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Telmisartan (Systemic)


VA CLASSIFICATION
Primary: CV805
Secondary: CV409

Commonly used brand name(s): Micardis.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive—

Indications

Accepted

Hypertension (treatment)—Telmisartan is indicated for the treatment of hypertension {01}{02}when diuretic or beta-adrenergic blocker therapy has failed, or is contraindicated, or in the event that side effects of these agents are too severe{02}. It may be used alone or in combination with other antihypertensive medications {01}{02}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Telmisartan: 514.63 {01}

Mechanism of action/Effect:

Telmisartan is a nonpeptide angiotensin II antagonist that selectively blocks the binding of angiotensin II to the AT 1 receptors in vascular smooth muscle and the adrenal gland {01}. In the renin-angiotensin system, angiotensin I is converted by angiotensin-converting enzyme (ACE) to form angiotensin II {01}. Angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, which decreases the excretion of sodium and increases the excretion of potassium {01}. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle {01}. By blocking the binding of angiotensin II to the AT 1 receptors, telmisartan causes vasodilation and decreases the effects of aldosterone {01}. The negative feedback regulation of angiotensin II on renin secretion also is inhibited, resulting in a rise in plasma renin concentrations and a consequent rise in angiotensin II plasma concentrations; however, these effects do not counteract the blood pressure–lowering effect that occurs {01}.


Other actions/effects:

Telmisartan may have an inhibitory effect on cytochrome P450 2C19 isozyme and may affect the metabolism of medications that are metabolized by this enzyme {01}.

Absorption:

Absolute bioavailability of telmisartan increases (with greater than proportional increments) with increasing doses {01}. Food slightly decreases the bioavailability of telmisartan; a decrease of about 6% is seen when the 40-mg dose is administered with food {01}.

Distribution:

Vol D—Approximately 500 liters (L) {01}.

Protein binding:

Very high (> 99.5%), mainly to albumin and alpha 1-acid glycoprotein {01}. Protein binding is constant, not affected by changes in dose {01}.

Biotransformation:

Elimination of telmisartan is primarily as unchanged drug {01}. Telmisartan undergoes conjugation to form an inactive acylglucuronide metabolite, the only metabolite identified in human plasma and urine {01}.

Half-life:


Elimination:

Approximately 24 hours {01}.


Time to peak concentration:

0.5 to 1 hour {01}.

Elimination:
    Elimination of telmisartan is primarily as unchanged drug {01}.


After intravenous or oral administration—
        Renal—Less than 1% {01}.
        Fecal (biliary)—Greater than 97% {01}.



In dialysis—
        Telmisartan is not removable by hemodialysis {01}.



Precautions to Consider

Carcinogenicity

No evidence of carcinogenicity was found when telmisartan was given to mice or rats for up to 2 years in doses of up to 1000 and 100 mg per kg of body weight (mg/kg) per day, respectively {01}. These doses represent approximately 59 and 13 times, respectively, the maximum recommended human daily dose (MRHDD) of 80 mg and provide an average systemic exposure to telmisartan of more than 100 and 25 times, respectively, the systemic exposure in humans {01}.

Mutagenicity

Telmisartan was not found to be mutagenic in the Ames bacterial mutagenicity test with Salmonella and Escherichia coli , a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test {01}.

Pregnancy/Reproduction
Fertility—
Reproductive performance was not affected in male and female rats given telmisartan at doses of 100 mg/kg per day, resulting in an average systemic exposure (as determined by the area under the plasma concentration–time curve [AUC] on day 6 of pregnancy) of approximately 50 times the average systemic exposure in humans at the MRHDD of 80 mg per day {01}. This dose represents about 13 times the MRHDD of telmisartan on a milligram per square meter of body surface area (mg/m 2) basis {01}.

Pregnancy—
Medications that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters {01}. Telmisartan should be discontinued as soon as possible when pregnancy is detected, unless no alternative therapy can be used {01}. In the latter instance, serial ultrasound examinations should be performed to assess the intra-amniotic environment {01}. If oligohydramnios is observed, telmisartan should be discontinued unless it is considered lifesaving for the mother {01}. Perinatal diagnostic tests, such as contraction-stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate during the applicable week of pregnancy {01}. However, oligohydramnios may not appear until after the fetus has sustained irreversible damage {01}.

Fetal exposure to drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause hypotension, reversible or irreversible renal failure, anuria, neonatal skull hypoplasia, and death in the fetus or neonate {01}. Maternal oligohydramnios, which may result from decreased fetal renal function, has been reported and is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development {01}. Other adverse effects that have been reported are prematurity, intrauterine growth retardation, and patent ductus arteriosus, although it is not clear how these effects are related to drug exposure {01}. When limited to the first trimester, exposure to this medication does not appear to be associated with these adverse effects {01}.

Infants exposed in utero to angiotensin II receptor antagonists should be observed closely for hypotension, oliguria, and hyperkalemia {01}. Oliguria should be treated with support of blood pressure and renal perfusion {01}. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function {01}.

No teratogenic effects were observed in pregnant rats given oral doses of telmisartan of up to 50 mg/kg per day or in pregnant rabbits given oral doses of up to 45 mg/kg per day {01}. Maternal toxicity in rabbits (as determined by reduced body weight gain and food consumption), at a dose of 45 mg/kg of body weight per day, resulted in embryolethality {01}. This dose represents about 6.4 times the MRHDD of 80 mg on a mg/m 2 basis {01}. Maternal toxicity in rats (as determined by a reduction in body weight gain and food consumption) given telmisartan in doses of 15 mg/kg per day during late gestation and lactation produced adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain {01}. This dose represents about 1.9 times the MRHDD on a mg/m 2 basis {01}. Telmisartan has been shown to be present in rat fetuses during late gestation and in the milk of rats {01}. The no-observed-effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg per day, respectively, are about 0.64 and 3.7 times, on a mg/m 2 basis, the MRHDD of telmisartan (80 mg per day).

FDA Pregnancy Category C (first trimester) {01}.

FDA Pregnancy Category D (second and third trimesters) {01}.

Breast-feeding

It is not known whether telmisartan is distributed into human breast milk {01}. However, telmisartan is distributed into the milk of lactating rats {01}. Because of the potential for adverse effects in the nursing infant, it is recommended that telmisartan not be administered to mothers who are breast-feeding {01}.

Pediatrics

No information is available on the relationship of age to the effects of telmisartan in pediatric patients. Safety and efficacy have not been established {01}.


Geriatrics


Use of telmisartan in patients 65 years of age and older (18.6% of patient in clinical trials) has not demonstrated geriatrics-specific problems that would limit the usefulness of telmisartan in the elderly {01}. The pharmacokinetics of telmisartan have not been shown to differ between individuals younger or older than 65 years of age {01}.


Pharmacogenetics

Females generally have twofold to threefold higher plasma concentrations of telmisartan than do males; however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension have been found in women and no dosage adjustment is necessary {01}. Black patients have a somewhat smaller response to the blood pressure–lowering effects of telmisartan {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Safety and efficacy of concurrent use of telmisartan with other angiotensin-converting enzyme inhibitors or beta-adrenergic blocking agents have not been established.

{02}
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Digoxin {01}    (concurrent use with telmisartan has resulted in median increases in digoxin peak plasma concentrations of 49% and in trough concentrations of 20% {01}; digoxin plasma concentrations should be monitored when initiating, adjusting, and discontinuing telmisartan {01})


Diuretics    (concurrent use with telmisartan may have additive hypotensive effects {01})


Warfarin {01}    (concurrent use with telmisartan for a period of 10 days has resulted in a slight decrease in the mean warfarin trough plasma concentration; however, this did not result in a change in international normalized ratio [INR] {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood urea nitrogen (BUN) {01} and
Creatinine, serum {01}    (increases in serum creatinine of 0.5 mg per dL or greater occurred in 0.4% of patients treated with telmisartan {01}; one patient discontinued treatment with telmisartan due to increases in serum creatinine and blood urea nitrogen {01})


Cholesterol{02}    (marked increases in serum cholesterol were reported in 6 patients (0.4%) treated with telmisartan{02}; two of these patients were followed over time and their cholesterol levels returned to baseline values{02})


Hemoglobin {01}    (in clinical studies, small decreases in hemoglobin values of > 2 grams per dL occurred in 0.8% of patients treated with telmisartan {01}; no patients discontinued telmisartan due to anemia {01})


Liver function tests    (in clinical studies, elevations of liver enzymes and/or serum bilirubin occurred infrequently in telmisartan-treated patients {01}; no patients discontinued telmisartan due to abnormal hepatic function {01})


Serum uric acid{02}    (clinically significant hyperuricemia (>10 mEq/L) was observed in 2.3% of telmisartan patients, primarily in those receiving in combination with hydrochlorothiazide{02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to telmisartan
Risk-benefit should be considered when the following medical problems exist
» Congestive heart failure, severe    (therapy with angiotensin receptor–antagonists in these patients, who may be especially susceptible to changes in the renin-angiotensin-aldosterone system, has been associated with oliguria, azotemia, acute renal failure, and/or death {01})


Dehydration
(sodium or volume depletion, due to excessive perspiration, vomiting, diarrhea, prolonged diuretic therapy, dialysis, or dietary salt restriction {01} )    (patients with reduced salt or fluid volume may have an increased risk of symptomatic hypotension {01})


Hepatic function impairment    (because telmisartan is eliminated primarily by the biliary route, patients with hepatic function impairment or biliary obstructive disorders may have increased plasma concentrations due to reduced elimination of telmisartan {01}; the absolute bioavailability of telmisartan in patients with hepatic function impairment is close to 100% {01})


Renal artery stenosis, unilateral or bilateral {01} or
Renal function impairment {01}    (increases in serum creatinine or blood urea nitrogen [BUN] have occurred in patients with unilateral or bilateral renal artery stenosis and treated with angiotensin-converting enzyme [ACE] inhibitors {01}; similar increases also may occur in patients treated with telmisartan {01}. Changes in renal function as a result of therapy with angiotensin receptor–antagonists in patients susceptible to changes in the renin-angiotensin-aldosterone system [such as patients with severe congestive heart failure] have been associated with oliguria, progressive azotemia, acute renal failure, and/or death {01})


» Valvular Stenosis{02}    (There is a theoretical risk of decreased coronary perfusion for patients with aortic stenosis, because they do not develop as much afterload reduction{02}.)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements {01}    (periodic monitoring is necessary for titration of dose according to the patient's response {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Angioedema {02}(large hives)
    
changes in vision {02}
    
hypotension or syncope{01} (dizziness, lightheadedness, or fainting)—usually seen in volume- or salt-depleted patients, such as those treated with diuretics, especially upon standing {01}
    
tachycardia (fast heartbeat){02}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Abdominal pain {01}{02}
    
acid reflux or dyspepsia {02}(heartburn)
    
appetite changes {02}
    
back pain {01}
    
diarrhea {01}
    
dizziness
    
dry mouth {02}
    
edema in extremities (swelling in hands, lower legs, and feet)
    
fatigue (general tiredness or weakness)
    
flatulence {02}(bloating or gas)
    
increased sweating {02}
    
muscle pain or spasm {02}
    
nausea {02}
    
nervousness {02}
    
pharyngitis {01} (sore throat)
    
sinusitis {01} (headache; stuffy nose)
    
skin rash {02}
    
urinary tract infection {02}(painful urination or changes in urinary frequency)
    
upper respiratory tract infection {01} (coughing; ear congestion or pain; fever; head congestion; nasal congestion ; runny nose; sneezing; sore throat)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Bradycardia{01} (slow heartbeat)—as a result of parasympathetic (vagal) stimulation{01}
    
dizziness{01}
    
hypotension{01} (dizziness, lightheadedness, or fainting)
    
tachycardia{01} (fast heartbeat)


Treatment of overdose
Treatment should be symptomatic and supportive {01}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Telmisartan (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to telmisartan

Pregnancy—Fetal and neonatal hypotension, skull hypoplasia, renal failure, and death have been reported; telmisartan should be discontinued as soon as possible when pregnancy is detected





Breast-feeding—Telmisartan is distributed into the milk of lactating rats; not recommended in mothers who are breast-feeding
Pharmacogenetics—Plasma concentrations of telmisartan may be higher in women; black patients may have a somewhat smaller therapeutic response
Other medical problems, especially severe congestive heart failure and valvular stenosis

Proper use of this medication
» Compliance with therapy; taking medication at the same time each day to maintain the antihypertensive effect

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

» Proper storage

Precautions while using this medication
Visiting the physician regularly to check progress

Notifying physician immediately if pregnancy is suspected

Not taking other medications without consulting the physician

Caution when driving, using machines, or doing other things that may be dangerous if dizziness or light-headedness occurs from hypotension

To prevent dehydration and hypotension, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution when exercising or during exposure to hot weather, because of the risk of dehydration and hypotension due to reduced fluid volume


Side/adverse effects
Signs of potential side effects, especially angioedema, changes in vision, hypotension or syncope, and tachycardia


General Dosing Information
Dosage must be adjusted, on the basis of clinical response, to meet the individual requirements of each patient.

Diet/Nutrition
Telmisartan may be taken with or without food {01}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Treatment of symptomatic hypotension involves placing the patient in a supine position and, if needed, administering normal saline intravenously {01}.



Oral Dosage Forms

TELMISARTAN TABLETS

Usual adult dose
Antihypertensive
Oral, initially 40 mg once a day {01}. Telmisartan may be administered in total daily doses ranging from 40 to 80 mg {01}. The antihypertensive effect is considerable within two weeks of therapy, and maximal antihypertensive effect usually is attained within four weeks of therapy {01}. If blood pressure is not controlled by telmisartan alone at a dose of 80 mg, a diuretic may be added {01}.

Patients with volume depletion (e.g., from diuretic treatment), on dialysis, with biliary obstructive disorders, or with hepatic function impairment should be closely monitored during initiation of therapy {01}.


Usual adult prescribing limits
80 mg per day {01}.

Usual pediatric dose
Safety and efficacy have not been established {01}.

Strength(s) usually available
U.S.—


40 mg (Rx) [Micardis (magnesium stearate) (meglumine) (povidone) (sodium hydroxide) (sorbitol)]


80 mg (Rx) [Micardis (magnesium stearate) (meglumine) (povidone) (sodium hydroxide) (sorbitol)]

Canada—


40 mg (Rx) [Micardis (sodium hydroxide) (meglumine) (povidone) (sorbitol) (magnesium stearate)]


80 mg (Rx) [Micardis (sodium hydroxide) (meglumine) (povidone) (sorbitol) (magnesium stearate)]

Packaging and storage:
Store at 25 ºC (77 ºF) {01}. Fluctuations between 15 and 30 °C (59 and 86 °F) are acceptable {01}. Telmisartan is hygroscopic and requires protection from moisture; therefore, the tablets should not be removed from the blister packaging until immediately before administration {01}.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.



Developed: 01/04/1999
Revised: 10/19/1999



References
  1. Telmisartan package insert (Boehringer Ingelheim—US), New 11/98, Rec 11/98.
  1. Product Information: Micardis (R), telmisartan. Boehringer Ingelheim, Burlington, Ontario, Canada, 1999.
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