TELMISARTE

Telmisartan tablets USP 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, USP is a white to slightly yellowish solid.

It is practically insoluble in water and in the pH range of to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.

Telmisartan is available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of telmisartan USP.

The tablets contain the following inactive ingredients: magnesium stearate, mannitol, meglumine, povidone, sodium hydroxide and sodium streayl fumarate.

Telmisartan tablets, USP are hygroscopic and require protection from moisture. telmisartan-structure.

Treatment of essential hypertension.

TELMISARTAN/HYDROCHLOROTHIAZIDE ACCORD fixed dose combination (80 mg telmisartan / 12.5 mg d-hydrochlorothiazide) is indicated in adults whose blood pressure is not adequately controlled by telmisartan as monotherapy.

The renal function of the patient is not affected by the renal function of the patient.

Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).

II is the principal pressor agent of the reninangiotensin 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 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. 12.2 Pharmacodynamics 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 dosedependent 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. 12.3 Pharmacokinetics Absorption: 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 and 160 mg the bioavailability was 42% and 58%, respectively.

The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 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.

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.

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.

No dosage adjustment is necessary in patients with decreased renal function.

Telmisartan is not removed from blood by hemofiltration.

In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% .

Plasma concentrations of telmisartan are generally 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.

The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years.

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 Cmax and AUC of ramipril 2.3-and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4-and 1.5-fold, respectively.

In contrast, Cmax 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.

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.

The pharmacotherapeutic class

Antagonists of l-angiotensin II and diuretics, ATC Code C09DA07.

TELMISARTAN/HYDROCLOROTHIAZIDE ACCORD is an association of an antagonist of the receptors of l-angiotensin II, telmisartan, and a thiazide diuretic, l-hydrochlorothiazide.

The combination of these active ingredients allows an additivity of their antihypertensive effects, and a reduction of the blood pressure greater than that observed with each active ingredient taken separately.

TELMISARTAN/HYDROCHOLOTHIAZIDE ACCORD results in an effective and progressive reduction of blood pressure in the therapeutic dose range.

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Summary of the safety profile

The most frequently reported adverse reaction is dizziness.

Serious angioedema may occur at a rare frequency (≥ 1/10,000 to < 1/1,000).

The overall incidence of adverse reactions reported with Telmisartan/Hydrochlorothiazide was comparable to that observed with telmisartan alone in randomised clinical trials including 1471 patients treated with telmisartan-hydrochlorothiazide or telmisartan alone.

No linear relationship was shown between dose and rate of occurrence of adverse reactions, no relationship was identified with sex, age, or ethnicity of patients.

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Limited data are available with regard to overdosage in humans.

The most likely manifestation of overdosage with telmisartan tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

If symptomatic hypotension should occur, supportive treatment should be instituted.

Telmisartan is not removed by hemodialysis.

Telmisartan is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product.

Do not co-administer aliskiren with telmisartan in patients with diabetes. .

Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product Do not co-administer aliskiren with telmisartan in patients with diabetes.

May be administered with or without food 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 Indication Starting Dose Dose Range Hypertension 40 mg once daily to 80 mg once daily Cardiovascular Risk Reduction 80 mg once daily 80 mg once daily 2.1 Hypertension Dosage must be individualized.

The usual starting dose of telmisartan tablets is 40 mg once a day. Blood pressure response is dose-related over the range of to 80 mg.

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. 2.2 Cardiovascular Risk Reduction 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 therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary.

Tablets, USP are supplied as below: 80 mg, white to off-white uncoated oval shaped tablets, biconvex with beveled edges, plain on one side and debossed “038”on other side.

NDC: 70518-3798-00 PACKAGING: 30 in 1 BOTTLE Store at 20 oto 25 oC (68 oto oF) .

Dispense in a tightly closed container.

Suite #4 Indiana, PA 1-724-465-8762.

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.

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.

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.

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.

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).

Safety and effectiveness in pediatric patients have not been established.

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 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.