Widaplik telmisartan, amlodipine and indapamide 10 mg; 1.25 mg; .625 mg Tablet, 30-count — NDC 24338-001-30 (Billing 24338-0001-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The active ingredients of Widaplik target 3 separate mechanisms involved in blood pressure regulation. 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-aldosterone 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. The increased plasma levels of angiotensin following AT 1 receptor blockade with telmisartan may stimulate the unblocked AT 2 receptor. Blockade of the renin-angiotensin-aldosterone 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 non-dihydropyridine 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. Indapamide Indapamide is a thiazide-like diuretic. Although the mechanism of action is not clear, indapamide appears to act principally on the distal convoluted tubules of the nephron.

The drug enhances the excretion of sodium, chloride, and water by inhibiting the transport of sodium ions across the renal tubule. The hypovolemic action of indapamide is believed to be responsible for the drug's beneficial cardiovascular effects. Decreased plasma and extracellular fluid volume, along with a decreased peripheral vascular resistance (secondary to loss of sodium, or to vascular autoregulatory feedback systems), act to lower blood pressure in hypertensive patients w… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The active ingredients of Widaplik target 3 separate mechanisms involved in blood pressure regulation. 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-aldosterone 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. The increased plasma levels of angiotensin following AT 1 receptor blockade with telmisartan may stimulate the unblocked AT 2 receptor. Blockade of the renin-angiotensin-aldosterone 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 non-dihydropyridine 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. Indapamide Indapamide is a thiazide-like diuretic. Although the mechanism of action is not clear, indapamide appears to act principally on the distal convoluted tubules of the nephron.

The drug enhances the excretion of sodium, chloride, and water by inhibiting the transport of sodium ions across the renal tubule. The hypovolemic action of indapamide is believed to be responsible for the drug's beneficial cardiovascular effects. Decreased plasma and extracellular fluid volume, along with a decreased peripheral vascular resistance (secondary to loss of sodium, or to vascular autoregulatory feedback systems), act to lower blood pressure in hypertensive patients who are receiving indapami… [Excerpted — this section continues on DailyMed.]

12.3Pharmacokinetics 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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Widaplik is a combination of three drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, an angiotensin II receptor blocker, telmisartan and a thiazide-like diuretic, indapamide. All three components lower the blood pressure by reducing peripheral resistance, but through complementary mechanisms, each working at a separate site and blocking different effector pathways. Widaplik has not been studied in indications other than hypertension.

Telmisartan An oral dose of 80 mg telmisartan, a dose higher than in Widaplik, inhibited the pressor response 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.

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. 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 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… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The efficacy of Widaplik in lowering blood pressure was evaluated in a randomized study designed to evaluate the efficacy and safety of two doses of Widaplik (10 mg/1.25 mg/0.625 mg and 20 mg/2.5 mg/1.25 mg) compared to placebo (Study 1, NCT04518306) and in a randomized study designed to evaluate the efficacy and safety of Widaplik (40 mg/5 mg/2.5 mg) as compared to each of its two-drug combinations at the same doses (Study 2, NCT04518293). Study 1 Study 1 (NCT04518306) was a 4-week, multi-center, randomized, double-blind, placebo-controlled, parallel group study that randomized 295 adults with systolic hypertension who were taking 0-1 antihypertensive medications at screening and who were at a low risk for cardiovascular disease per local guidelines (e.g., pooled cohorts equation 10-year atherosclerotic cardiovascular disease risk <10% in the United States).

The study excluded patients with a clinic seated blood pressure ≥160/100 mmHg at screening and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at randomization. Following a 2-week placebo run-in period during which any monotherapy was discontinued, eligible patients with a home systolic blood pressure between 130 and 154 mmHg were randomized 2:2:1 to receive Widaplik (10 mg/1.25 mg/0.625 mg), Widaplik (20 mg/2.5 mg/1.25 mg), or placebo. The primary endpoint was the change from randomization to Week 4 in home systolic blood pressure.

At baseline, mean age was 51 years (range 19 to 83 years), 44% of patients were male, 61% were White, 17% Black, and 21% Asian. The change from randomization to Week 4 in home systolic and diastolic pressure in the Widaplik (10 mg/1.25 mg/0.625 mg), Widaplik (20 mg/2.5 mg/1.25 mg), and placebo arms, is shown in Table 3. Both doses of Widaplik showed statistically significant greater reductions in home systolic blood pressure compared to placebo (see Table 3).

Most of the home systolic blood pressure lowering effect occurred within the first two weeks of treatment with Widaplik for both doses. The findings for clinic blood pressure were consistent with the results for home blood pressure. Table 3: Changes from Randomization to Week 4 in Home Blood Pressure, Comparing Widaplik (10 mg/1.25 mg/0.625 mg) or Widaplik (20 mg/2.5 mg/1.25 mg) vs Placebo (Study 1) Placebo (N=63) Widaplik 10 mg/1.25 mg/0.625 mg (N=113) Widaplik 20 mg/2.5 mg/1.25 mg (N=119) Home systolic blood pressure, mmHg Randomization, Mean (SD) 138.7 (6.9) 138.4 (6.7) 138.8 (6.3) Week 4, Mean (SD) 136.4 (8.9) 129.2 (9.5) 128.0 (12.0) LSM change from randomization, Mean (SE) -2.2 (1.2) -9.6 (1.0) -10.4 (1.3) Difference to placebo in LSM (95% CI) P-value - -7.3 (-10.2, -4.5) p <0.0001 -8.2 (-11.3, -5.2) p <0.0001 Home diastolic blood pressure, mmHg Randomization, Mean (SD) 85.8 (8.6) 85.2 (7.3) 86.9 (7.2) LSM change from randomization, Mean (SE) -1.1 (0.8) -5.1 (0.8) -6.6 (0.6) Difference to placebo in LSM (95% CI) - -4.0 (-6.0, -2.0) -5.5 (-7.3, -3.7) CI= confidence interval; LSM = least squares mean; SD = standard deviation; SE = standard error.

Study 2 Study 2 (NCT04518293) was a 12-week, multi-center, randomized, double-blind, parallel group study designed to evaluate the efficacy of Widaplik up to 40 mg/5 mg/2.5 mg as compared to each of its two-drug combinations at the same doses: telmisartan/indapamide (TI), telmisartan/amlodipine (TA), or amlodipine/indapamide (AI). Enrolled patients were required to have a mean systolic blood pressure of 140 to 179 mmHg if on no antihypertensive medications, 130 to 170 mmHg if on one, 120 to 160 mmHg if on two, or 110 to 150 mmHg if on three.

The study excluded patients with a history of cardiovascular disease, New York Heart Association (NYHA) class III or IV congestive heart failure, or an eGFR <60 mL/min/ 1.73 m 2 at screening. Following discontinuation of any antihypertensive medications, 2,244 patients entered a 4-week, single-blind, run-in period where all patients received Widaplik (20 mg/2.5 mg/ 1… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Widaplik No carcinogenicity, mutagenicity, or fertility studies have been conducted with this combination. However, these studies have been conducted for amlodipine, telmisartan and indapamide alone. Based on preclinical safety and human pharmacokinetic studies, there is no indication of any toxicologically significant adverse interaction between these components.

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 (1,000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m 2 basis, about 59 and 13 times, respectively, the 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 mg, 1.25 mg, 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 MRHD of 10 mg amlodipine/day.

For the rat, the highest dose was, on a mg/m 2 basis, about 2.5 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).

Indapamide Both mouse and rat lifetime carcinogenicity studies were conducted. There was no significant difference in the incidence of tumors between the indapamide-treated animals (up to 100 mg/kg/day) and the control groups. Doses up to 6,250 times the therapeutic human dose have revealed no evidence of impaired fertility as tested in rats, mice and rabbits.