Telmisartan and Amlodipine 80 mg; 5 mg Tablet, 360-count

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. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis (5.2) Titrate slowly in patients with hepatic (5.4) or severe renal impairment (5.5) Heart failure: Monitor for worsening (5.8) Avoid concomitant use with an ACE inhibitor (5.6) Myocardial infarction: Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of telmisartan and amlodipine tablets, particularly in patients with severe obstructive coronary artery disease (5.7).

5.1Fetal Toxicity Pregnancy Category D Telmisartan 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 telmisartan and amlodipine tablets as soon as possible [see Use in Specific Populations (8.1)] .

5.2Hypotension Telmisartan 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 telmisartan and amlodipine tablets. Either correct this condition prior to administration of telmisartan and amlodipine tablets, or start treatment under close medical supervision with a reduced dose. If hypotension does occur, place the patient in the supine position and, if necessary, give 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. Amlodipine Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.3Hyperkalemia Telmisartan 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.

5.4Patients with Impaired Hepatic Function Telmisartan 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 Dosage and Administration (2.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)] . Amlodipine Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with impaired hepatic function.

Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine at 2.5 mg in patients with hepatic impairment. The lowest dose of telmisartan and amlodipine tablet is 40/5 mg; therefore, initial therapy with telmisartan and amlodipine tablet is not recommended in hepatically impaired patients [see Use in Specific Populations (8.6)] .

5.5Renal Function Impairment Telmisartan 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 wi…

6 ADVERSE REACTIONS In the placebo-controlled factorial design study, the most common reasons for discontinuation of therapy with telmisartan and amlodipine tablets were peripheral edema, dizziness, and hypotension, each leading to discontinuation of ≤0.5% of telmisartan and amlodipine tablets-treated patients. Adverse reactions that occurred at a ≥2% higher incidence on telmisartan and amlodipine tablets than placebo were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), and back pain (2.2% vs 0%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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. Telmisartan and amlodipine tablets The concomitant use of telmisartan and amlodipine has been evaluated for safety in more than 3700 patients with hypertension; approximately 1900 of these patients were exposed for at least 6 months and over 160 of these patients were exposed for at least one year.

Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In the placebo-controlled factorial design study, the population treated with a telmisartan and amlodipine combination had a mean age of 53 years and included approximately 50% males, 79% were Caucasian, 17% Blacks, and 4% Asians. Patients received doses ranging from 20/2.5 mg to 80/10 mg orally, once daily.

The frequency of adverse reactions was not related to gender, age, or race. The adverse reactions that occurred in the placebo-controlled factorial design trial in ≥2% of patients treated with telmisartan and amlodipine tablets and at a higher incidence in telmisartan and amlodipine tablets-treated patients (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), and back pain (2.2% vs 0%). Edema (other than peripheral edema), hypotension, and syncope were reported in <2% of patients treated with telmisartan and amlodipine tablets.

In the placebo-controlled factorial design trial, discontinuation due to adverse events occurred in 2.2% of all treatment cells of patients in the telmisartan/amlodipine-treated patients and in 4.3% in the placebo-treated group. The most common reasons for discontinuation of therapy with telmisartan and amlodipine tablets were peripheral edema, dizziness, and hypotension (each ≤0.5%). Peripheral edema is a known, dose-dependent adverse reaction of amlodipine, but not of telmisartan.

In the factorial design study, the incidence of peripheral edema during the 8 week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg. Table 1: Incidence of Peripheral Edema During the 8 Week Treatment Period Telmisartan Placebo 40 mg 80 mg Amlodipine Placebo 0% 0.8% 0.7% 5 mg 0.7% 1.4% 2.1% 10 mg 17.8% 6.2% 11.3% Telmisartan Telmisartan 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 only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20 to 160 mg) monotherapy for up to 12 weeks, an overall incidence of adverse events was similar to the patients treated with placebo. Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 2.

Table 2: Adverse Events Occurring at an Incidence of ≥1% in Patients Treated with T…

7 DRUG INTERACTIONS NSAIDS: Increased risk of renal impairment and loss of antihypertensive effect (7) If simvastatin is co-administered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin (7) Do not co-administer aliskiren with telmisartan and amlodipine tablets in patients with diabetes (7.2)

7.1Drug Interactions with Telmisartan and Amlodipine Tablets The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered. No drug interaction studies have been conducted with telmisartan and amlodipine tablets and other drugs, although studies have been conducted with the individual amlodipine and telmisartan components of telmisartan and amlodipine tablets, as described below:

7.2Drug Interactions with Telmisartan Aliskiren: Do not co-administer aliskiren with telmisartan and amlodipine tablets in patients with diabetes. Avoid use of aliskiren with telmisartan and amlodipine tablets in patients with renal impairment (GFR <60 mL/min). Digoxin: When telmisartan 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 telmisartan. 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 C max and AUC of ramipril 2.3- and 2.1-fold, respectively, and C max and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C max 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. Co-administration of telmisartan 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.

7.3Drug Interactions with Amlodipine In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs. Simvastatin: Co-administration of multi…