeClinical Studies (14.1)] .

MICARDIS 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 for cardiovascular events can be evidenced by a 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 [see Clinical Studies (14.2)] .  MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy) [see Clinical Studies (14.2)] .

Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. 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 [see Warnings and Precautions (5.6)] .

Dosage must be individualized.  The usual starting dose of MICARDIS tablets is 40 mg once a day.  Blood pressure response is dose-related over the range of 20 to 80 mg [see Clinical Studies (14.1)] .

Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks.  When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added.

No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored.

MICARDIS tablets may be administered with other antihypertensive agents.

MICARDIS tablets may be administered with or without food.

The recommended dose of MICARDIS tablets is 80 mg once a day and can be administered with or without food. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing the risk of cardiovascular morbidity and mortality.

When initiating MICARDIS therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate adjustment of medications that lower blood pressure may be necessary.

MICARDIS is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product [see Adverse Reactions (6.2)] .

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women.  Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors.  When pregnancy is detected, discontinue MICARDIS tablets as soon as possible [see Boxed Warning] .

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skullhypoplasia, anuria, reversible or irreversible renal failure, and death.  Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.  Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were related to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.  Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second and third trimester exposure.  Nonetheless, when patients become pregnant or are considering pregnancy, have the patient discontinue the use of MICARDIS tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found.  In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, MICARDIS should be discontinued unless they are considered life-saving for the mother.  Contraction stress testing (CST), a non-stress test (NST), or biophysicalprofiling (BPP) may be appropriate, depending upon the week of pregnancy.  Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist 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 or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDIS.  Either correct this condition prior to administration of MICARDIS, or start treatment under close medical supervision with a reduced dose.

If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.  A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.

As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance.  Initiate telmisartan at low doses and titrate slowly in these patients [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .

As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals.  In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with MICARDIS [see Clinical Pharmacology (12.3)] .

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed.  There has been no long term use of MICARDIS in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported.   Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.

The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of MICARDIS and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acuterenal failure) compared with groups receiving telmisartan alone or ramipril alone.  Concomitant use of MICARDIS and ramipril is not recommended.

The following adverse reaction is described elsewhere in labeling:

        Renal dysfunction upon use with ramipril [see Warnings and Precautions (5.6)]

Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Hypertension MICARDIS has been eva luated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year.  Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy.

In placebo-controlled trials involving 1041 patients treated with various doses of MICARDIS (20 to 160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo.

Adverse events occurring at an incidence of ≥1% in patients treated with MICARDIS and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.

Table 1 Adverse Events Occurring at an Incidence of ≥1% in Patients Treated with MICARDIS and at a Greater Rate Than Patients Treated with Placebo

In addition to the adverse events in the table, the followingevents occurred at a rate of ≥1% but were at least as frequent in theplacebo group:  influenza-like symptoms, dyspepsia, myalgia, urinary tractinfection, abdominal pain, headache, dizziness, pain, fatigue, coughing,hypertension, chest pain, nausea, and peripheral edema. Discontinuation oftherapy because of adverse events was required in 2.8% of 1455 patients treatedwith MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlledclinical trials.

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

The incidence of cough occurring with telmisartan in 6placebo-controlled trials was identical to that noted for placebo-treatedpatients (1.6%).

In addition to those listed above, adverse events thatoccurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapyin controlled or open trials are listed below.  It cannot be determined whetherthese events were causally related to MICARDIS tablets:

Autonomic Nervous System :  impotence, increased sweating,flushing; Body as a Whole :  allergy, fever, leg pain, malaise; Cardiovascular : palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormalECG; CNS :  insomnia, somnolence, migraine, vertigo, paresthesia,involuntary muscle contractions, hypoesthesia; Gastrointestinal : flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids,gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specificgastrointestinal disorders; Metabolic :  gout, hypercholesterolemia, diabetesmellitus; Musculoskeletal :  arthritis, arthralgia, leg cramps; Psychiatric : anxiety, depression, nervousness; Resistance Mechanism :  infection,fungal infection, abscess, otitis media; Respiratory :  asthma,bronchitis, rhinitis, dyspnea, epistaxis; Skin :  dermatitis, rash,eczema, pruritus; Urinary :  micturition frequency, cystitis; Vascular :  cerebrovascular disorder; and Special Senses :  abnormal vision,conjunctivitis, tinnitus, earache.

During initial clinical studies, a single case of angioedemawas reported (among a total of 3781 patients treated).

Clinical LaboratoryFindings

In placebo-controlled clinical trials, clinically relevantchanges in standard laboratory test parameters were rarely associated withadministration of MICARDIS tablets.

Hemoglobin:  A greater than 2 g/dL decrease inhemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebopatients.  No patients discontinued therapy because of anemia.

Creatinine:  A 0.5 mg/dL rise or greater in creatininewas observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy because of increases increatinine and blood urea nitrogen.

Liver Enzymes:  Occasional elevations of liverchemistries occurred in patients treated with telmisartan; all markedelevations occurred at a higher frequency with placebo.  No telmisartan-treatedpatients discontinued therapy because of abnormal hepatic function.

Cardiovascular RiskReduction

Because common adverse reactionswere well characterized in studies of telmisartan in hypertension, only adverseevents leading to discontinuation and serious adverse events were recorded insubsequent studies of telmisartan for cardiovascular risk reduction. InTRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations foradverse events were 8.4% on telmisartan and 7.6% on placebo. The only seriousadverse events at least 1% more common on telmisartan than placebo wereintermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).

The following adverse reactions have been identified during post-approval use of MICARDIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:  (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS.

The most frequent spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder (more commonly seen in Japanese patients), renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).

Rare cases of rhabdomyolysis have been reported in patientsreceiving angiotensin II receptor blockers, including MICARDIS.

Digoxin : When MICARDIS was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.

Lithium : Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including MICARDIS. Therefore, monitor serum lithium levels during concomitant use.

Ramipril and Ramiprilat : Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthysubjects increases steady-state C and AUC of ramipril 2.3- and 2.1-fold, respectively, and C and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of MICARDIS and ramipril is not recommended.

Other Drugs : Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Teratogenic Effects, Pregnancy Categories C (firsttrimester) and D (second and third trimesters). See Warnings and Precautions (5.1) .

It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology (12.3)] .

Of the total number of patients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Of the total number of patients receiving MICARDIS in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency [see Warningsand Precautions (5.4)] .

Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

MICARDIS is a non-peptide angiotensin II receptor (type AT) antagonist.

Telmisartan is chemically described as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is CHNO, its molecular weight is 514.63, and its structural formula is:

Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.

MICARDIS is available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of telmisartan. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate. MICARDIS tablets are hygroscopic and require protection from moisture.

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effectsthat include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.  Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor in many tissues, such as vascular smooth muscle and the adrenal gland.  Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT receptor found in many tissues, but AT is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT receptor than for the AT receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

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 plasma concentrations with approximately 40% inhibition persisting for 24 hours.

Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significantchanges in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).

In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance.

Following oral administration, peak concentrations (C) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (Cand AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10 to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.

Distribution Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding.

Metabolism and Elimination Following either intravenous or oral administration of C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).

Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma andurine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.

Specific Populations Renal Insufficiency No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see Warnings and Precautions (5.5) and Dosage and Administration (2.1)] . Hepatic Insufficiency In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)] . Gender Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. Geriatric Patients The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see Dosage and Administration (2.1)] . Pediatric Patients Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.

There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m basis, the MRHD oftelmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

There is no clinical experience with the use of MICARDIS tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/mbasis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/mbasis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown tobe present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/mbasis,the maximum recommended human dose of telmisartan (80 mg/day).

The antihypertensive effects of MICARDIS have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once dailyadministration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.

Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with MICARDIS tablets,blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.

In a controlled study, the addition of telmisartan to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to telmisartan.

The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan ismaintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of telmisartan was 70 to 100% for bothsystolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).

There were no changes in the heart rate of patients treated with telmisartan in controlled trials.

Support for use to reduce therisk of cardiovascular events was obtained in a pair of studies. Both enrolledsubjects age ≥55 years, at high cardiovascular risk as evidenced by coronary artery disease (75%), diabetesmellitus (27%) accompanied with end-organ damage (e.g., retinopathy, leftventricular hypertrophy, and, in ONTARGET only, macro- or microalbuminuria),stroke (16%), peripheral vascular disease (13%), or transient ischemic attack(4%). Patients without a history of intolerance to ACE inhibitors enteredONTARGET, and those with such a history, usually cough (90%), entered TRANSCEND,but patients with >1+ proteinuria on dipstick were excluded from TRANSCEND. For both ONTARGET and TRANSCEND trials, the primary4-component composite endpoint was death from cardiovascular causes, myocardialinfarction, stroke, and hospitalization for heart failure. The secondary3-component composite endpoint was death from cardiovascular causes, myocardialinfarction, and stroke.

ONTARGET was a randomized, active-controlled, multinational,double-blind study in 25,620 patients who were randomized to telmisartan 80 mg,ramipril 10 mg, or their combination.  The population studied was 73%male, 74% Caucasian, 14% Asian, and 57% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (76%), lipid lowering agents(64%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%), anddiuretics (28%).  The mean duration of follow up was about 4 years and 6months.  During the study, 22.0% (n=1878) of telmisartan patientsdiscontinued the active treatment, compared to 24.4% (n=2095) of ramiprilpatients and 25.3% (n=2152) of telmisartan/ramipril patients.

TRANSCEND randomized patientsto telmisartan 80 mg (n=2954) or placebo (n=2972). The mean duration of followup was 4 years and 8 months. Thepopulation studied was 57% male, 62% Caucasian, 21% Asian, and 60% were 65years of age or older.  Baseline therapy included acetylsalicylic acid(75%), lipid lowering agents (58%), beta-blockers (58%), calcium channelblockers (41%), nitrates (34%) and diuretics (33%). During the study, 17.7%(n=523) of telmisartan patients discontinued the active treatment, compared to19.4% (n=576) of placebo patients.

The results for the TRANSCENDtrial are summarized in Table 2, and the results for ONTARGET are summarized inTable 3, below:

Althoughthe event rates in ONTARGET were similar on telmisartan and ramipril, theresults did not unequivocally rule out that MICARDIS may not preserve ameaningful fraction of the effect of ramipril in reducing cardiovascular events. However, theresults of both ONTARGET and TRANSCEND do adequately support MICARDIS beingmore effective than placebo would be in this setting, particularly for the end pointof time to cardiovascular death, myocardial infarction, or stroke.

In ONTARGET, there was noevidence that combining ramipril and MICARDIS reduced the risk of death fromcardiovascular causes, myocardial infarction, stroke, or hospitalization for heartfailure greater than ramipril alone; instead, patients who received thecombination of ramipril and telmisartan in ONTARGET experienced an increasedincidence of clinically important renal dysfunction (e.g., acute renal failure)compared to patients receiving MICARDIS or ramipril alone.

Multiple sub-group analysesdid not demonstrate any differences in the 4-component composite primaryendpoint based on age, gender, or ethnicity for either ONTARGET or TRANSCENDtrial.

MICARDIS is available as white or off-white, uncoated tablets containing telmisartan 20 mg, 40 mg, or 80 mg. Tablets are marked with the BOEHRINGER INGELHEIM logo on one side, and on the other side, with either 50H, 51H, or 52H for the 20 mg, 40 mg, and 80 mg strengths, respectively. Tablets are provided as follows:

MICARDIS tablets 20 mg are round and individually blister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0039-37).

MICARDIS tablets 40 mg are oblong shaped and individually blister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0040-37).

MICARDIS tablets 80 mg are oblong shaped and individually blister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0041-37).

Storage Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Tablets should not be removed from blisters until immediately before administration.

See FDA-approved Patient Labeling

Inform female patients of childbearing age about the consequences of exposure to drugs that act on the renin-angiotensin system. Advise these patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1)] .

Since side effects such as syncope, somnolence, dizziness, or vertigo may occur with use of antihypertensive agents such as MICARDIS tablets, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany

Copyright 2011 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

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Patient Information

MICARDIS(my-CAR-dis) (telmisartan)Tablets

Read this Patient Information before you start taking MICARDIS tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about MICARDIS tablets?

MICARDIS is not for pregnant women. Taking MICARDIS tablets during your pregnancy can cause injury and even death to your unborn baby. If you get pregnant, stop taking MICARDIS tablets and call your doctor right away. If you plan to become pregnant, talk to your doctor about other ways to lower your blood pressure.

What is MICARDIS?

MICARDIS is a prescription medicine used:

It is not known if MICARDIS is safe and effective in children.

Who should not take MICARDIS?

You should not take MICARDIS tablets if you are allergic (hypersensitive) to the active ingredient (telmisartan) or any of the other ingredients listed at the end of this leaflet.

What should I tell my doctor before taking MICARDIS tablets?

Before you take MICARDIS tablets, tell your doctor if you:

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

MICARDIS may affect the way other medicines work, and other medicines may affect how MICARDIS works. Especially tell your doctor if you take:

Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine.

How should I take MICARDIS tablets?

What important safety information should I know about MICARDIS tablets?

What are the possible side effects of MICARDIS tablets?

MICARDIS tablets may cause serious side effects, including

Rare, serious allergic reactions may happen. Tell your doctor right away if you get any of these symptoms:

The most common side effects of MICARDIS tablets include:

These are not all the possible side effects with MICARDIS tablets. Tell your doctor if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store MICARDIS tablets?

Keep MICARDIS tablets and all medicines out of the reach of children.

General information about MICARDIS tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MICARDIS tablets for a condition for which it was not prescribed. Do not give MICARDIStablets to other people, even if they have the same condition you have. It may harm them.

This Patient Information leaflet summarizes the most important information about MICARDIS tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor forinformation about MICARDIS tablets that is written for health professionals.

For more information, call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.

What are the ingredients in MICARDIS tablets?

Active Ingredient: telmisartan

Inactive Ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate 

What is High Blood Pressure (Hypertension)?

Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much.  MICARDIS tablets can help your blood vessels relax so your blood pressure is lower. High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems.

What is Cardiovascular Risk?

Patients older than 55 years of age who have been diagnosed with blood vessel disease in the heart, legs, or brain (coronary, peripheral, or cerebral vascular disease) or diabetes with end organ damage (for example: kidney, heart, and brain) are at higher risk of cardiovascular events (for example: death from cardiovascular causes, stroke, and/or heart attack).

How to open the blister:

1. Tear (You may also use scissors to tear the blister apart)

2. Peel (Peel off the paper layer from the aluminum foil)

3. Push (Push the tablet through the foil)

Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany

Copyright 2011 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

Revised: January 2011

OT1200LA182011090340194/7

IT12004HA18201110005385/5

Micardis

20 mg

30 Tablets

NDC 0597-0039-37

Micardis

40 mg

30 Tablets

NDC 0597-0040-37

Micardis

40 mg

7 Tablets

NDC 0597-0040-70

Micardis

80 mg

7 Tablets

NDC 0597-0041-70

Micardis

80 mg

30 Tablets

NDC 0597-0041-37

Manufacturer

Boehringer Ingelheim Pharmaceuticals, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011