Telmisartan, Amlodipine And Indapamide

1 INDICATIONS AND USAGE Widaplik (telmisartan/amlodipine/indapamide) is indicated for the treatment of hypertension in adult patients, to lower blood pressure. Widaplik may be used as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals. 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, dihydropyridine calcium channel blockers and thiazide-like diuretics. There are no controlled trials demonstrating risk reduction with Widaplik. 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. 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 the goal with a triple combination product compared with mono- or dual therapy when deciding whether to use Widaplik as initial therapy. Individual blood pressure goals may vary based upon the patient’s risk. WIDAPLIK is a combination tablet of telmisartan, an angiotensin II receptor blocker, amlodipine, a dihydropyridine calcium channel blocker and indapamide, a thiazide-like diuretic. Widaplik is indicated for the treatment of hypertension, including as initial treatment, to lower blood pressure. ( 1 ) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1 )

2 DOSAGE AND ADMINISTRATION For initial treatment of hypertension, start with Widaplik (10 mg/ 1.25 mg/0.625 mg) or Widaplik (20 mg/2.5 mg/1.25 mg) orally once daily. Titrate up to a maximum dose of Widaplik (40 mg/5 mg/2.5 mg) orally once daily. ( 2.2 ) Dosage may be increased after 2 weeks to a maximum dose of 40 mg/5 mg/2.5 mg orally once daily to achieve more rapid control. ( 2.1 ) Almost all of the antihypertensive effect is apparent within 2 weeks of initiating treatment. ( 2.1 ) 2.1 General Considerations Dose orally once daily. Dosage must be individualized and may be increased after 2 weeks of treatment. Almost all the antihypertensive effect is apparent within 2 weeks of initiating treatment. Swallow tablets whole. Do not cut, crush, or chew tablets. Widaplik may be taken with or without food. Correct imbalances of intravascular volume- or salt-depletion, before initiating therapy with Widaplik [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage The recommended starting dosage is with Widaplik (10 mg/1.25 mg/0.625 mg) orally once daily or Widaplik (20 mg/2.5 mg/1.25 mg) orally once daily, based on anticipated need for blood pressure reduction. In elderly patients consider starting with Widaplik (10 mg/1.25 mg/0.625 mg) orally once daily [see Use in Specific Populations, Geriatric Use ( 8.5 )]. The maximum recommended dose is Widaplik (40 mg/5 mg/2.5 mg) orally once daily.

6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: • Fetal toxicity [see Warnings and Precautions ( 5.1 )] • Hypotension [see Warnings and Precautions ( 5.2 )] • Electrolyte and Glucose Imbalances [see Warnings and Precautions ( 5.3 )] • Impaired Renal Function [see Warnings and Precautions ( 5.4 )] • Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion [see Warnings and Precautions ( 5.5 )] • Hyperuricemia [see Warnings and Precautions ( 5.6 )] The most common adverse reaction is symptomatic hypotension. Low sodium and potassium values were recorded more often with Widaplik compared to placebo ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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 clinical practice. Widaplik Safety data were obtained from two randomized controlled studies that included 1,680 randomized patients with hypertension of whom 782 received Widaplik. Given the well-established safety profiles of the component medicines, only serious adverse events and the following adverse events of special interest were recorded: symptomatic hypotension, abnormal laboratory findings (sodium, potassium, uric acid, glucose, lipids, creatinine, eGFR), headache, peripheral edema, or other reason for discontinuation of study medication. Study 1 In Study 1 (NCT04518306), 295 adult patients who were not receiving antihypertensive treatment for two weeks with baseline home systolic blood pressure 130-154 mmHg were randomized in a 2:2:1 ratio to Widaplik (10 mg/1.25 mg/0.625 mg), Widaplik (20 mg/2.5 mg/1.25 mg), or placebo. The study was 4 weeks in duration and randomized 232 patients to Widaplik and 63 to placebo. The proportion of patients who discontinued study medication due to an adverse event was 0% for Widaplik (10 mg/1.25 mg/0.625 mg), 5.1% for Widaplik (20 mg/2.5 mg/1.25 mg), and 1.6% for placebo. Symptomatic hypotension, hyponatremia, and hypokalemia were more common with Widaplik than placebo (see Table 1). Most cases were mild to moderate in severity. Table 1: Adverse Reactions Reported in >2% of Patients Treated with Widaplik during the 4-Week Placebo-Controlled Treatment Period of Study 1 Widaplik (10 mg/1.25 mg/0.625 mg) (n=113) Widaplik (20 mg/2.5 mg/1.25 mg) (n=118) Placebo (n=62) Symptomatic hypotension n (%) 4 (3.5%) 6 (5.1%) 0 (0%) Sodium <135 mmol/L at week 4, n (%) 4 (3.5%) 1 (0.8%) 0 (0%) Potassium <3.5 mmol/L at week 4, n (%) 4 (3.5%) 6 (5.1%) 1 (1.6%) Study 2 Study 2 (NCT04518293) enrolled 2,242 patients on 0-3 antihypertensive medications at the screening visit. After a 4-week active run-in period during which all patients were initially switched to Widaplik (20 mg/2.5 mg/1.25 mg), patients then entered a double-blind period where they were randomized 2:1:1:1 to either continue on Widaplik (20 mg/2.5 mg/1.25 mg) or switch to telmisartan/amlodipine (TA) 20 mg/2.5 mg, telmisartan/indapamide (TI) 20 mg/1.25 mg, or amlodipine/indapamide (AI) 2.5 mg/1.25 mg. After 6 weeks in the double-blind period, doses were doubled in all treatment groups and treatment was continued for an additional 6 weeks. The study randomized 551 patients to Widaplik and 834 to one of the two-drug combinations. During the 4-week active run-in period on Widaplik, 3.2% of patients had symptomatic hypotension. During the run-in period, 3.2% of patients discontinued study medication due to an adverse event, including 0.8% of patients who discontinued due to symptomatic hypotension. Because of this run-in design, the proportion of patients with adverse reactions described below is lower than expected in practice (see Table 2). The proportion of patients who discontinued study medication due to an adverse event over the 12-week treatment period was 2.0% for Widaplik and 1.4%, 1.1%, and 1.4% for the telmisartan/indapamide, telmisartan/amlodipine, and amlodipine/indapamide groups, respectively. Most adverse reactions were generally mild to moderate in severity. Table 2: Adverse Reactions Reported in >2% of Patients Treated with Widaplik during the 12-Week Treatment Period of Study 2 Widaplik (n = 547) Telmisartan/ Indapamide (n = 275) Telmisartan/ Amlodipine (n = 282) Amlodipine/ Indapamide (n = 276) Symptomatic hypotension, n (%) 32 (5.9%) 11 (4.0%) 5 (1.8%) 4 (1.4%) Sodium <135 mmol/L at week 12, n (%) 40 (7.3%) 19 (6.9%) 9 (3.2%) 10 (3.6%) Potassium <3.5 mmol/L at week 12, n (%) 37 (6.8%) 13 (4.7%) 0 (0%) 35 (12.7%) 6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience with telmisartan, amlodipine or indapamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Telmisartan The most frequently reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioedema, urticaria, sweating increased, erythema, dyspepsia, diarrhea, pain, erectile dysfunction, abdominal pain, myalgia, eosinophilia, thrombocytopenia, anemia, and increased CPK, rhabdomyolysis, drug eruption (e.g., toxic skin eruption mostly reported as toxicoderma, rash, and urticaria). Amlodipine Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), extrapyramidal disorder. Indapamide Exacerbation of systemic lupus erythematous, choroidal effusion, acute myopia, and angle-closure glaucoma.

12.3 Pharmacokinetics Absorption Following single-dose oral administration of Widaplik (40 mg/5 mg/2.5 mg) to healthy subjects in the fasted state, the extent of absorption (AUC) and rate of absorption (C max ) of telmisartan was 750 ng.h/mL and 64.7 ng/mL, the AUC and C max of amlodipine was 102,000 pg.h/mL and 2,850 pg/mL, and the AUC and C max of indapamide was 2,170 ng.h/mL and 144 ng/mL, respectively. The peak plasma concentrations of telmisartan, amlodipine and indapamide are achieved at approximately 1.8 hours, 7.5 hours, and 0.9 hours, respectively, under fasting conditions. Effect of Food A food-effect study involving administration of Widaplik (40 mg/5 mg/2.5 mg) to healthy subjects after a high-fat, high calorie breakfast indicated that the C max of telmisartan decreased 41%, while AUC remained unchanged, the C max and AUC of amlodipine and indapamide remained unchanged, when compared to administration under fasting conditions. The T max of telmisartan, amlodipine and indapamide was delayed by approximately 2 hours, 1 hour, and 1.5 hours, respectively, under fed conditions. Distribution Telmisartan Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 L 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. Indapamide Indapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to 3.5:1 at eight hours. From 71 to 79% of the indapamide in plasma is reversibly bound to plasma proteins. 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. 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. Indapamide Indapamide is an extensively metabolized drug, with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48 hours after administration. The urinary elimination of 14 C-labeled indapamide and metabolites is biphasic with a terminal half-life of excretion of total radioactivity of 26 hours. A minimum of 70% of a single oral dose is eliminated by the kidneys and an additional 23% by the gastrointestinal tract, probably including the biliary route. The half-life of indapamide in whole blood is approximately 14 hours. Specific Populations Geriatric Patients Telmisartan : The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years. Amlodipine : Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Indapamide: The pharmacokinetics of indapamide in geriatric patients is unknown. Male and Female Patients Telmisartan: 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. Patients with Renal Impairment Telmisartan: Renal impairment does not increase the AUC of telmisartan. Telmisartan is not removed from blood by hemodialysis. Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Indapamide: The effect of renal impairment on the pharmacokinetics of indapamide is unknown. Patients with Hepatic Impairment Telmisartan : In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see 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%. Indapamide: The effect of hepatic impairment on the pharmacokinetics of indapamide is unknown [see Use in Specific Populations ( 8.6 )] . 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 C max and AUC of ramipril 2.3- and 2.1-fold, respectively, and C max and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C max and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. 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. Amlodipine In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin. Impact of other drugs on amlodipine Co-administered cimetidine, magnesium- and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine. CYP3A 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 CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions ( 7.2 )]. Impact of amlodipine on other drugs Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates. Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time. 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 [see Drug Interactions ( 7.2 )]. Cyclosporine : A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions ( 7.2 )]. Tacrolimus : A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions ( 7.2 )].