Micardis (telmisartan 80 mg) Dailymed

MICARDIS is an angiotensin II receptor blocker (ARB) indicated for:

• Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (1.1)
• Cardiovascular (CV) risk reduction in patients unable to take ACE inhibitors (1.2)

1.1 Hypertension

MICARDIS is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
MICARDIS may be used alone or in combination with other antihypertensive agents [see Clinical Studies (14.1)] .

1.2 Cardiovascular Risk Reduction

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 the possibility that telmisartan 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)] .

2 Dosage And Administration

• May be administered with or without food (2.1)
• When used for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary (2.2)

Indication	Starting Dose	Dose Range
Hypertension (2.1)	40 mg once daily	40 to 80 mg once daily
Cardiovascular Risk Reduction (2.2)	80 mg once daily	80 mg once daily

2.1 Hypertension

Dosage must be individualized.  The usual starting dose of MICARDIS tablets is 40 mg orally 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.
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.

2.2 Cardiovascular Risk Reduction

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.

3 Dosage Forms And Strengths

• 20 mg, white or off-white, round, uncoated tablets imprinted with BI logo on one side and "50H" on the other side
• 40 mg, white or off-white, oblong, uncoated tablets imprinted with BI logo on one side and "51H" on the other side
• 80 mg, white or off-white, oblong, uncoated tablets imprinted with BI logo on one side and "52H" on the other side

• Tablets: 20 mg, 40 mg, 80 mg (3)

4 Contraindications

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)] .
Do not co-administer aliskiren with MICARDIS in patients with diabetes [see Drug Interactions (7)].

• Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product (4)
• Do not co-administer aliskiren with MICARDIS in patients with diabetes (4)

5 Warnings And Precautions

• Avoid fetal or neonatal exposure (5.1)
• Hypotension: Correct any volume or salt depletion before initiating therapy.  Observe for signs and symptoms of hypotension. (5.2)
• Monitor carefully in patients with impaired hepatic (5.4) or renal function (5.5)
• Avoid concomitant use of an ACE inhibitor and angiotensin receptor blocker (5.6)

5.1 Fetal Toxicity

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue MICARDIS as soon as possible [see Use in Specific Populations (8.1)] .

5.2 Hypotension

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.

5.3 Hyperkalemia

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.

5.4 Impaired Hepatic Function

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)] .

5.5 Impaired Renal Function

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.

5.6 Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAS)

Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
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., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone.
In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on MICARDIS and other agents that affect the RAS.
Do not co-administer aliskiren with MICARDIS in patients with diabetes. Avoid concomitant use of aliskiren with MICARDIS in patients with renal impairment (GFR <60 mL/min/1.73 m²).

6 Adverse Reactions

The following adverse reaction is described elsewhere in labeling:

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

• Hypertension:  The most common adverse events (≥1%) reported in hypertension trials are back pain, sinusitis, and diarrhea (6.1)
• Cardiovascular risk reduction:  The serious adverse events (≥1%) reported in cardiovascular risk reduction trials were intermittent claudication and skin ulcer (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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 evaluated 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

Â	Telmisartann=1455%	Placebon=380%
Upper respiratory tract infection	7	6
Back pain	3	1
Sinusitis	3	2
Diarrhea	3	2
Pharyngitis	1	0

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group:  influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.
The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.
The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%).
In addition to those uled above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are uled below.  It cannot be determined whether these 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, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; 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 angioedema was reported (among a total of 3781 patients treated).
Clinical Laboratory Findings
In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets.
Hemoglobin:  A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients.  No patients discontinued therapy because of anemia.
Creatinine:  A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients.  One telmisartan-treated patient discontinued therapy because of increases in creatinine and blood urea nitrogen.
Liver Enzymes:  Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo.  No telmisartan-treated patients discontinued therapy because of abnormal hepatic function.
Cardiovascular Risk Reduction
Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).

6.2 Postmarketing Experience

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.

Blood and Lymphatic System Disorders: Anemia, eosinophilia, thrombocytopenia Gastrointestinal Disorders: Abdominal pain, diarrhea, dyspepsia, nausea General Disorders and Administration Site Conditions: Asthenia, chest pain, edema, face edema, fatigue, lower limb edema, pain, weakness Hepato-biliary: Abnormal hepatic function/liver disorder Immune System Disorders: Anaphylactic reaction, hypersensitivity Investigations: Increased CPK, uric acid increased Metabolism and Nutrition Disorders: Hyperkalemia, hypoglycemia (in diabetic patients), hyponatremia Musculoskeletal and Connective Tissue Disorders: Myalgia Nervous System Disorders: Dizziness, headache, syncope Renal and Urinary Disorders: Renal impairment including acute renal failure Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Coughing Skin and Subcutaneous Tissue Disorders: Angioedema (with fatal outcome), angioneurotic edema, drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), erythema, sweating increased, urticaria Vascular Disorder: Hypotension (including postural hypotension)
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.