Telmisartan and Amlodipine

Telmisartan and amlodipine tablet is an angiotensin II receptor blocker (ARB) and a dihydropyridine calcium channel blocker (DHP-CCB) combination product indicated for the treatment of hypertension alone or with other antihypertensive agents to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1 ) Telmisartan and amlodipine tablets are indicated as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals ( 1 ) Telmisartan and amlodipine tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents 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 angiotensin II receptor blockers and dihydropyridine calcium channel blockers. There are no controlled trials demonstrating risk reduction with telmisartan and amlodipine tablets. 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. Telmisartan and amlodipine tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. Base the choice of telmisartan and amlodipine tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of telmisartan and amlodipine tablets. Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use telmisartan and amlodipine tablets as initial therapy. Individual blood pressure goals may vary based upon the patient's risk. Data from an 8-week, placebo-controlled, multidose, factorial trial provide estimates of the probability of reaching a blood pressure goal with telmisartan and amlodipine tablets compared to telmisartan or amlodipine monotherapy and placebo [see CLINICAL STUDIES ( 14.1 )]. The figures below provide estimates of the likelihood of achieving systolic and diastolic blood pressure control with telmisartan and amlodipine tablets 80/10 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. Figure 1a: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 Figure 1b: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8 Figure 2a: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 Figure 2b: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8 The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal at 8 weeks. For example, a patient with a baseline blood pressure of 160/110 mmHg has about a 16% likelihood of achieving a goal of <140 mmHg (systolic) and 16% likelihood of achieving <90 mmHg (diastolic) on placebo. The likelihood of achieving these same goals on telmisartan is about 46% (systolic) and 26% (diastolic). The likelihood of achieving these same goals on amlodipine is about 69% (systolic) and 22% (diastolic). These likelihoods rise to 79% for systolic and 55% for diastolic with telmisartan and amlodipine tablets. a fig 2 fig 3 fig4

Tablets: 40/5 mg, 40/10 mg, 80/5 mg, 80/10 mg ( 3 ) Telmisartan and amlodipine tablets USP are formulated for oral administration in the following strength combinations: 40 mg/5 mg Oval shaped, biconvex, bilayer, uncoated tablets where Amlodipine layer is white but may have yellow specks, debossed with 'C54' and Telmisartan layer is yellow in colour but may have white specks, debossed with 'LU'. 40 mg/10 mg Oval shaped, biconvex, bilayer, uncoated tablets where Amlodipine layer is white but may have red specks, debossed with 'C55' and Telmisartan layer is red in colour but may have white specks, debossed with 'LU'. 80 mg/5 mg Capsule shaped, biconvex, bilayer, uncoated tablets where Amlodipine layer is white but may have red specks, debossed with 'C56' and Telmisartan layer is red in colour but may have white specks, debossed with 'LU'. 80 mg/10 mg Capsule shaped, biconvex, bilayer, uncoated tablet where Amlodipine layer is white but may have yellow specks, debossed with 'C57' and Telmisartan layer is yellow in colour but may have white specks, debossed with 'LU'.

Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine or any other component of this product ( 4 ) Do not co-administer aliskiren with telmisartan and amlodipine in patients with diabetes ( 4 ) Telmisartan and amlodipine tablets are contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine, or any other component of this product [see ADVERSE REACTIONS ( 6.2 )]. Do not co-administer aliskiren with telmisartan and amlodipine tablets in patients with diabetes [see DRUG INTERACTIONS ( 7.2 )].

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, particularly in patients with severe obstructive coronary artery disease ( 5.7 )

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 telmisartan and amlodipine tablets as soon as possible [see USE IN SPECIFIC POPULATIONS ( 8.1 )].

5.2 Hypotension 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.

5.3 Hyperkalemia 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.

5.4 Patients 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 )].

5.5 Renal 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 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 may be anticipated in patients treated with telmisartan [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 telmisartan 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) Telmisartan 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, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan 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 telmisartan and amlodipine and other agents that affect the RAS. Do not co-administer aliskiren with telmisartan and amlodipine in patients with diabetes. Avoid concomitant use of aliskiren with telmisartan and amlodipine in patients with renal impairment (GFR <60 mL/min /1.73 m 2 ).

5.7 Risk of Myocardial Infarction or Increased Angina Amlodipine 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.

5.8 Heart Failure Amlodipine Closely monitor patients with heart failure. Amlodipine (5 to10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8 to12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. In the PRAISE-2 study, 1654 patients with NYHA class III (80%) or IV (20%) heart failure without evidence of underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis (99%), and diuretics (99%) were randomized 1:1 to receive placebo or amlodipine and followed for a mean of 33 months. While there was no statistically significant difference between amlodipine and placebo in the primary endpoint of all cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine), there were more reports of pulmonary edema in the patients on amlodipine.

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% vs 2.2%), and back pain (2.2% vs 0%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561, 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. 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 and at a higher incidence in telmisartan and amlodipine-treated patients (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3% 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 5 mg 10 mg 0% 0.7% 17.8% 0.8% 1.4% 6.2% 0.7% 2.1% 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 Telmisartan 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 telmisartan 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 >0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan 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 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 telmisartan 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 due to 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 due to 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 due to abnormal hepatic function. Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (n=1730) in doses up to 10 mg to placebo (n=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and was not significantly different from that seen in placebo-treated patients (about 1%). The most common side effects were headache and edema. The incidence (%) of side effects which occurred in a dose-related manner are presented in Table 3. […]

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 in patients with diabetes ( 7.2 )

7.1 Drug 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:

7.2 Drug 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.

7.3 Drug 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 multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily. Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporin and tacrolimus and dose adjustment when appropriate is recommended. The following have no clinically relevant effects on the pharmacokinetics of amlodipine: cimetidine, grapefruit juice, magnesium and aluminum hydroxide antacid, sildenafil. Amlodipine has no clinically relevant effects on the pharmacokinetics or pharmacodynamics of the following: atorvastatin, digoxin, warfarin. CYP3A4 Inhibitors Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors. CYP3A4 Inducers No information is available on the quantitative effects of CYP3A4 inducers ( e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampicin, St. John's Wort) on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers.

Patients ≥75 years of age or hepatically impaired patients: Start with amlodipine or add amlodipine 2.5 mg to telmisartan ( 2.5 , 8.5 , 8.6 ) Lactation: Do not breastfeed during treatment with telmisartan and amlodipine tablets ( 8.2 )

8.1 Pregnancy Risk Summary Telmisartan and amlodipine tablets can cause fetal harm when administered to a pregnant woman. 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 (see Clinical Considerations) . 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. Studies in rats and rabbits with telmisartan showed fetotoxicity only at maternally toxic doses (see Data) . In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times the maximum recommended human dose (MRHD), respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose ( see Data ). When pregnancy is detected, discontinue telmisartan and amlodipine tablets as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal adverse reactions: Use of drugs that act on the RAS in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. 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. In patients taking telmisartan and amlodipine tablets during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue telmisartan and amlodipine tablets, unless it is considered lifesaving for the mother. 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 telmisartan and amlodipine tablets for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, support 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 [see USE IN SPECIFIC POPULATIONS ( 8.4 )] . Data Animal Data: No reproductive toxicity studies have been conducted with the combination of telmisartan and amlodipine besylate. However, these studies have been conducted for telmisartan and amlodipine besylate alone. Telmisartan: 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. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m 2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m 2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m 2 basis, the maximum recommended human dose of telmisartan (80 mg/day). Amlodipine: No evidence of teratogenicity or embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

8.2 Lactation Risk Summary There is no information regarding the presence of telmisartan and amlodipine tablets or telmisartan in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that amlodipine is present in human milk. However, there is insufficient information to determine the effects of amlodipine on the breastfed infant. There is no available information on the effects of amlodipine on milk production. Telmisartan is present in the milk of lactating rats (see Data) . Because of the potential for serious adverse reactions in the breastfed infant including hypotension, hyperkalemia and renal impairment, advise a nursing woman not to breastfeed during treatment with telmisartan and amlodipine tablets. Data: Telmisartan was present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration.

8.4 Pediatric Use Safety and effectiveness of telmisartan and amlodipine tablets in pediatric patients have not been established. Neonates with a history of in utero exposure to telmisartan and amlodipine If oliguria or hypotension occurs, support 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.

8.5 Geriatric Use Telmisartan and Amlodipine Tablets Of the total number of 3282 hypertensive patients receiving a telmisartan/amlodipine combination in clinical studies, 605 (18%) patients were 65 years of age or older and of these, 88 (3%) patients were 75 years and older. No overall differences in efficacy or safety of telmisartan and amlodipine tablets were observed in this patient population. Telmisartan Of the total number of patients receiving telmisartan in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years and 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. […]

Telmisartan Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT 1 receptor than for the AT 2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure. Amlodipine Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.