DailyMed Label: Telmisartan and Hydrochlorothiazide

DailyMed Label: Telmisartan

2024

DailyMed Prescription

Telmisartan

Telmisartan

Preferred Pharmaceuticals Inc.

NDC: 68788-8665

NDC: 68788-8665

NDC: 68788-8665

Telmisartan is a non-peptide angiotensin II receptor (type AT 1 ) antagonist. 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 , its molecular weight is 514.63, and its structural formula is: 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 tablets, USP, are available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of telmisartan, USP. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, mannitol, and magnesium stearate. Telmisartan tablets are hygroscopic and require protection from moisture. Structure

Telmisartan is an angiotensin II receptor blocker (ARB) indicated for: • Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) • Cardiovascular (CV) risk reduction in patients unable to take ACE inhibitors ( 1.2 ) Telmisartan tablets are indicated for the treatment of hypertension, 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 the class to which this drug principally belongs. 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 tablets may be used alone or in combination with other antihypertensive agents [see Clinical Studies ( 14.1 )]. Telmisartan tablets are indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage [see Clinical Studies ( 14.2 )]. Telmisartan tablets can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy) [see Clinical Studies ( 14.2 )] . Studies of telmisartan in this setting do not exclude the possibility that telmisartan may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves. Use of telmisartan with an ACE inhibitor is not recommended [ see Warnings and precautions ( 5.6 ) ].

• May be administered with or without food ( 2.1 ) • When used for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary ( 2.2 )  Indication  Starting Dose  Dose Range  Hypertension ( 2.1 )  40 mg once daily  40 to 80 mg once daily Cardiovascular Risk Reduction ( 2.2 ) 80 mg once daily 80 mg once daily Dosage must be individualized. The usual starting dose of telmisartan tablets is 40 mg orally once a day. Blood pressure response is dose-related over the range of 20 to 80 mg [ see Clinical Studies ( 14.1 ) ]. Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. Telmisartan tablets may be administered with other antihypertensive agents. Telmisartan tablets may be administered with or without food. The recommended dose of telmisartan tablets is 80 mg once a day and can be administered with or without food. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing the risk of cardiovascular morbidity and mortality. When initiating telmisartan tablets therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary.

• 20 mg, white to off-white, round, uncoated tablets debossed with “511” on one side and “S” on the other side • 40 mg, white to off-white, oval, uncoated tablets debossed with “512” on one side and “S” on the other side • 80 mg, white to off-white, oval, uncoated tablets debossed with “513” on one side and “S” on the other side • Tablets: 20 mg, 40 mg, 80 mg ( 3 )

Telmisartan tablets are contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product [see Adverse Reactions ( 6.2 )]. Do not co-administer aliskiren with telmisartan tablets in patients with diabetes [see Drug Interactions ( 7 )]. • Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product ( 4 ) • Do not co-administer aliskiren with telmisartan tablets in patients with diabetes ( 4 )

• Avoid fetal or neonatal exposure ( 5.1 ) • Hypotension: Correct any volume or salt depletion before initiating therapy. Observe for signs and symptoms of hypotension ( Error! Hyperlink reference not valid. ) • Monitor carefully in patients with impaired hepatic ( Error! Hyperlink reference not valid. ) or renal function ( Error! Hyperlink reference not valid. ) • Avoid concomitant use of an ACE inhibitor and angiotensin receptor blocker ( Error! Hyperlink reference not valid. ) Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue telmisartan tablets as soon as possible [see Use in Specific Populations ( 8.1 )]. In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with telmisartan tablets. Either correct this condition prior to administration of telmisartan tablets, or start treatment under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk. As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients [ see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with telmisartan tablets [see Clinical Pharmacology ( 12.3 )] . In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of telmisartan tablets in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors. Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. The ONTARGET trialenrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on telmisartan and other agents that affect the RAS. Do not co-administer aliskiren with telmisartan in patients with diabetes. Avoid concomitant use of aliskiren with telmisartan in patients with renal impairment (GFR <60 mL/min/1.73 m 2 ).

The following adverse reaction is described elsewhere in labeling:

Aliskiren: Do not co-administer aliskiren with telmisartan in patients with diabetes. Avoid use of aliskiren with telmisartan 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. • NSAIDS: Increased risk of renal impairment and loss of anti-hypertensive effect ( 7 ) • Do not co-administer aliskiren with telmisartan tablets in patients with diabetes ( 7 )

• Lactation: Do not breastfeed during treatment with telmisartan tablets ( 8.2 ) • Geriatric Patients: No overall difference in efficacy or safety vs younger patients, but greater sensitivity of some older individuals cannot be ruled out ( 8.5 ) Risk Summary Telmisartan 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) . When pregnancy is detected, discontinue Telmisartan 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 birth defects 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 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, 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 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 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). Risk Summary There is no information regarding the presence of telmisartan in human milk, the effects on the breastfed infant, or the effects 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. 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. Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology ( 12.3 )]. Neonates with a history of in utero exposure to telmisartan 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. Of the total number of patients receiving telmisartan in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or 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. Of the total number of patients receiving telmisartan in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. 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. Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] .

Telmisartan tablets, USP, are available as white to off-white, uncoated tablets containing telmisartan 20 mg, 40 mg, or 80 mg. Tablets are marked with “S” on one side, and on the other side, with either “511”, “512”, or “513” for the 20 mg, 40 mg, and 80 mg strengths, respectively. Tablets are provided as follows: Telmisartan tablets, USP, 40 mg are oval and packaged in: bottles of 30 (NDC 68788-8665-3) bottles of 60 (NDC 68788-8665-6) bottles of 90 (NDC 68788-8665-9) Storage Store at 20°Cto 25°C (68°F to 77°F); excursions permitted to 15°Cto 30°C (59°Fto 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed. Tablets should not be removed from bottle until immediately before administration.

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. 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. 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 mg and 160 mg, the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 mg 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. Distribution 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. Metabolism and Elimination 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 acyl glucuronide; 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. Specific Populations Renal Insufficiency No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration and is not dialyzable [see Warnings and Precautions ( 5.5 ) and Dosage and Administration ( 2.1 )] . Hepatic Insufficiency 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 )] . 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 The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see Dosage and Administration ( 2.1 )] . Pediatric Patients Telmisartan pharmacokinetics have not been investigated in patients <18 years of age. 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.

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).

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 to13/6 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 tablets, 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. There are no trials of telmisartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. Support for use to reduce the risk of cardiovascular events was obtained in a pair of studies. Both enrolled subjects age ≥55 years, at high cardiovascular risk as evidenced by coronary artery disease (75%), diabetes mellitus (27%) accompanied with end-organ damage (e.g., retinopathy, left ventricular hypertrophy, and, in ONTARGET only, macro- or microalbuminuria), stroke (16%), peripheral vascular disease (13%), or transient ischemic attack (4%). Patients without a history of intolerance to ACE inhibitors entered ONTARGET, and those with such a history, usually cough (90%), entered TRANSCEND, but patients with >1+ proteinuria on dipstick were excluded from TRANSCEND. For both ONTARGET and TRANSCEND trials, the primary 4-component composite endpoint was death from cardiovascular causes, myocardial infarction, stroke, and hospitalization for heart failure. The secondary 3-component composite endpoint was death from cardiovascular causes, myocardial infarction, and stroke. ONTARGET was a randomized, active-controlled, multinational, double-blind study in 25,620 patients who were randomized to telmisartan 80 mg, ramipril 10 mg, or their combination. The population studied was 73% male, 74% Caucasian, 14% Asian, and 57% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (76%), lipid lowering agents (64%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%), and diuretics (28%). Mean blood pressure at randomization was 134/77 mmHg. The mean duration of follow up was about 4 years and 6 months. During the study, 22.0% (n=1878) of telmisartan patients discontinued the active treatment, compared to 24.4% (n=2095) of ramipril patients and 25.3% (n=2152) of telmisartan/ramipril patients. TRANSCEND randomized patients to telmisartan 80 mg (n=2954) or placebo (n=2972). The mean duration of follow up was 4 years and 8 months. The population studied was 57% male, 62% Caucasian, 21% Asian, and 60% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (75%), lipid lowering agents (58%), beta-blockers (58%), calcium channel blockers (41%), nitrates (34%) and diuretics (33%). Mean blood pressure at randomization was 135/78 mmHg. During the study, 17.7% (n=523) of telmisartan patients discontinued the active treatment, compared to 19.4% (n=576) of placebo patients. The results for the TRANSCEND trial are summarized in Table 2, and the results for ONTARGET are summarized in Table 3, below: Table 2 Incidence of the Primary and Secondary Outcomes from TRANSCEND Telmisartan vs. Placebo (n=2954) (n=2972) No. of Events Telmisartan / Placebo Hazard Ratio 95% CI p-value * Composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure 465 (15.7%) / 504 (17.0%) 0.92 (0.81-1.05) 0.2129 * Composite of CV death, myocardial infarction, or stroke 384 (13.0%) / 440 (14.8%) 0.87 (0.76-1.00) 0.0483 Individual components of the primary composite endpoint No. of Events Telmisartan / Placebo Hazard Ratio 95% CI p-value ** All non-fatal MI 114 (3.9%) / 145 (4.9%) 0.79 (0.62-1.01) 0.0574 ** All non-fatal strokes 112 (3.8%) / 136 (4.6%) 0.83 (0.64-1.06) 0.1365 * The primary endpoint was defined as the time to first event. In case of multiple simultaneous events, all individual events were considered; the sum of patients with individual outcomes may exceed the number of patients with composite (primary or secondary) outcomes. ** For individual components of the primary composite endpoints, all events, regardless whether or not they were the first event, were considered. Therefore, they are more than the first events considered for the primary or secondary composite endpoint. Table 3 Incidence of the Primary and Secondary Outcomes from ONTARGET Telmisartan vs. Ramipril (n=8542) (n=8576) No. of Events Telmisartan / Ramipril Hazard Ratio 97.5% CI Composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure 1423 (16.7%) / 1412 (16.5%) 1.01 (0.93 – 1.10) Composite of CV death, myocardial infarction, or stroke 1190 (13.9%) / 1210 (14.1%) 0.99 (0.90 – 1.08) Although the event rates in ONTARGET were similar on telmisartan and ramipril, the results did not unequivocally rule out that telmisartan tablets may not preserve a meaningful fraction of the effect of ramipril in reducing cardiovascular events. However, the results of both ONTARGET and TRANSCEND do adequately support telmisartan tablets being more effective than placebo would be in this setting, particularly for the endpoint of time to cardiovascular death, myocardial infarction, or stroke. In ONTARGET, there was no evidence that combining ramipril and telmisartan tablets reduced the risk of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure greater than ramipril alone; instead, patients who received the combination of ramipril and telmisartan in ONTARGET experienced an increased incidence of clinically important renal dysfunction (e.g., acute renal failure) compared to patients receiving telmisartan tablets or ramipril alone. Multiple sub-group analyses did not demonstrate any differences in the 4-component composite primary endpoint based on age, gender, or ethnicity for either ONTARGET or TRANSCEND trial.

Container Label-40 mg Rx only NDC 68788-8665 Telmisartan Tablets, USP Each tablet contains 40 mg of telmisartan, USP. Dosage: Read accompanying prescribing information. Important: Moisture sensitive tablets – do not remove from bottle until immediately before administration. Store at 20°C to 25°C (68°F to 77°F); excursions permitted within 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed. Print Patient Information available at: www.solcohealthcare.com/medguide/telmisartan-tablets.pdf Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Xunqiao, Linhai, Zhejiang 317024, China Distributed by:        Solco Healthcare US, LLC Somerset, NJ 08873, USA Rev.: 06/2022 200451-02 Repackaged By: Preferred Pharmaceuticals Inc. Telmisartan Tablets 40mg