SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 13 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17

PART II: SCIENTIFIC INFORMATION 18

PHARMACEUTICAL INFORMATION 18 CLINICAL TRIALS 19 DETAILED PHARMACOLOGY 21 TOXICOLOGY 21 REFERENCES 24

PART III: CONSUMER INFORMATION. 25

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

MICARDIS (telmisartan) is contraindicated in patients who are hypersensitive to any components of this product.

Sorbitol: 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.

WARNINGS AND PRECAUTIONS

Valvular Stenosis: 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.

Hypotension: 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.

Hyperkalemia: 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.

Hepatic Impairment: 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 Cmax 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).

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. 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.

Pregnant Women:

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when administered to pregnant women. If pregnancy is detected, MICARDIS (telmisartan) should be discontinued as soon as possible. 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 skull hypoplasia, 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 due 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. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS as soon as possible unless it is considered life-saving for the mother. Rarely, probably less often than once in every thousand pregnancies, no alternative to an angiotensin II AT1 receptor antagonist will be found. In these rare cases, the physician should apprise mothers of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra amniotic environment. If oligohydramnios is observed, contraction stress testing (CST), a non-stress test (NTS), or biophysical profiling (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 AT1 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 may be required as a means of reversing hypotension and/or substituting for disordered renal function. Telmisartan is not removed from plasma by hemodialysis. 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.

Nursing Women:

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, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (< 18 years of age):

Geriatrics (> 65 years of age)

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 and Renal) and DRUG INTERACTIONS sections.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

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. 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.

All Clinical Trials

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 (>=1/10000, <1/1000); very rare (< 1/10000)

Body as a Whole, General:

Common:Back pain (e.g.sciatica), chest pain, influenza-like symptoms, symptoms of infection (e.g. urinary tract infections including cystitis), fatigue, conjunctivitis. Uncommon:Abnormal vision, sweating increased.

Cardiovascular System:

Common:Edema, palpitation.

Central and Peripheral Nervous System:

Very Common:Headache. Common:Dizziness, insomnia. Uncommon:Vertigo.

Gastro-Intestinal System:

Common:Abdominal pain, diarrhoea, dyspepsia, nausea, constipation, gastritis. Uncommon:Dry mouth, flatulence.

Musculo-Skeletal System:

Common:Arthralgia, cramps in legs or leg pain, myalgia, arthritis, arthrosis. Uncommon:Tendinitis like symptoms.

Psychiatric System:

Common:Anxiety, depression, nervousness.

Respiratory System:

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

Skin and Appendages System:

Common:Skin disorders like eczema, rash.

Hemoglobin:

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

Placebo-Controlled Trials

The overall incidence of adverse events reported with MICARDIS (41.4%) was usually comparable to placebo (43.9%) in placebo-controlled trials. Adverse events occurring in 1% or more of 1395 hypertensive patients treated with MICARDIS monotherapy in placebo-controlled clinical trials, regardless of drug relationship, include the following:

Table 1: Adverse Events Occurring in > 1% of Hypertensive Patients Treated with MICARDIS Monotherapy

Adverse Event, by System	MICARDIS Total N = 1395 %	Placebo N = 583 %
Body as a Whole
Back Pain	2.7	0.9
Chest Pain	1.3	1.2
Fatigue	3.2	3.3
Influenza-Like Symptoms	1.7	1.5
Pain	3.5	4.3
Central & Peripheral Nervous System
Dizziness	3.6	4.6
Headache	8.0	15.6
Somnolence	0.4	1.0
Gastrointestinal System
Diarrhea	2.6	1.0
Dyspepsia	1.6	1.2
Nausea	1.1	1.4
Vomiting	0.4	1.0
Musculoskeletal System
Myalgia	1.1	0.7
Respiratory System
Coughing	1.6	1.7
Pharyngitis	1.1	0.3
Sinusitis	2.2	1.9
Upper Respiratory Tract Infection	6.5	4.6
Heart Rate and Rhythm Disorders
ECG abnormal specific	0.2	1.0
Palpitation	0.6	1.0
Cardiovascular Disorders, General
Hypertension	1.0	1.7
Oedema peripheral	1.0	1.2

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

Less Common Clinical Trial Adverse Drug Reactions (<1%)

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

Autonomic Nervous System Disorders:

sweating increased.

Body as a Whole: Cardiovascular Disorders, General: Central & Peripheral Nervous System Disorder:

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

hypotension, hypotension-postural, leg edema.

hypertonia, migraine-aggravated, muscle

contraction-involuntary.

Gastrointestinal System Disorders:

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

Heart Rate & Rhythm Disorders:

arrhythmia, tachycardia.

Metabolic & Nutritional Disorders:

diabetes mellitus, hypokalaemia.

Musculoskeletal System Disorders:

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

Myo Endo Pericardial & Valve Disorders:

myocardial infarction.

Psychiatric Disorders:

nervousness.

Red Blood Cell Disorders:

anemia.

Reproductive Disorders, Female:

vaginitis.

Resistance Mechanism Disorders:

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

Respiratory System Disorders:

bronchospasm, epistaxis, pneumonia, bronchitis.

Skin & Appendage Disorders:

rash, skin dry.

Urinary System Disorders:

Dysuria, hematuria, micturition disorder, urinary tract infection.

Vascular (Extracardiac) Disorders:

cerebrovascular disorder, purpura.

Vision Disorders:

vision abnormal.

Abnormal Hematologic and Clinical Chemistry Findings

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.

Creatinine, Blood Urea Nitrogen:

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.

Hemoglobin, Hemotocrit:

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.

Serum Uric Acid:

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 (>10mEq/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.

Liver Function Tests:

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.

Serum Potassium:

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%.

Cholesterol:

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.

Post-Market Adverse Drug Reactions

Since the introduction of telmisartan in the market, cases of erythema, pruritus, syncope/faint, insomnia, depression, stomach upset, vomiting, hypotension (including orthostatic hypotension), bradycardia, tachycardia, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, hyperkalemia, dyspnoea, anaemia, eosinophilia, thrombocytopenia, weakness and lack of efficacy 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.

DRUG INTERACTIONS

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 Cmax 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.

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.

DOSAGE AND ADMINISTRATION

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.

OVERDOSAGE

Limited data are available with regard to overdosage in humans. The most prominent manifestations of overdosage were hypotension and/or tachycardia; bradycardia also occurred. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

ACTION AND CLINICAL PHARMACOLOGY

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 homeostatis. 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.

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.

Absorption:

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 (Cmax 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.

Metabolism:

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. Excretion: 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.

Distribution:

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.

Pediatrics:

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

Geriatrics:

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

Gender:

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

Hepatic Insufficiency:

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).

Renal Insufficiency:

Renal excretion of telmisartan is negligible. No dosage adjustment is necessary in patients with renal insufficiency. In patients on hemodialysis both Cmax 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)

Genetic Polymorphism:

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

STORAGE AND STABILITY

MICARDIS tablets are hygroscopic and require protection from moisture. Tablets are packaged in blisters and should be stored at room temperature, 15-30degC (59-86degF). Tablets should not be removed from blisters until immediately prior to administration.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MICARDIS is available as white, oblong-shaped, uncoated tablets containing telmisartan 40 mg or 80 mg. Tablets are marked with the Boehringer Ingelheim logo on one side, and on the other side, either 51H or 52H for the 40 mg and 80 mg strengths, respectively. MICARDIS Tablets 40 mg are individually blister sealed in cartons of 28 tablets as 4 cards containing 7 tablets each. MICARDIS Tablets 80 mg are individually blister sealed in cartons of 28 tablets as 4 cards containing 7 tablets each.

PHARMACEUTICAL INFORMATION

Drug Substance

[1,1'-Biphenyl]-2-carboxylic acid,4'-[(1,4'- dimethyl-2'-propyl[2,6'-bi- 1H-benzimidazol]-1'-yl)methyl]-(CAS)

Description: Telmisartan is a white to off-white, odorless crystalline powder. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except HCL), and soluble in strong base. Polymorphism: Exhibits two different polymorphic modifications, Form A (thermodynamically more stable) and Form B, and a third pseudo polymorphic form. Melting Point: 269 +- 1degC (polymorphic Form A) 183 +- 1degC (polymorphic Form B) Apparent partition coefficient: log papp = 3.2

CLINICAL TRIALS

Study demographics and trial design

Table 3: Summary of patient demographics for clinical trials in specific indication

Study results

DETAILED PHARMACOLOGY

In in vitro studies, telmisartan displaced 125I-angiotensin II from its binding site at the AT1 receptor with an inhibitor constant (Ki) of 3.7 nM. In isolated strips of rabbit aorta, telmisartan exerted potent angiotensin II antagonism: the calculated dissociation constant was KB 3.3 *10-10M.

results showed that telmisartan was a potent and long acting antagonist of the functional response to exogenously administered angiotensin II in rats, rabbits and dogs after both intravenous and oral administration. Telmisartan showed dose dependent and long lasting (>24h) antihypertensive effects after single or repeated oral administration in various rodent models of experimental hypertension.

TOXICOLOGY

In acute oral toxicity studies no deaths and no changes occurred in rats or dogs at 2000 mg/kg, the highest oral dose tested. The i.v. LD50 in rats was 150-200 mg/kg in males and 200-250 mg/kg in females.

Chronic oral toxicity of telmisartan was evaluated in studies following administration of doses up to 500 mg/kg for up to 26 weeks in rats, and up to one year in dogs. Chronic intravenous toxicity was evaluated in studies of up to four weeks at doses up to 20 mg/kg in rats and up to 50 mg/kg in dogs. Repeated dose administration of telmisartan resulted in marked and long lasting hypotension, hyperplasia of juxtaglomerular apparatus and lesions of the gastrointestinal tract. Further effects were reduced body weight gain, heart weight and red blood cell indices, increased potassium and AST and ALT, the latter in the absence of morphological evidence of toxicity. No effect doses were not identified for decreased erythroid indices, increased BUN and juxtaglomerular hypertrophy/hyperplasia in rats and dogs.

In studies on fertility and reproductive performance in male and female rats no effect on mating performance, reproductive organs, or fertility in either sex, or on litter parameters was observed with telmisartan doses of 5-100 mg/kg. No teratogenic or embryotoxic potential in rats was observed at doses up to 50 mg/kg administered from day 7 through day 16 of pregnancy. Telmisartan was detectable in the placenta, fetus and amniotic fluid of rats after single oral doses of 1 mg/kg.

Telmisartan was not mutagenic at a concentration range of 10 to 2500 ug/plate in the bacterial reverse mutation assay, with or without metabolic activation. No potential for chromosomal damage was found in the mouse micronucleus test at a dose range of 250 to 1000 mg/kg. No forward mutations at the HPRT locus in V79 cells were induced at a concentration range of 10 to 100 ug/ml, with or without metabolic activation. No chromosomal aberrations were induced in human peripheral lymphocytes in vitro at concentrations up to 100 ug/ml without metabolic activation and concentrations up to 200 ug/ml with metabolic activation.

The carcinogenic potential of telmisartan was assessed in 2-year feeding studies in mice at doses of 10, 100 and 1000 mg/kg and in rats at 3, 15 and 100 mg/kg. Drug administration did not affect survival time in either study and also tumor mortality was not increased. Incidence and time to appearance of palpable masses showed no treatment influence in mice and rats. No increases were observed in overall tumor incidence, incidence of benign and malignant tumors or tumor multiplicity.

Gastric and/or duodenal mucosal erosions and ulcers were seen in rats given >=4 mg/kg orally or >=2 mg/kg i.v. and in dogs given >=40 mg/kg orally. Most lesions were small, focal or multifocal in distribution and limited to the mucosa and submucosa. Ulcers and erosions healed rapidly after drug withdrawal.

Hypertrophy of the juxtaglomerular apparatus and increased granularity of renin-producing cells of the juxtaglomerular apparatus, afferent arterioles and interlobular arteries of the kidney were observed in rats at doses of 1 mg/kg and higher and in dogs at 5 mg/kg and higher. In rats and dogs subjected to long term treatment with telmisartan, plasma renin activity returned to normal levels after 26 to 52 weeks of treatment. Reversible slight to mild increases in serum potassium levels occurred in rats at oral doses of 4 mg/kg and higher. In dogs, non-progressive increases in serum potassium levels were noted at 50 and 500 mg/kg in the 52 week oral study.Minimal to mild, reversible increases in blood urea nitrogen and creatinine were evident at oral doses of 4 mg/kg and higher in rats and 5 mg/kg and higher in dogs.

Slight to mild reversible reductions of red blood cell count, hematocrit, and/or hemoglobin were observed after repeated oral dosing with telmisartan >=50 mg/kg in the rat and >=5 mg/kg in the dog.

REFERENCES

This leaflet is part III of a three-part "Product Monograph" published when MICARDIS was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about MICARDIS. Contact your doctor or pharmacist if you have any questions about the drug.

Your doctor has prescribed MICARDIS to treat your mild to moderate high blood pressure.

that causes the blood vessels to constrict, thus making the blood pressure higher. MICARDIS lowers blood pressure by specifically blocking the action of angiotensin II, and thus relaxing the blood vessels. As a result blood pressure is lowered.

Patients who are hypersensitive to this drug or to any non- medicinal ingredient in the formulation (see the section "What the

If you are on a special diet, or if you are allergic to any substance, ask your doctor or pharmacist whether any of these ingredients may cause a problem for you.

diuretics, herbal preparations or any other medications you can buy without a prescription.

If you have been told by your doctor that you have an intolerance to some sugars

Drugs like MICARDIS can cause fetal injury or death especially in the second and third trimesters of pregnancy. Therefore MICARDIS should not be administered to women during pregnancy. If you become pregnant, your doctor should direct you in the discontinuation of MICARDIS as soon as possible, unless your doctor thinks that the benefits to you outweigh the risk to the unborn baby. It is not known whether MICARDIS can pass into human milk, therefore do not breast-feed during treatment. Should you wish to continue breastfeeding, your doctor may be able to prescribe another medication to control your blood pressure.

MICARDIS has been prescribed to treat your condition. Do not give it to other people

As with most medicines, interaction with other drugs is possible. Therefore, do not take any other medication without your doctor's or pharmacist's advice.

Drugs that may interact with MICARDIS include: Warfarin, Digoxin, Lithium and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ASA.

may be taken with or without food, but it should be taken the same way each day. You should follow any other direction that your doctor has given you for the treatment and/or monitoring of your condition.

If you experience dizziness and/or fainting or racing heart rate, contact your doctor immediately or go to the nearest emergency

Try to take your dose at the same time each day, preferably in the morning. However, if you have forgotten to take your dose during

Like any drug product, MICARDIS may cause some unwanted effects along with good effects. Tell your doctor or pharmacist promptly about these or any other unusual symptoms.

If you develop an allergic reaction involving swelling of the face, lips and/or tongue, stop taking MICARDIS and contact your physician immediately.

Side effects such as muscle pain, muscle weakness, muscle inflammation and a muscle-wasting disease, in rare cases leading to kidney failure, have been reported with the use of angiotensin II receptor blockers, the class of drugs to which MICARDIS belongs. You should contact your physician promptly if you experience muscle pain that you cannot explain, muscle tenderness or weakness, generalised weakness, or when you notice dark/brown urine.

This is not a complete list of side effects. For any unexpected effects while taking MICARDIS, contact your doctor or pharmacist.

MICARDIS tablets should be stored at room temperature (15degC - 30degC). Tablets should not be removed from blisters until immediately prior to administration. Avoid excessive heat and moisture.

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

This document plus the full product monograph, prepared for health professionals can be found at:

This leaflet was prepared by Boehringer Ingelheim (Canada) Ltd. Last revised: June 19, 2008

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
oral	tablet 40 mg , 80 mg	sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate

Telmisartan	Effect	Clinical comment
Agents increasing serum potassium		Since the telmisartan reduces the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution. Concomitant thiazide diuretic use may attenuate any effect that telmisartan may have on serum potassium.
Digoxin	When telmisartan was co- administered with digoxin, mean increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed.	It is recommended that digoxin levels be monitored with appropriate dose adjustments when initiating, adjusting or discontinuing MICARDIS, to maintain appropriate plasma digoxin concentrations.
Diuretics	Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with telmisartan.	The possibility of symptomatic hypotension with the use of telmisartan can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of telmisartan (see WARNINGS AND PRECAUTIONS - Cardiovascular , Hypotension and DOSAGE AND ADMINISTRATION). No drug interaction of clinical significance has been identified with thiazide diuretics.
Telmisartan	Effect	Clinical comment
Lithium salts		Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have also been reported with angiotensin II receptor antagonists including MICARDIS. Therefore, serum lithium level monitoring is advisable during concomitant use.
Nonsteroidal Anti- Inflammatory Drugs (NSAIDs)		Combinations of angiotensin-II antagonists (MICARDIS) and NSAIDs (including ASA and COX-2 inhibitors) might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and kidney function should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure. NSAIDs (including ASA and COX-2 inhibitors) and angiotensin-II receptor antagonists exert a synergistic effect on the decrease of glomerular filtration. In patients with pre-existing renal impairment, this may lead to acute renal failure. Monitoring of renal function at the beginning and during the course of the treatment should be recommended. Co-administration of MICARDIS did not result in a clinically significant interaction with ibuprofen.
Warfarin	MICARDIS (telmisartan) administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR).
Other		Coadministration of MICARDIS also did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, or hydrochlorothiazide.

Study #	Trial design	Dosage, route of administration and duration	Study subjects (n=number)	Mean age (Range)	Gender
502.202	Randomized, Double blind, Placebo- controlled	Treatment doses: 40 mg, 80 mg, 120 mg (40 mg + 80 mg) once daily Route of Administration: Oral Duration of treatment: 4 weeks	207	51.8 (30-68)	62% male/ 38% female
502.203	Randomized, Double blind, Placebo- controlled	Treatment doses: 20 mg, 40 mg, 80 mg, 120 mg (40 mg + 80 mg), 160 mg (80 mg + 80 mg) once daily Route of Administration: Oral Duration of treatment: 4 weeks	274	52.3 (28-72)	69% male/ 31% female
502.206	Randomized, Double blind, Placebo- controlled	Treatment doses: 40 mg, 80 mg, 120 mg, 160 mg (80 mg + 80 mg) once daily Route of Administration: Oral Duration of treatment: 12 weeks	440	54.1 (21-83)	64% male/ 36% female

Study #	Primary Endpoint(s)	Efficacy Results
502.202	Change from baseline in supine DBP at trough (24 hours post dosing) at last double-blind visit.	Intent-to-Treat Supine Blood Pressure Results Adjusted Mean Changes from Baseline (mmHg) Treatment N Systolic Diastolic Placebo 43 +3.5 -1.5 Telmisartan 40 mg 40 -10.0 * * * * -7.9 * * * Telmisartan 80 mg 41 -15.5 * * * * -8.7 * * * Telmisartan 120 mg 41 -12.5 * * * * -9.8 * * * * * * : p < 0.001 vs. Placebo * * *: p < 0.0001 vs. Placebo
502.203	Change from baseline in supine DBP at trough (24- hours post- dosing) at the last observation during the double-blind phase	Intent-to-Treat Analysis of the Change from Baseline in Supine Blood Pressure Adjusted 1 Mean Change (S.E.) (mmHg) Treatment N Diastolic Systolic (baseline = 102.4) (baseline = 151.2) Placebo 46 -0.4 (1.2) 3.2 (1.9) Telmisartan 20 mg 47 -6.9 (1.1) * * * * -3.3 (1.8) * Telmisartan 40 mg 47 -8.6 (1.2) * * * * -7.8 (1.9) * * * * Telmisartan 80 mg 44 -10.5 (1.2) * * * * -9.8 (1.9) * * * * Telmisartan 120 mg 45 -8.9 (1.2) * * * * -9.1 (1.9) * * * * Telmisartan 160 mg 44 -9.4 (1.2) * * * * -11.7 (2.0) * * * * 1 Based on a model with the effects of baseline blood pressure, center, treatment and treatment- by-center interaction. Legend for treatment comparison with placebo: : p < 0.05 (two-sided test) * * *: p < 0.0001
502.206	Change from baseline in supine DBP and SBP at trough (24 hours post- dosing) at the last observation during the double-blind phase.	Intent-to-Treat Analysis of the Change from Baseline in Supine Blood Pressure at Trough Adjusted 1 Mean Changes (S.E.) (mmHg) Treatment N Diastolic Systolic (baseline = 100.4) (baseline = 153.9) Placebo 74 -1.8 (0.9) +0.8 (1.6) Telmisartan 40 mg 72 -9.3 (0.9) * * * * -11.6 (1.6) * * * *
Study #	Primary Endpoint(s)	Efficacy Results
		Telmisartan 80 mg 71 -9.7 (0.9) * * * * -11.8 (1.6) * * * * Telmisartan 120 mg 72 -8.8 (0.9) * * * * -10.0 (1.5) * * * * Telmisartan 160 mg 73 -8.6 (0.9) * * * * -11.9 (1.5) * * * * 1 Based on a model with the effects of baseline blood pressure, center, treatment and treatment-by- center interaction * * * *: p < 0.0001 Note: Significance of the treatment-by-center interaction was 0.5789 and 0.1557 for diastolic and systolic, respectively.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect		Talk with your doctor or pharmacist		Stop taking drug and call your doctor or pharmacist
Symptom / effect		Only if severe	In all cases
	Kidney disease/failure Liver disorder Syncope/ faintness		T T T
Not known	Allergic Reaction: swelling of the face, lips and/or tongue accompanied by difficulty breathing Dark brown urine Muscle pain Muscle wasting disease Muscle weakness Weakness	T	T T T	T T T

PART I: HEALTH PROFESSIONAL INFORMATION 3