CARDOMYL

Telmisartan is an angiotensin

II receptor antagonist (ARB) used in the management of hypertension.

Generally, angiotensin II receptor blockers (ARBs) such as telmisartan bind to the angiotensin II type 1 (AT1) receptors with high affinity, causing inhibition of the action of angiotensin II on vascular smooth muscle, ultimately leading to a reduction in arterial blood pressure. 1, 2 Recent studies suggest that telmisartan may also have PPAR-gamma agonistic properties that could potentially confer beneficial metabolic effects.

Used alone or in combination with other classes of antihypertensives for the treatment of hypertension. 5.

Also used in the treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus, as well as the treatment of congestive heart failure (only in patients who cannot tolerate ACE inhibitors).

Telmisartan is an Oral active nonpeptide angiotensin II antagonist that acts on the AT 1 receptor subtype.

It has the highest affinity for the AT 1 receptor among commercially available ARBs and has minimal affinity for the AT 2 receptor.

New studies suggest that telmisartan may also have PPARγ agonistic properties that could potentially confer beneficial metabolic effects, as PPARγ is a nuclear receptor that regulates specific gene transcription, and whose target genes are involved in the regulation of glucose and lipid metabolism, as well as anti-inflammatory responses.

This observation is currently being explored in clinical trials.

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 renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.

Telmisartan works by blocking the vasoconstrictor and aldosterone secretory effects of angiotensin II. 2, 5.

Peroxisome proliferator-activated receptor gamma Partial agonist

Type-1 angiotensin II receptor Antagonist.

Oral telmisartan follows nonlinear pharmacokinetics over the dose range of 20 mg to 160 mg. Both C max and AUC present greater than proportional increases at higher doses.

With once-daily dosing, telmisartan has trough plasma concentrations of about 10% to 25% of peak plasma concentrations.

The absolute bioavailability of telmisartan depends on the dosage.

At 40 mg and 160 mg, the bioavailability was 42% and 58%, respectively.

Food slightly decreases bioavailability.

For instance, when the 40 mg dose is administered with food, a decrease of about 6% is seen, and with the 160 mg dose, there is a decrease of about 20%.

Telmisartan has a volume of distribution of approximately 500 liters.

Minimally 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.

The cytochrome

P450 isoenzymes are not involved in the metabolism of telmisartan.

Following either intravenous or oral administration of 14C-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 displays bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours.

Telmisartan has a total plasma clearance of >800 mL/min.

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LD in rats is 150-200 mg/kg in males and 200-250 mg/kg in females.

Acute oral toxicity is low: no deaths and no changes occurred in rats or dogs at 2000 mg/kg, the highest dose tested.

Limited data are available with regard to overdosage in humans.

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

Supportive treatment should be instituted if symptomatic hypotension occurs.

Telmisartan is not removed by hemofiltration and is not dialyzable.

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.

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Dispense in a tightly closed container.

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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.