Telmisartan, Amlodipine and Indapamide

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 )

Widaplik tablets are available as follows: 10 mg/1.25 mg/0.625 mg: 10 mg telmisartan/1.25 mg amlodipine/0.625 mg indapamide tablets – white to off-white oval tablet, debossed with “ULD” on one side and plain on the other side. 20 mg/2.5 mg/1.25 mg: 20 mg telmisartan/2.5 mg amlodipine/1.25 mg indapamide tablets – white to off-white round tablet, debossed with “LD” on one side and plain on the other side. 40 mg/5 mg/2.5 mg: 40 mg telmisartan/5 mg amlodipine/2.5 mg indapamide tablets – white to off-white oval tablet, debossed with “SD” on one side and plain on the other side. Tablets: (telmisartan/amlodipine/indapamide) 10 mg/1.25 mg/ 0.625 mg, 20 mg/2.5 mg/1.25 mg, 40 mg/5 mg/2.5 mg ( 3 )

Do not use in patients with anuria, known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine, indapamide, or to other sulfonamide-derived drugs, or to any other component of this product. Do not co-administer aliskiren with Widaplik in patients with diabetes [see Drug Interactions ( 7.1 )] . Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine, indapamide, or to other sulfonamide-derived drugs, or to any other component of this product ( 4 ) Do not co-administer aliskiren with Widaplik in patients with diabetes ( 4 ) Anuria ( 4 )

Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Electrolyte and Glucose Imbalances: Monitor serum electrolytes and glucose ( 5.3 ) Impaired Renal Function: Monitor renal function ( 5.4 ) Acute angle closure glaucoma can develop ( 5.5 ) Hyperuricemia may occur ( 5.6 )

5.1 Fetal Toxicity Use of drugs that act on the renin-angiotensin-aldosterone system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Widaplik as soon as possible [see Use in Specific Populations ( 8.1 ) ].

5.2 Hypotension Widaplik can cause symptomatic hypotension. Patients with hypovolemia, salt depletion, or aortic stenosis are at increased risk. Monitor blood pressure and adjust dose as needed. Hypotension leading to worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Widaplik because of the amlodipine component, particularly in patients with severe obstructive coronary artery disease.

5.3 Electrolyte and Glucose Imbalances Thiazide-like diuretics can cause hyponatremia, hypomagnesemia and hypokalemia and can also alter serum glucose and affect insulin requirements. Drugs that inhibit the renin angiotensin-aldosterone system can cause hyperkalemia. Patients with renal impairment or heart failure are at increased risk for hyperkalemia. Monitor serum electrolytes and glucose periodically.

5.4 Impaired Renal Function Inhibiting the renin-angiotensin-aldosterone system or diuresis can precipitate renal dysfunction, oliguria and acute renal failure. Patients with severe congestive heart failure or renal dysfunction are at increased risk [see Clinical Pharmacology ( 12.3 ) ]. Monitor renal function periodically and adjust dose as needed.

5.5 Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion Sulfonamide or sulfonamide-derivative drugs, like indapamide, can cause an idiosyncratic reaction resulting in acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. Symptoms may include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated, the angle-closure glaucoma may result in permanent visual field loss. The primary treatment is to discontinue Widaplik as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

5.6 Hyperuricemia Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide-like diuretics.

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.

NSAIDs: Increased risk of renal impairment and loss of anti-hypertensive effect ( 7.1 ) If simvastatin is co-administered with Widaplik, do not exceed doses greater than 20 mg daily of simvastatin ( 7.2 ) Do not co-administer aliskiren with Widaplik in patients with diabetes ( 7.1 )

7.1 Drug Interactions with Telmisartan Aliskiren and other renin-angiotensin-aldosterone system (RAAS) inhibitors: Do not co-administer aliskiren with Widaplik in patients with diabetes. Most patients receiving the combination of two RAAS inhibitors do not obtain any additional benefit compared to monotherapy [see Contraindications ( 4 )] . Avoid use of aliskiren with Widaplik in patients with renal impairment (GFR <60 mL/min) [see Warnings and Precautions ( 5.4 )]. Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Monitor digoxin levels when initiating, adjusting, and discontinuing Widaplik to keep the digoxin level within the therapeutic range. Lithium: Increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan. Monitor serum lithium levels during concomitant use [see Drug Interactions with Indapamide ( 7.3 )] . 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 Widaplik and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.2 Drug Interactions with Amlodipine Impact of other drugs on amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when Widaplik is co-administered with CYP3A inhibitors to determine the need for dose adjustment. CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when Widaplik is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with Widaplik. Impact of amlodipine on other drugs Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on Widaplik 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 cyclosporine and tacrolimus and dose adjustment when appropriate is recommended.

7.3 Drug Interactions with Indapamide Lithium: In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy. Norepinephrine: Indapamide, like thiazide diuretics, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Lactation: Breastfeeding is not recommended ( 8.2 ) Geriatric Patients: Severe cases of hyponatremia, accompanied by hypokalemia have been reported with use of indapamide in elderly females; consider initiation at lower doses for patients ≥65 years of age ( 8.5 ) Hepatic Impairment: Monitor carefully and start treatment at low doses ( 8.6 )

8.1 Pregnancy Risk Summary Widaplik can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin-aldosterone 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-aldosterone system from other antihypertensive agents. Studies in rats and rabbits showed fetotoxicity only at maternally toxic doses of telmisartan ( see Data ). When pregnancy is detected, discontinue Widaplik 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 Telmisartan Use of drugs that act on the RAAS 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-aldosterone system for a particular patient, apprise the mother of the potential risk to the fetus. In patients taking Widaplik 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 Widaplik, 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 neonates with histories of in utero exposure to Widaplik 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. Indapamide Diuretics are known to cross the placental barrier and appear in cord blood. There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult. Data Animal Data No reproductive toxicity studies have been conducted with Widaplik. However, these studies have been conducted for telmisartan, amlodipine and indapamide 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 MHRD 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. Indapamide Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to indapamide. Postnatal development in rats and mice was unaffected by pretreatment of parent animals during gestation.

8.2 Lactation Risk Summary There is no information regarding the presence of Widaplik 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 at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production. There is no information regarding the presence of telmisartan in human milk. Telmisartan is present in the milk of lactating rats (see Data) . It is not known whether indapamide is excreted in human milk. 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 Widaplik. 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 Widaplik in pediatric patients have not been established. Neonates with a history of in utero exposure to Widaplik 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 Widaplik In subgroup analysis in subjects ≥65 years (n= 176) the antihypertensive effect of Widaplik was not substantially different compared to younger subjects, however the number of elderly patients enrolled in both Widaplik studies was small. 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 with amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. […]

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 indapamide. The drug may also produce calcium-channel blockade in smooth muscle cells, thereby causing arteriolar vasodilation.