WARNING: FETAL TOXICITY When pregnancy is detected, discontinue MICARDIS as soon as possible [see Warnings and Precautions (5.1)] . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)]. WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue MICARDIS as soon as possible (5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1)
|Warnings and Precautions || |
| || Dual Blockade of the Renin-Angiotensin-Aldosterone System (5.6) ||12/2014 |
1 INDICATIONS AND USAGE 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. It 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)] .
| 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 |
3 DOSAGE FORMS AND STRENGTHS 20 mg, white or off-white, round, uncoated tablets imprinted with BI logo on one side and 50 H on the other side 40 mg, white or off-white, oblong, uncoated tablets imprinted with BI logo on one side and 51 H on the other side 80 mg, white or off-white, oblong, uncoated tablets imprinted with BI logo on one side and 52 H 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 Pregnancy Category D 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 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) S542-6257 or (800) 459-9906 TTY, 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 Telmisartan n=1455 % Placebo n=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 listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS. The most frequent spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome). Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.
7 DRUG INTERACTIONS Aliskiren: Do not co-administer aliskiren with MICARDIS in patients with diabetes. Avoid use of aliskiren with MICARDIS in patients with renal impairment (GFR <60 mL/min). Digoxin : When MICARDIS was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range. Lithium : Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including MICARDIS. Therefore, monitor serum lithium levels during concomitant use. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors. Ramipril and Ramiprilat : Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of MICARDIS and ramipril is not recommended. Other Drugs : Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19. NSAIDS: Increased risk of renal impairment and loss of anti-hypertensive effect (7) Do not co-administer aliskiren with MICARDIS in patients with diabetes (7)
8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Choose to discontinue nursing or drug (8.3) Geriatric Patients: No overall difference in efficacy or safety vs younger patients, but greater sensitivity of some older individuals cannot be ruled out (8.5) 8.1 Pregnancy Pregnancy Category D. [See Warnings and Precautions (5.1)] . 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. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue MICARDIS, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to MICARDIS for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)] . 8.3 Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Neonates with a history of in utero exposure to MICARDIS: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology (12.3)] . 8.5 Geriatric Use Of the total number of patients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Of the total number of patients receiving MICARDIS in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency [see Warnings and Precautions (5.4)] .