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.  Itmay be used alone or in combination with other antihypertensive agents [ seeClinical Studies (14.1) ].

MICARDIS is indicated forreduction of the risk of myocardial infarction, stroke, or death fromcardiovascular causes in patients 55 years of age or older at high risk ofdeveloping major cardiovascular events who are unable to take ACE inhibitors.

High risk for cardiovascular events can beevidenced by a history of coronary artery disease, peripheral arterial disease,stroke, transient ischemic attack, or high-riskdiabetes (insulin-dependent or non-insulin dependent) with evidence ofend-organ damage [ see Clinical Studies (14.2) ].  MICARDIS can be used inaddition to other needed treatment (such as antihypertensive, antiplatelet orlipid-lowering therapy) [ see Clinical Studies (14.2) ].

Studies of telmisartan in thissetting do not exclude that it may not preserve a meaningful fraction of theeffect of the ACE inhibitor to which it was compared. Consider using the ACEinhibitor first, and, if it is stopped for cough only, consider re-trying theACE inhibitor after the cough resolves.

Use of telmisartan with an ACEinhibitor is not recommended [ see Warnings and Precautions (5.6) ] .

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

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

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

MICARDIS tablets may be administered with otherantihypertensive agents.

MICARDIS tablets may be administered with or without food.

Therecommended dose of MICARDIS tablets is 80 mg once a day and can beadministered with or without food. It is not known whether doses lower than 80mg of telmisartan are effective in reducing the risk of cardiovascularmorbidity and mortality.

Wheninitiating MICARDIS therapy for cardiovascular risk reduction, monitoring ofblood pressure is recommended, and if appropriate adjustment of medicationsthat lower blood pressure may be necessary.

None.

Drugs that act directly on the renin-angiotensin system cancause fetal and neonatal morbidity and death when administered to pregnantwomen.  Several dozen cases have been reported in the world literature inpatients who were taking angiotensin converting enzyme inhibitors.  When pregnancyis detected, discontinue MICARDIS tablets as soon as possible [ see BoxedWarning ].

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

These adverse effects do not appear to have resulted fromintrauterine drug exposure that has been limited to the first trimester.  Informmothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonistonly during the first trimester that most reports of fetal toxicity have beenassociated with second and third trimester exposure.  Nonetheless, whenpatients become pregnant or are considering pregnancy, have the patientdiscontinue the use of MICARDIS tablets as soon as possible.

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

If oligohydramnios is observed, MICARDIS should bediscontinued 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 notappear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to anangiotensin II receptor antagonist should be closely observed for hypotension,oliguria, and hyperkalemia.  If oliguria occurs, attention should be directedtoward support of blood pressure and renal perfusion.  Exchange transfusion ordialysis may be required as a means of reversing hypotension and/orsubstituting for disordered renal function.

In patients with an activated renin-angiotensin system, suchas volume- or salt-depleted patients (e.g., those being treated with high dosesof diuretics), symptomatic hypotension may occur after initiation of therapywith 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 thesupine position and, if necessary, given an intravenous infusion of normalsaline.  A transient hypotensive response is not a contraindication to further treatment,which usually can be continued withoutdifficulty once the blood pressure has stabilized.

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

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

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

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

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

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

The following adverse reaction is described elsewhere inlabeling:

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

Becauseclinical studies are conducted under widely varying conditions, adversereactions rates observed in the clinical studies of a drug cannot be directlycompared to rates in the clinical studies of another drug andmay not reflect the rates observed in practice.

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

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

Adverse events occurring at an incidence of ≥1% inpatients treated with MICARDIS and at a greater rate than in patients treatedwith placebo, irrespective of their causal association, are presented in Table1.

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

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 voluntarilyfrom a population of uncertain size, it is not always possible to estimatereliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one ormore of the following factors:  (1) seriousness of the reaction, (2) frequencyof reporting, or (3) strength of causal connection to MICARDIS.

The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, faceedema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity,sweating increased, erythema, chest pain, atrial fibrillation, congestive heartfailure, myocardial infarction, blood pressure increased, hypertensionaggravated, hypotension (including postural hypotension), hyperkalemia,syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectiledysfunction, back pain, abdominal pain, muscle cramps (including leg cramps),myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormalhepatic function/liver disorder, renal impairment including acute renalfailure, anemia, increased CPK, anaphylactic reaction, and tendon pain(including tendonitis, tenosynovitis).

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

Digoxin : When MICARDIS was co-administered with digoxin, median increasesin 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 levelwithin the therapeutic range.

Lithium : Reversible increases in serum lithium concentrations and toxicityhave been reported during concomitant administration of lithium withangiotensin II receptor antagonists including MICARDIS. Therefore, monitor serumlithium levels during concomitant use.

Ramipril and Ramiprilat :  Co-administrationof telmisartan 80 mg once daily and ramipril 10 mg once daily to healthysubjects increases steady-state C and AUC of ramipril 2.3- and2.1-fold, respectively, and C and AUC of ramiprilat 2.4- and 1.5-fold,respectively. In contrast, C and AUC of telmisartan decrease by31% and 16%, respectively. When co-administering telmisartan and ramipril, theresponse may be greater because of the possibly additive pharmacodynamiceffects of the combined drugs, and also because of the increased exposure toramipril and ramiprilat in the presence of telmisartan.  Concomitant use ofMICARDIS and ramipril is not recommended.

Other Drugs : Co-administration of telmisartan did notresult in a clinically significant interaction with acetaminophen, amlodipine, glyburide,simvastatin, hydrochlorothiazide, warfarin, or ibuprofen.  Telmisartan is notmetabolized by the cytochrome P450 system and had no effects in vitro oncytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan isnot expected to interact with drugs that inhibit cytochrome P450 enzymes; it isalso not expected to interact with drugs metabolized by cytochrome P450enzymes, except for possible inhibition of the metabolism of drugs metabolizedby 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 isexcreted in human milk, but telmisartan was shown to be present in the milk oflactating rats.  Because of the potential for adverse effects on the nursinginfant, decide whether to discontinue nursing or discontinue the drug, takinginto account the importance of the drug to the mother.

Safety and effectiveness in pediatricpatients have not been established.

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

Ofthe total number of patients receiving MICARDIS in the cardiovascular riskreduction study (ONTARGET), the percentage of patients ≥65 to <75years of age was 42%; 15% of patients were ≥75 years old. No overalldifferences in effectiveness and safety were observed in these patientscompared to younger patients and other reported clinical experience has notidentified 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 withbiliary obstructive disorders or hepatic insufficiency [ see Warningsand Precautions (5.4) ].

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

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

Telmisartan is chemically described as4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid.  Itsempirical formula is CHNO,its molecular weight is 514.63, and its structural formula is:

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

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

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

There is also an AT receptor found in manytissues, but AT is not known to be associated with cardiovascularhomeostasis.  Telmisartan has much greater affinity (>3,000 fold) for the ATreceptor 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 widelyused in the treatment of hypertension.  ACE inhibitors also inhibit thedegradation of bradykinin, a reaction also catalyzed by ACE.  Becausetelmisartan does not inhibit ACE (kininase II), it does not affect the responseto bradykinin.  Whether this difference has clinical relevance is not yetknown.  Telmisartan does not bind to or block other hormone receptors or ionchannels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negativeregulatory feedback of angiotensin II on renin secretion, but the resultingincreased plasma renin activity and angiotensin II circulating levels do notovercome the effect of telmisartan on blood pressure.

In normal volunteers, a dose oftelmisartan 80 mg inhibited the pressor response to an intravenous infusion ofangiotensin II by about 90% at peak plasma concentrations with approximately40% inhibition persisting for 24 hours.

Plasma concentration of angiotensin II and plasma reninactivity (PRA) increased in a dose-dependent manner after single administrationof telmisartan to healthy subjects and repeated administration to hypertensivepatients.  The once-daily administration of up to 80 mg telmisartan to healthysubjects did not influence plasma aldosterone concentrations.  In multiple dosestudies 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 treatedfor 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination withhydrochlorothiazide 12.5 mg, there were no clinically significant changes frombaseline 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 0.5-1 hour after dosing.  Food slightly reducesthe bioavailability of telmisartan, with a reduction in the area under theplasma concentration-time curve (AUC) of about 6% with the 40 mg tablet andabout 20% after a 160 mg dose.  The absolute bioavailability of telmisartan isdose dependent.  At 40 and 160 mg the bioavailability was 42% and 58%,respectively.  The pharmacokinetics of orally administered telmisartan arenonlinear over the dose range 20-160 mg, with greater than proportionalincreases of plasma concentrations (Cand AUC) with increasingdoses.  Telmisartan shows bi-exponential decay kinetics with a terminalelimination half life of approximately 24 hours. Trough plasma concentrationsof telmisartan with once daily dosing are about 10-25% of peak plasmaconcentrations.  Telmisartan has an accumulation index in plasma of 1.5 to 2.0upon repeated once daily dosing.

Distribution Telmisartan is highly bound toplasma proteins (>99.5%), mainly albumin and α - acid glycoprotein. Plasma protein binding isconstant over the concentration range achieved with recommended doses.  Thevolume of distribution for telmisartan is approximately 500 liters indicatingadditional tissue binding.

Metabolism andElimination Following either intravenous or oral administration of C-labeledtelmisartan, most of the administered dose (>97%) was eliminated unchangedin 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 apharmacologically inactive acyl glucuronide; the glucuronide of the parentcompound is the only metabolite that has been identified in human plasma andurine.  After a single dose, the glucuronide represents approximately 11% ofthe measured radioactivity in plasma.  The cytochrome P450 isoenzymes are notinvolved 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.

Special Populations RenalInsufficiency No dosage adjustment isnecessary in patients with decreased renal function.  Telmisartan is notremoved from blood by hemofiltration [ see Warnings and Precautions(5.5)and Dosage and Administration (2.1) ]. HepaticInsufficiency In patients with hepaticinsufficiency, plasma concentrations of telmisartan are increased, and absolutebioavailability approaches 100% [ see Warnings and Precautions (5.4) and Usein Specific Populations (8.6) ]. Gender Plasma concentrations oftelmisartan are generally 2-3 times higher in females than in males.  Inclinical trials, however, no significant increases in blood pressure responseor in the incidence of orthostatic hypotension were found in women.  No dosageadjustment is necessary. GeriatricPatients Thepharmacokinetics of telmisartan do not differ between the elderly and thoseyounger than 65 years [see Dosage and Administration(2.1) ]. PediatricPatients Telmisartanpharmacokinetics have not been investigated in patients <18 years of age.

There was no evidence of carcinogenicity when telmisartan wasadministered in the diet to mice and rats for up to 2 years.  The highest dosesadministered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/mbasis, about 59 and 13 times, respectively, the maximum recommended humandose (MRHD) of telmisartan.  These same doses have been shown to provideaverage 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-relatedeffects at either the gene or chromosome level.  These assays includedbacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with humanlymphocytes, and a mouse micronucleus test.

No drug-related effects on the reproductive performance ofmale and female rats were noted at 100 mg/kg/day (the highest doseadministered), 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 theaverage systemic exposure in humans at the MRHD (80 mg/day).

There is no clinical experience with the use of MICARDIStablets in pregnant women.  No teratogenic effects were observed whentelmisartan 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.  Inrabbits, embryolethality associated with maternal toxicity (reduced body weightgain and food consumption) was observed at 45 mg/kg/day [about 12 times themaximum 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 produceadverse 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 noobserved effect doses for developmental toxicity in rats and rabbits, 5 and 15mg/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 demonstratedin six principal placebo-controlled clinical trials, studying a range of 20-160mg; one of these examined the antihypertensive effects of telmisartan andhydrochlorothiazide in combination.  The studies involved a total of 1773patients with mild to moderate hypertension (diastolic blood pressure of 95-114mmHg), 1031 of whom were treated with telmisartan.  Following once dailyadministration of telmisartan, the magnitude of blood pressure reduction frombaseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg.  Larger doses (upto 160 mg) did not appear to cause a further decrease in blood pressure.

Upon initiation of antihypertensive treatment withtelmisartan, blood pressure was reduced after the first dose, with a maximalreduction by about 4 weeks.  With cessation of treatment with MICARDIS tablets,blood pressure gradually returned to baseline values over a period of severaldays to one week.  During long term studies (without placebo control) theeffect 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 Caucasianpatients.  This has been true for most, but not all, angiotensin II antagonistsand ACE inhibitors.

In a controlled study, the addition of telmisartan tohydrochlorothiazide produced an additional dose-related reduction in bloodpressure that was similar in magnitude to the reduction achieved withtelmisartan monotherapy.  Hydrochlorothiazide also had an added blood pressureeffect when added to telmisartan.

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

There were no changes in the heart rate of patients treatedwith 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 54868-6193-0).

MICARDIS tablets 40 mg are oblong shaped and individually blister-sealedin cartons of 30 tablets as 3 x 10 cards (NDC 54868-4539-1).

MICARDIS tablets 80 mg are oblong shaped and individuallyblister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 54868-4605-1) and individually blister-sealed in cartons as 9 x 10 cards (NDC 54868-4605-2).

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.

         SeeFDA-approved Patient Labeling (17.2).

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

Patient labeling is provided as a tear-off leaflet atthe end of this prescribing information.

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

Licensed from:  Boehringer Ingelheim International GmbH, Ingelheim, Germany

©Copyright 2009 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

Micardis Tablets are coveredby U.S. Patent No. 5,591,762

Rev: November 2009

OT1200KK0309090340194/7

IT12004GK030910005385/4

Relabeling of "Additional Barcode" label by:Physicians Total Care, Inc.Tulsa, OK      74146

Patient Information

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

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

What is the most important information I should know aboutMICARDIS tablets?

MICARDIS isnot for pregnant women.  Taking MICARDIS tablets during your pregnancy cancause injury and even death to your unborn baby. If you get pregnant, stoptaking MICARDIS tablets and call your doctor right away. If you plan to becomepregnant, talk to your doctor about other ways to lower your blood pressure.

What isMICARDIS?

MICARDIS is a prescription medicine used:

It is notknown if MICARDIS is safe and effective in children.

What shouldI 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 andnon-prescription medicines, vitamins, and herbal supplements.

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

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

Howshould I take MICARDIS tablets?

What arethe possible side effects of MICARDIS tablets?

MICARDIS tablets may cause serious side effects, including

Rare, serious allergic reactions may happen. Tell your doctor right awayif 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.  Tellyour doctor if you have any side effect that bothers you or that does not goaway.  Call your doctor for medical advice about side effects.  You may reportside effects to FDA at 1-800-FDA-1088.

Howshould I store MICARDIS tablets?

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

General information about MICARDIS tablets

Medicines are sometimes prescribed for purposesother than those listed in a Patient Information leaflet.  Do not use MICARDIStablets 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 mayharm them.

This Patient Information leaflet summarizes the mostimportant information about MICARDIS tablets.  If you would like moreinformation, 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. at1-800-542-6257, or (TTY) 1-800-459-9906.

What are the ingredients in MICARDIS tablets?

Active Ingredient:   telmisartan

Inactive Ingredients:   sodium hydroxide, meglumine, povidone, sorbitol, andmagnesium stearate 

What is High Blood Pressure(Hypertension)?

Blood pressure is the force in your blood vessels when your heart beatsand 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 islower.  High blood pressure makes the heart work harder to pump bloodthroughout the body and causes damage to the blood vessels. If high bloodpressure 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 bloodvessel disease in the heart, legs, or brain (coronary, peripheral, or cerebralvascular disease) or diabetes with end organ damage (for example: kidney,heart, and brain) are at higher risk of cardiovascular events (for example: death fromcardiovascular 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:BoehringerIngelheim Pharmaceuticals, Inc.Ridgefield, CT  06877 USA

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany

©Copyright 2009 Boehringer IngelheimInternational GmbHALL RIGHTS RESERVED

MicardisTablets are covered by U.S. Patent No. 5,591,762

Rev:November 2009

OT12004KK0309090340194/7

IT12004GK030910005385/4

40 mg

30 Tablets

Micardis

80 mg

30 Tablets

Micardis

20 mg

30 Tablets

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

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