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Losartan (Systemic)


VA CLASSIFICATION
Primary: CV805
Secondary: CV409

Commonly used brand name(s): Cozaar.

Other commonly used names are
DuP 753 and MK594 .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypertensive—

angiotensin II receptor antagonist—

Indications

Accepted

Hypertension (treatment)—Losartan is indicated for the treatment of hypertension . {01} It may be used alone or in combination with other antihypertensive agents. {01}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Losartan potassium: 461.01 {01} {02}

Mechanism of action/Effect:

Losartan is a nonpeptide angiotensin II receptor antagonist with high affinity and selectivity for the AT 1 receptor. {01} {03} {04} {05} {06} {08} Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by inhibiting the binding of angiotensin II to the AT 1 receptor. {01} {05} {09} AT 1 receptor blockade results in an increase in plasma renin activity (PRA) followed by increases in plasma angiotensin II concentration. {04} {06} {07} The potential clinical consequences of these increases are not clear. {04} {06} {07} Angiotensin II agonist effects have not been demonstrated. {05} {06} {08} {10}


Other actions/effects:

In vitro platelet aggregometry shows that losartan appears to be a weak antagonist to human platelet thromboxane A 2/prostaglandin H 2 (TP) receptors. {17} The clinical relevance of this effect is presently unclear. {17} Losartan also appears to have a uricosuric effect. {21} {22} {23} {24} However, the clinical significance of this effect has not been delineated.

Absorption:

Well-absorbed following oral administration. {01} {12} Bioavailability is approximately 33%. {01} {09}

Protein binding:

Losartan—Very high (98.7%). {01}

Carboxylic acid metabolite—Very high (99.8%). {01}

Biotransformation:

Losartan undergoes substantial first-pass metabolism by the cytochrome P450 system. {01} {05} {12} Biotransformation results in a major active carboxylic acid metabolite that is 10 to 40 times {01} {09} {11} {12} more potent than the parent compound and is responsible for most of the pharmacologic activity. {01} {09} {12} In addition, there are 5 minor metabolites that are much less active than the parent compound. {13}

Half-life:


Elimination:

Losartan: Approximately 2 hours. {01} {11}

Carboxylic acid metabolite: Approximately 6 to 9 hours. {01} {14}


Time to peak concentration:

Losartan—Approximately 1 hour. {01} {11} {12}

Carboxylic acid metabolite—Approximately 2 to 4 hours. {01} {05} {11}

Time to peak effect:

Approximately 6 hours. {15}

Duration of action:

Single dose—24 hours or more. {14} {15} {16}

Elimination:
    Renal—Approximately 35% (4% of dose as parent and 6% of dose as active metabolite). {01}
    Fecal (biliary)—Approximately 60%. {01}
    In dialysis—Losartan and its carboxylic acid metabolite are not removable by hemodialysis. {01}


Precautions to Consider

Carcinogenicity

Losartan was not carcinogenic in rats and mice given maximally tolerated doses of 270 mg per kg of body weight (mg/kg) per day and 200 mg/kg per day, respectively, for 105 and 92 weeks, respectively. {01} However, female rats had a slightly higher incidence of pancreatic acinar adenoma. {01} The maximally tolerated doses of losartan provided systemic exposures of up to 160 times (rats) and 30 times (mice) the exposure of a 50 kg human given 100 mg per day. {01}

Mutagenicity

Losartan was not mutagenic in a number of in vitro and in vivo assays. {01}

Pregnancy/Reproduction
Fertility—
Studies in male rats given oral doses of up to 150 mg/kg per day did not reveal adverse effects on fertility or reproductive performance. {01} However, toxic doses of 300 and 200 mg/kg per day given to females resulted in significant decreases in the number of corpora lutea, implants, and live fetuses. {01} The relationship of these findings to losartan is uncertain. {01}

Pregnancy—
Medications affecting the renin-angiotensin system, such as losartan, can cause fetal and neonatal morbidity and mortality when administered to pregnant women. {01} Losartan should be discontinued as soon as possible when pregnancy is detected. {01}

Fetal exposure to medications affecting the renin-angiotensin system during the second and third trimesters of pregnancy have been associated with hypotension, neonatal skull hypoplasia, anuria, renal failure, and even death in the newborn. {01} Maternal oligohydramnios has also been reported, probably reflecting decreasing fetal renal function. {01} Oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. {01} Prematurity, intrauterine growth retardation, and patent ductus arteriosus also have been reported. {01} However, it is not clear that these occurrences were related to drug exposure. {01}

It is recommended that infants exposed in utero to losartan be closely observed for hypotension, oliguria, and hyperkalemia. {01} Oliguria should be treated with support of blood pressure and renal perfusion. {01} If oligohydramnios is observed, losartan should be discontinued unless it is considered lifesaving for the mother. {01} Oligohydramnios, however, may not appear until after the fetus has sustained irreversible damage. {01}

Losartan exposure during late gestation at doses approximately 3 times the maximum recommended human dose on a mg per square meter of body surface area basis produced adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality, and renal toxicity. {01}

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

Breast-feeding

It is not known whether losartan is distributed into breast milk. {01} However, significant concentrations of losartan and its active metabolite are present in the milk of rats. {01}

Pediatrics

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


Geriatrics


Use of losartan in a limited number of patients 65 years of age and over has not demonstrated geriatrics-specific problems that would limit the usefulness of losartan in the elderly. {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: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin{18}{19}{20}    (NSAIDs may antagonize the antihypertensive effect of losartan by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained)


Blood from blood bank (may contain up to 30 mEq [mmol] of potassium per L of plasma or up to 65 mEq [mmol] per L of whole blood when stored for more than 10 days) or
Cyclosporine or
Diuretics, potassium-sparing or
Low-salt milk (may contain up to 60 mEq [mmol] of potassium per liter) or
Potassium-containing medications or
Potassium supplements or substances containing high concentrations of potassium or
Salt substitutes (most contain substantial amounts of potassium)    (concurrent administration with losartan may result in hyperkalemia since reduction of aldosterone production induced by losartan may lead to elevation of serum potassium; determination of serum potassium concentrations is recommended if concurrent use of these agents is necessary)


» Diuretics{01}    (symptomatic hypotension may occur after initiation of losartan therapy in patients taking a diuretic; caution and a lower starting dose are recommended)


Hypotension-producing medications, other (See Appendix II )    (concurrent use with losartan may produce additive hypotensive effects)


Sympathomimetics    (concurrent use of these agents may reduce the antihypertensive effects of losartan; the patient should be carefully monitored to confirm that the desired effect is being obtained)



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
Alanine aminotransferase (ALT) and
Aspartate aminotransferase (AST)    (transient increases have been reported rarely; these increases were infrequently greater than 2 or 3 times the upper limit of normal {21})


Bilirubin, serum    (concentrations may be increased {01})


Hemoglobin and
Hematocrit    (small increases occur frequently, but are rarely of clinical significance {01})


Potassium, serum{01}{21}{25}    (concentrations may be slightly increased as a result of reduced aldosterone concentrations)


Uric acid, serum    (concentrations may be decreased, reflecting losartan's uricosuric effect {22} {23})


Uric acid, urine    (concentrations may be increased; losartan appears to significantly increase uric acid excretion; this effect appears to be related to the parent compound, losartan, and not the carboxylic acid metabolite {21} {22} {23} {24})


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).


Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment{01}    (increased plasma concentrations may occur; total plasma clearance of losartan may be 50% lower and oral bioavailability about 2 times higher than in individuals with normal hepatic function; lower dosages are recommended)


» Renal artery stenosis, bilateral or in a solitary kidney{07}    (increased risk of renal function impairment)


Renal function impairment, moderate to severe{01}    (losartan area under the curve [AUC] may be increased by approximately 50%; however, dosage adjustments are not necessary unless patient is volume-depleted)

    (in patients whose renal function is dependent on the renin-angiotensin-aldosterone system, especially those with congestive heart failure, there may be a risk of losartan-induced renal failure)


Sensitivity to losartan
» Caution is recommended in patients who are sodium- or volume-depleted.{01} Symptomatic hypotension may occur following initiation of losartan therapy.{01} Sodium- or volume-depletion should be corrected or a lower starting dose is recommended in these patients.{01}

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    (recommended at periodic intervals; selected patients may be taught to monitor their blood pressure at home and report the results at regular physician visits)


Renal function determinations    (recommended at periodic intervals, especially in patients who are sodium- and volume-depleted as a result of diuretic therapy or who have severe congestive heart failure)




Side/Adverse Effects

Note: A case of angioedema has been reported in a patient being treated with losartan. {01}

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 less frequent
    
Dizziness {01}{21}
    
upper respiratory infection (cough, fever, or sore throat)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache{21}

Incidence less frequent
    
Back pain {01}
    
diarrhea {01}
    
fatigue {01}{21}
    
nasal congestion

Incidence rare
    
Cough, dry{01}{21}
    
insomnia (trouble in sleeping){01}
    
leg pain {01}
    
muscle cramps or pain {01}
    
sinus problems{01}





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:

Bradycardia due to vagal stimulation {01}

hypotension {01}

tachycardia{01}

Treatment of overdose
Symptomatic and supportive. {01}


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

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

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to losartan

Pregnancy—Can cause fetal and neonatal morbidity and mortality; not recommended for use during pregnancy
Other medications, especially diuretics
Other medical problems, especially hepatic and renal function impairment, renal artery stenosis, or sodium or volume depletion

Proper use of this medication
Compliance with therapy; taking medication at the same time(s) each day to maintain the therapeutic effect

Possible need for control of weight and diet, especially sodium intake; risks associated with sodium depletion; not taking salt substitutes or using low-salt milk unless approved by physician

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension

May be taken with or without food

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

» Proper storage

Precautions while using this medication
» Notifying physician immediately if pregnancy is suspected

Making regular visits to physician to check progress

» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician

Caution when driving or doing other things requiring alertness, because of possible dizziness, especially after initial dose of losartan in patients taking diuretics

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

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

» Caution in using alcohol because of the risk of dehydration and hypotension due to reduced fluid volume


Side/adverse effects
Signs of potential side effects, especially dizziness or upper respiratory infection


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

Although there does not appear to be a rebound effect after abrupt withdrawal of losartan, {01} gradual dosage reduction is recommended to minimize any risk of a rebound effect. {28}

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery may be undesirable. However, the anesthesiologist must be aware of such therapy. {27}

Diet/Nutrition
Losartan may be taken with or without food.


Oral Dosage Forms

LOSARTAN POTASSIUM TABLETS

Usual adult dose
Antihypertensive


Initial:
Oral, 50 mg once a day. {01}

Note: In patients with possible volume depletion and patients with a history of hepatic function impairment an initial dose of 25 mg once a day is recommended. {01}




Maintenance:
Oral, 25 to 100 mg a day. Dose may be given once a day or divided into two doses. {01}



Note: If adequate blood pressure control is not achieved by losartan alone, a low dose of a diuretic may be added for an additive effect. {01}


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


25 (Rx) [Cozaar (potassium 2.12 mg [0.054 mEq])]


50 (Rx) [Cozaar (potassium 4.24 mg [0.108 mEq])]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tightly closed container. {01} Protect from light. {01}

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



Revised: 08/19/1998



References
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  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 393.
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  1. Liu EC, Hedberg A, Goldenberg HJ, Harris DN, Webb ML. DuP 753, the selective angiotensin II receptor blocker, is a competitive antagonist to human platelet thromboxane A 2/Prostaglandin H 2 (TP) receptors. Prostaglandins 1992; 44: 89-99.
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  1. Mills EH, Whitworth JA, Andrews J, Kincaid-Smith P. Nonsteroidal anti-inflammatory drugs and blood pressure. Aust N Z J Med 1982; 12: 478-82.
  1. Houston MC. Nonsteroidal anti-inflammatory drugs and antihypertensives. Am J Med 1991; 90(suppl 5A): 42S-47S.
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  1. Tsunoda K, Abe K, Hagino T, et al. Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Am J Hypertens 1993; 6: 28-32.
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  1. Panel consensus, 1/93.
  1. Panel comment, 7/95.

Further information

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