Telmisartan and Amlodipine

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% 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. Table 3: Incidence (%) of Dose-Related Adverse Effects with Amlodipine at Doses of 2.5 mg, 5.0 mg, and 10.0 mg or Placebo Header Adverse Event Amlodipine 2.5 mg n=275 % Amlodipine 5.0 mg n=296 % Amlodipine 10.0 mg n=268 % Placebo n=520 % Edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitations 0.7 1.4 4.5 0.6 Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1% in placebo-controlled clinical trials are presented in Table 4. Table 4: Incidence (%) of Adverse Effects Not Clearly Dose Related but Reported at an Incidence of >1% in Placebo-Controlled Clinical Trials Adverse Event Amlodipine n = 1730 % Placebo n = 1250 % Headache 7.3 7.8 Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal pain 1.6 0.3 Somnolence 1.4 0.6 The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis Central and Peripheral Nervous System: Hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo Gastrointestinal: Anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia, change of bowel habit General: Allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease Musculoskeletal System: Arthralgia, arthrosis, muscle cramps,** myalgia Psychiatric: Sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization, mood change Respiratory System: Dyspnea,** epistaxis Skin and Appendages: Angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular Special Senses: Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus Urinary System: Micturition frequency, micturition disorder, nocturia Autonomic Nervous System: Dry mouth, sweating increased Metabolic and Nutritional: Hyperglycemia, thirst Hemopoietic: Leukopenia, purpura, thrombocytopenia. **These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina. Amlodipine has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles. Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc ® . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of telmisartan or amlodipine. 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 telmisartan or amlodipine. Telmisartan The most frequently 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, and increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (e.g. 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 telmisartan. Amlodipine Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

4 CONTRAINDICATIONS 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 )].

11 DESCRIPTION Telmisartan and amlodipine tablet USP is a fixed dose combination of telmisartan and amlodipine. Telmisartan and amlodipine tablets USP contain telmisartan, a non-peptide angiotensin II receptor (type AT 1 ) antagonist. Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base. Telmisartan is chemically described as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C 33 H 30 N 4 O 2 and its structural formula is: Telmisartan and amlodipine tablets USP contain the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate's chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Its empirical formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S and its structural formula is: Telmisartan and amlodipine tablets USP are formulated in four strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 40 mg, or 80 mg of telmisartan provided in the following four combinations: 40/5 mg, 40/10 mg, 80/5 mg, and 80/10 mg. Telmisartan and amlodipine tablets USP also contain the following inactive ingredients: colloidal silicon dioxide, crosscarmellose sodium, ferric oxide red, ferric oxide yellow, mannitol, magnesium stearate, povidone, sodium hydroxide and sodium starch glycolate. Telmisartan and amlodipine tablets USP are hygroscopic and require protection from moisture. Telmisartan and amlodipine tablets USP require protection from light. t am

2 DOSAGE AND ADMINISTRATION Substitute telmisartan and amlodipine tablets for its individually titrated components for patients on amlodipine and telmisartan. Telmisartan and amlodipine tablets may also be given with increased amounts of amlodipine, telmisartan, or both, as needed. ( 2.2 , 2.3 ) Use telmisartan and amlodipine tablets to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with telmisartan (or another angiotensin receptor blocker) alone ( 2.3 ) Dosage may be increased after at least 2 weeks to a maximum dose of 80/10 mg once daily, usually by increasing one component at a time but both components can be raised to achieve more rapid control ( 2.1 , 2.2 ) Majority of antihypertensive effect is attained within 2 weeks ( 2.1 ) Initiate with 40/5 mg or 80/5 mg once daily ( 2.4 ) Switch patients who experience dose-limiting adverse reactions on amlodipine to telmisartan and amlodipine tablets containing a lower dose of that component ( 2.3 ) 2.1 General Considerations Telmisartan is an effective treatment of hypertension in once daily doses of 20 to 80 mg while amlodipine is effective in doses of 2.5 to 10 mg. Dosage must be individualized and may be increased after at least 2 weeks. Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. The maximum recommended dose of telmisartan and amlodipine tablets is 80/10 mg once daily. The adverse reactions of telmisartan are uncommon and independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter [see ADVERSE REACTIONS ( 6.1 )]. Telmisartan and amlodipine tablets may be taken with or without food. 2.2 Replacement Therapy Patients receiving amlodipine and telmisartan from separate tablets may instead receive telmisartan and amlodipine tablets containing the same component doses once daily. When substituting for individual components, increase the dose of telmisartan and amlodipine tablets if blood pressure control has not been satisfactory. 2.3 Add-on Therapy for Patients with Hypertension Not Adequately Controlled on Antihypertensive Monotherapy Telmisartan and amlodipine tablets may be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with telmisartan (or another angiotensin receptor blocker) alone. Patients treated with 10 mg amlodipine who experience any dose-limiting adverse reactions such as edema, may be switched to telmisartan and amlodipine tablets 40/5 mg once daily, reducing the dose of amlodipine without reducing the overall expected antihypertensive response [see ADVERSE REACTIONS ( 6.1 )]. 2.4 Initial Therapy A patient may be initiated on telmisartan and amlodipine tablets if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose of telmisartan and amlodipine tablet is 40/5 mg once daily. Patients requiring larger blood pressure reductions may be started on telmisartan and amlodipine tablet 80/5 mg once daily. Initial therapy with telmisartan and amlodipine tablet is not recommended in patients ≥75 years old or with hepatic impairment [see DOSAGE AND ADMINISTRATION ( 2.5 ), WARNINGS AND PRECAUTIONS ( 5.4 ) , and USE IN SPECIFIC POPULATIONS ( 8.5 , 8.6 )]. Correct imbalances of intravascular volume- or salt-depletion, before initiating therapy with telmisartan and amlodipine tablets [see WARNINGS AND PRECAUTIONS ( 5.2 )]. 2.5 Dosing in Specific Populations Renal Impairment No initial dosage adjustment is required for patients with mild or moderate renal impairment. Titrate slowly in patients with severe renal impairment. Hepatic Impairment In most patients, initiate amlodipine therapy at 2.5 mg. Titrate slowly in patients with hepatic impairment. Patients 75 Years of Age and Older In most patients, initiate amlodipine therapy at 2.5 mg. Titrate slowly in patients 75 years of age and older.

1 INDICATIONS AND USAGE 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

10 OVERDOSAGE Telmisartan Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan tablets would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. Amlodipine Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

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 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics Telmisartan and Amlodipine Tablets Telmisartan and amlodipine tablets have been shown to be effective in lowering blood pressure. Telmisartan and amlodipine tablet is a combination of two drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, telmisartan. Both telmisartan and amlodipine lower blood pressure by reducing peripheral resistance but through complementary mechanisms. Telmisartan In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours. Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid). In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance. Telmisartan has indications other than hypertension which can be found in the Micardis ® (telmisartan) tablets package insert. Amlodipine Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina. With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg). In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria. As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks. Amlodipine has indications other than hypertension which can be found in the Norvasc ® package insert. 12.3 Pharmacokinetics Telmisartan and Amlodipine Tablets The pharmacokinetics of amlodipine and telmisartan when combined are similar to the pharmacokinetics of amlodipine and telmisartan when administered separately. After administering telmisartan and amlodipine tablets 80/10 mg with a high-fat meal, the total area under the plasma concentration-time curve (AUC) and C max for telmisartan decreased by about 24% and 60%, respectively. For amlodipine, AUC and C max were not altered [see DOSAGE AND ADMINISTRATION ( 2.1 )]. Telmisartan Following oral administration, peak concentrations (C max ) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (C max and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing. Amlodipine Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Distribution Telmisartan: Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α 1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding. Amlodipine: The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. Metabolism and Elimination Telmisartan: Following either intravenous or oral administration of 14 C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively). Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose. Amlodipine: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Specific Populations Renal Insufficiency: Telmisartan No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see WARNINGS AND PRECAUTIONS ( 5.5 )]. Amlodipine The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Hepatic Insufficiency: Telmisartan In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see WARNINGS AND PRECAUTIONS ( 5.4 ) and USE IN SPECIFIC POPULATIONS ( 8.6 )]. Amlodipine Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine. Gender: Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. Geriatric Patients: Telmisartan The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see DOSAGE AND ADMINISTRATION ( 2.1 )]. Amlodipine Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine [see DOSAGE AND ADMINISTRATION ( 2.5 )]. Drug Interaction Studies Telmisartan: 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, 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. 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.

12.1 Mechanism of Action 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.

12.2 Pharmacodynamics Telmisartan and Amlodipine Tablets Telmisartan and amlodipine tablets have been shown to be effective in lowering blood pressure. Telmisartan and amlodipine tablet is a combination of two drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, telmisartan. Both telmisartan and amlodipine lower blood pressure by reducing peripheral resistance but through complementary mechanisms. Telmisartan In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours. Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid). In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance. Telmisartan has indications other than hypertension which can be found in the Micardis ® (telmisartan) tablets package insert. Amlodipine Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina. With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg). In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria. As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks. Amlodipine has indications other than hypertension which can be found in the Norvasc ® package insert.

12.3 Pharmacokinetics Telmisartan and Amlodipine Tablets The pharmacokinetics of amlodipine and telmisartan when combined are similar to the pharmacokinetics of amlodipine and telmisartan when administered separately. After administering telmisartan and amlodipine tablets 80/10 mg with a high-fat meal, the total area under the plasma concentration-time curve (AUC) and C max for telmisartan decreased by about 24% and 60%, respectively. For amlodipine, AUC and C max were not altered [see DOSAGE AND ADMINISTRATION ( 2.1 )]. Telmisartan Following oral administration, peak concentrations (C max ) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (C max and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing. Amlodipine Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Distribution Telmisartan: Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α 1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding. Amlodipine: The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. Metabolism and Elimination Telmisartan: Following either intravenous or oral administration of 14 C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively). Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose. Amlodipine: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Specific Populations Renal Insufficiency: Telmisartan No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see WARNINGS AND PRECAUTIONS ( 5.5 )]. Amlodipine The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Hepatic Insufficiency: Telmisartan In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see WARNINGS AND PRECAUTIONS ( 5.4 ) and USE IN SPECIFIC POPULATIONS ( 8.6 )]. Amlodipine Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine. Gender: Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. Geriatric Patients: Telmisartan The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see DOSAGE AND ADMINISTRATION ( 2.1 )]. Amlodipine Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine [see DOSAGE AND ADMINISTRATION ( 2.5 )]. Drug Interaction Studies Telmisartan: 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, 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. 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.

20231215

10

3 DOSAGE FORMS AND STRENGTHS 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'.

Telmisartan and Amlodipine Telmisartan and Amlodipine TELMISARTAN TELMISARTAN AMLODIPINE BESYLATE AMLODIPINE CROSCARMELLOSE SODIUM FERRIC OXIDE RED FERRIC OXIDE YELLOW MAGNESIUM STEARATE MANNITOL POVIDONE SILICON DIOXIDE SODIUM HYDROXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO White-yellow Layer oval LU;C54 Telmisartan and Amlodipine Telmisartan and Amlodipine TELMISARTAN TELMISARTAN AMLODIPINE BESYLATE AMLODIPINE CROSCARMELLOSE SODIUM FERRIC OXIDE RED FERRIC OXIDE YELLOW MAGNESIUM STEARATE MANNITOL POVIDONE SILICON DIOXIDE SODIUM HYDROXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO White-red specks and Red Layers oval LU;C55 Telmisartan and Amlodipine Telmisartan and Amlodipine TELMISARTAN TELMISARTAN AMLODIPINE BESYLATE AMLODIPINE CROSCARMELLOSE SODIUM FERRIC OXIDE RED FERRIC OXIDE YELLOW MAGNESIUM STEARATE MANNITOL POVIDONE SILICON DIOXIDE SODIUM HYDROXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO White-red specks and Red Layers capsule LU;C56 Telmisartan and Amlodipine Telmisartan and Amlodipine TELMISARTAN TELMISARTAN AMLODIPINE BESYLATE AMLODIPINE CROSCARMELLOSE SODIUM FERRIC OXIDE RED FERRIC OXIDE YELLOW MAGNESIUM STEARATE MANNITOL POVIDONE SILICON DIOXIDE SODIUM HYDROXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO White-yellow Layer capsule LU;C57

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Telmisartan There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m 2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m 2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Amlodipine Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m 2 basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m 2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.) Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m 2 basis).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Telmisartan There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m 2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m 2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Amlodipine Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m 2 basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m 2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.) Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m 2 basis).

ANDA201586

Telmisartan and Amlodipine

Telmisartan and Amlodipine

68180-196

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL TELMISARTAN AND AMLODIPINE TABLETS Rx Only 40 mg/5 mg NDC 68180-196-06 A Bottle of 30 tablets TELMISARTAN AND AMLODIPINE TABLETS Rx Only 40 mg/10 mg NDC 68180-197-06 A Bottle of 30 tablets TELMISARTAN AND AMLODIPINE TABLETS Rx Only 80 mg/5 mg NDC 68180-198-06 A Bottle of 30 tablets TELMISARTAN AND AMLODIPINE TABLETS Rx Only 80 mg/10 mg NDC 68180-199-06 A Bottle of 30 tablets p 2 c g

® The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Goa 403 722 INDIA Revised: April 2019 ID#: 258261

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Pregnancy Advise female patients of childbearing age about the consequences of exposure to telmisartan and amlodipine tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients should be asked to report pregnancies to their physicians as soon as possible [see WARNINGS AND PRECAUTIONS ( 5.1 ) and USE IN SPECIFIC POPULATIONS ( 8.1 )]. Lactation Advise nursing women not to breastfeed during treatment with telmisartan and amlodipine tablets [see USE IN SPECIFIC POPULATIONS ( 8.2 )]. Symptomatic Hypotension Advise patients that lightheadedness can occur, especially during the first days of therapy, and to report it to their healthcare provider. Inform patients that inadequate.fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible.syncope. Advise patients to contact their healthcare provider if syncope occurs [see WARNINGS AND PRECAUTIONS ( 5.2 )] .

14 CLINICAL STUDIES 14.1 Telmisartan and Amlodipine Tablets The efficacy of telmisartan and amlodipine tablets for treatment of hypertension was studied in 1 placebo-controlled and 2 active-controlled trials. An 8-week multicenter, randomized, double-blind, placebo-controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with telmisartan and amlodipine tablet was more effective in reducing blood pressure compared to the respective monotherapies. The study randomized 1461 patients with baseline systolic blood pressure between 117 and 179 mmHg (mean 153 mmHg) and a baseline diastolic blood pressure between 90 and 119 (mean 102 mmHg) to one of the 16 treatment arms. Patients assigned to receive amlodipine 10 mg started on amlodipine 5 mg or combinations thereof for the first two weeks. The four key treatment combinations (including combinations of telmisartan 40 or 80 mg and amlodipine 5 or 10 mg) had statistically significant reduction in in-clinic seated trough cuff systolic and diastolic blood pressure compared to the respective individual monotherapies (Table 5). Table 5: Placebo-Subtracted Mean Change from Baseline in Seated Systolic/Diastolic Blood Pressure (mmHg): Combination Therapy vs Monotherapy Components Header$ Amlodipine, mg Telmisartan, mg 0 40 80 0 — -12.1/-7.2 -11.8/-7.8 5 -12.9/-7.2 -19.3/-10.3 -19.6/-12.0 10 -18.2/-10.9 -22.2/-14.0 -23.9/-13.9 The majority of the antihypertensive effect of the telmisartan/amlodipine combination was attained within 2 weeks after initiation of therapy. In patients receiving a telmisartan/amlodipine combination significantly larger reductions in seated diastolic and systolic blood pressure compared to patients treated with the respective monotherapies were observed at every assessment (Week 2, 4, 6, and 8). The antihypertensive effect of telmisartan and amlodipine tablets was similar in patients ≥65 years than below 65 years of age, in male and female patients, and in patients with and without diabetes. The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients). Automated ambulatory blood pressure monitoring (ABPM) performed in a subset of 562 patients confirmed the results seen with in-clinic systolic and diastolic blood pressure reductions over the entire 24-hour dosing period. In a double-blind, active-controlled study, a total of 1097 patients with mild to severe hypertension (mean baseline systolic/diastolic BP 149.5/96.6 mmHg) who were not adequately controlled on amlodipine 5 mg received telmisartan and amlodipine (40/5 mg or 80/5 mg) or amlodipine alone (5 mg or 10 mg). After 8 weeks administration, each of the combination treatments was statistically significantly superior to both amlodipine monotherapy doses in reducing diastolic and systolic blood pressures. Edema related events (peripheral edema, generalized edema, and edema) in patients who received telmisartan and amlodipine (40/5 mg or 80/5 mg) were significantly lower as compared to patients who received amlodipine 10 mg (4.3% vs 27.2%, respectively). Table 6: Effect on Seated Systolic/Diastolic Blood Pressure: Combination Therapy vs Monotherapy 1 p<0.05 2 Mean change from baseline at Week 8 in seated systolic/diastolic blood pressure Header$ Treatment Group Mean Change 2 Difference from amlodipine 5 mg Difference from amlodipine 10 mg Telmisartan and amlodipine 40/5 mg; n=270 -13.6 / -9.4 -7.4 1 / - 3.6 1 -2.4 1 / -1.4 1 Telmisartan and amlodipine 80/5 mg; n=271 -15.0 / -10.6 -8.8 1 / -4.9 1 -3.9 1 / -2.7 1 Amlodipine 5 mg; n=255 -6.2 / -5.7 ---- ---- Amlodipine 10 mg; n=261 -11.1 / -8.0 ---- ---- In a second double-blind, active-controlled study, a total of 947 patients with mild to severe hypertension (mean baseline systolic/diastolic BP 147.5/95.6 mmHg) who were not adequately controlled on amlodipine 10 mg received telmisartan and amlodipine (40/10 mg or 80/10 mg) or amlodipine alone (10 mg). After 8 weeks, each of the combination treatments was statistically significantly superior to amlodipine monotherapy in reducing diastolic and systolic blood pressures. Table 7: Effect on Seated Systolic/Diastolic Blood Pressure: Combination Therapy vs Monotherapy Treatment Group Mean Change Mean change from baseline at Week 8 in seated systolic/diastolic blood pressure Difference from amlodipine 10 mg Telmisartan and amlodipine 40/10 mg; n=306 -11.1 / -9.2 -3.7 p<0.05 / -2.8 Telmisartan and amlodipine 80/10 mg; n=310 -11.3 / -9.3 -3.9 / -2.8 Amlodipine 10 mg; n=305 -7.4 / -6.5 ---- There are no trials of telmisartan and amlodipine demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. 14.2 Telmisartan The antihypertensive effects of telmisartan have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6 to 8/6 mmHg for 20 mg, 9 to 13/6 to 8 mmHg for 40 mg, and 12 to 13/7 to 8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure. Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with telmisartan tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors. In a controlled study, the addition of telmisartan to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to telmisartan. The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of telmisartan was 70% to 100% for both systolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%). There were no changes in the heart rate of patients treated with telmisartan in controlled trials. 14.3 Amlodipine The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours post-dose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect.

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. Amlodipine Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of telmisartan and amlodipine tablet is 40/5 mg; therefore, initial therapy with telmisartan and amlodipine tablets is not recommended in patients 75 years of age and older [see DOSAGE AND ADMINISTRATION ( 2.5 )].

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.

8.1 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 USE IN SPECIFIC POPULATIONS 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. Amlodipine Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of telmisartan and amlodipine tablet is 40/5 mg; therefore, initial therapy with telmisartan and amlodipine tablets is not recommended in patients 75 years of age and older [see DOSAGE AND ADMINISTRATION ( 2.5 )]. 8.6 Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency [see DOSAGE AND ADMINISTRATION ( 2 ) and WARNINGS AND PRECAUTIONS ( 5.4 )]. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. 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 DOSAGE AND ADMINISTRATION ( 2.4 )]. 8.7 Race The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).

16 HOW SUPPLIED/STORAGE AND HANDLING Telmisartan and amlodipine tablets USP are available as 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'. Telmisartan and amlodipine tablets USP are supplied for oral administration in the following strengths and package configurations: Tablet strength ( telmisartan / amlodipine besylate equivalent to amlodipine ) mg Package Configuration NDC # 40 mg/5 mg Bottles of 30 Bottles of 90 A box containing 100 Tablets (10 X 10 unit-dose) 68180-196-06 68180-196-09 68180-196-13 40 mg/10 mg Bottles of 30 Bottles of 90 A box containing 100 Tablets (10 X 10 unit-dose) 68180-197-06 68180-197-09 68180-197-13 80 mg/5 mg Bottles of 30 Bottles of 90 A box containing 100 Tablets (10 X 10 unit-dose) 68180-198-06 68180-198-09 68180-198-13 80 mg/10 mg Bottles of 30 Bottles of 90 A box containing 100 Tablets (10 X 10 unit-dose) 68180-199-06 68180-199-09 68180-199-13 Storage Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Do not remove from blisters until immediately before administration. Protect from moisture and light.

WARNING: FETAL TOXICITY WARNING: FATAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue telmisartan and amlodipine tablets as soon as possible ( 5.1 , 8.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus ( 5.1 , 8.1 ) When pregnancy is detected, discontinue telmisartan and amlodipine tablets as soon as possible [see WARNING AND PRECAUTIONS ( 5.1 ) and USE IN SPECIFIC POPULATIONS ( 8.1 )]. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see WARNING AND PRECAUTIONS ( 5.1 ) and USE IN SPECIFIC POPULATIONS ( 8.1 )] .