7 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.
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.
Concomitant use of telmisartan and ramipril is not recommended.
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.
NSAIDs: Increased risk of renal impairment and loss of antihypertensive effect (7) Do not co-administer aliskiren with telmisartan in patients with diabetes (7)
10 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.
11 Telmisartanis 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.
The tablets contain the following inactive ingredients: mannitol, sodium hydroxide, meglumine, povidone, sodium stearyl fumarate and magnesium stearate.
Telmisartan tablets are hygroscopic and require protection from moisture.
Hypertension 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 to 13/6 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, 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.
16 /STORAGE AND HANDLING Telmisartan Tablets, USP are supplied as below: 20 mg, white to off-white color, round, flat, beveled edge, uncoated tablets debossed with ‘L202’ on one side and plain on other side.
NDC 0603-5914-16 bottle of 30 units NDC 0603-5914-32 bottle of 1000 units NDC 0603-5914-20 blister of 100 units as 10 x 10 cards 40 mg, white to off-white color, oval shape, biconvex, uncoated tablets debossed with ‘L203’ on one side and plain on other side.
NDC 0603-5915-16 bottle of 30 units NDC 0603-5915-32 bottle of 1000 units NDC 0603-5915-20 blister of 100 units as 10 x 10 cards 80 mg, white to off-white color, oval shape, biconvex, uncoated tablets debossed with ‘L204’ on one side and plain on other side.
NDC 0603-5916-16 bottle of 30 units NDC 0603-5916-32 bottle of 1000 units NDC 0603-5916-20 blister of 100 units as 10 x 10 cards Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Tablets should not be removed from blisters or bottles until immediately before administration.
RECENT MAJOR CHANGES
Warnings and Precautions Dual Blockade of the Renin-Angiotensin-Aldosterone System (5.6) 12/2014
8.5 Geriatric Use 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.
DOSAGE FORMS AND STRENGTHS
3 · 20 mg, white to off-white color, round, flat, beveled edge, uncoated tablets debossed with ‘L202’ on one side and plain on other side.
· 40 mg, white to off-white color, oval shape, biconvex, uncoated tablets debossed with ‘L203’ on one side and plain on other side.
· 80 mg, white to off-white color, oval shape, biconvex, uncoated tablets debossed with ‘L204’ on one side and plain on other side.
Tablets: 20 mg, 40 mg, 80 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action 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.
INDICATIONS AND USAGE
1 Telmisartanis 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) 1.1.
Hypertension Telmisartan is 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.
It may be used alone or in combination with other antihypertensive agents [see Clinical Studies (14.1)] .
8.4 Pediatric Use Neonates with a history of in utero exposure to telmisartan : If oliguria or hypotension occurs, direct attention toward support of 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.
Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology (12.3)].
8.1 Pregnancy Pregnancy Category D.
[See Warnings and Precautions (5.1)].
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 as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.
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.
Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
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.
Perform serial ultrasound examinations to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue telmisartan, unless it is considered lifesaving for the mother.
Fetal testing may be appropriate, based on the week of pregnancy.
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 [see Use in Specific Populations (8.4)].
8.3 Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats.
Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
WARNING: FETAL TOXICITY When pregnancy is detected, discontinue telmisartan as soon as possible [see Warnings and Precautions (5.1]) .
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)] .
WARNING: FETAL TOXICITY See full prescribing information for complete boxed warnings.
When pregnancy is detected, discontinue telmisartan as soon as possible (5.1) Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus (5.1)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Avoid fetal or neonatal exposure (5.1) Hypotension: Correct any volume or salt depletion before initiating therapy.
Observe for signs and symptoms of hypotension (5.2) Monitor carefully in patients with impaired hepatic (5.4) or renal function (5.5) Avoid concomitant use of an ACE inhibitor and angiotensin receptor blocker (5.6) 5.1.
Fetal Toxicity Pregnancy Category D 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 as soon as possible [see Use in Specific Populations (8.1)].
Hypotension 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.
Either correct this condition prior to administration of telmisartan, 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 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.
Impaired Hepatic Function 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)] .
Impaired Renal Function 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 [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 in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.
Dual Blockade of the Renin-Angiotensin-Aldosterone System 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 trial enrolled 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 ).
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling.
Pregnancy Female patients of childbearing age should be told about the consequences of exposure to telmisartan during pregnancy.
Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1)].
Manufactured for: QUALITEST PHARMACEUTICALS.
Huntsville, AL 35811 Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P.
Tajpura, Near Baska, Taluka-Halol, Panchmahal 389350, Gujarat, India.
DOSAGE AND ADMINISTRATION
2 •May be administered with or without food (2.1) Indication Starting Dose Dose Range Hypertenstion (2.1) 40 mg once daily 40 to 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 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.
When additional blood pressure reduction beyond that achieved with 80 mg telmisartan is required, a diuretic may be added.
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.