Losartan Potassium

Losartan potassium tablets are angiotensin II receptor blocker (ARB) indicated for:

• Treatment of hypertension, to lower blood pressure in adults and children greater than 6 years old. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (
  1.1 Hypertension

  Losartan potassium tablets are indicated for the treatment of hypertension in adults and pediatric patients 6 years of age and older, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan.

  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 1 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.

  Losartan potassium tablets may be administered with other antihypertensive agents.
  )
• Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients. (
  1.2 Hypertensive Patients with Left Ventricular Hypertrophy

  Losartan potassium tablets are indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients

  [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].
  )
• Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. (
  1.3 Nephropathy in Type 2 Diabetic Patients

  Losartan potassium tablets are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥ 300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, losartan potassium tablets reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation)

  [see Clinical Studies (14.3)].
  )

Hypertension

• Usual adult dose: 50 mg once daily. (
  2.1 Hypertension

  Adult Hypertension

  The usual starting dose of losartan potassium tablets is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure

  [see Clinical Studies (14.1)].

  A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

  Pediatric Hypertension

  The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension

  [see Dosage and Administration (2.5)]

  . Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients

  [see Clinical Pharmacology (12.3), Clinical Studies (14.1), and Warnings and Precautions (5.2)].

  Losartan potassium tablets are not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m²

  [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14)].
  )
• Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg). (
  2.1 Hypertension

  Adult Hypertension

  The usual starting dose of losartan potassium tablets is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure

  [see Clinical Studies (14.1)].

  A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

  Pediatric Hypertension

  The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension

  [see Dosage and Administration (2.5)]

  . Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients

  [see Clinical Pharmacology (12.3), Clinical Studies (14.1), and Warnings and Precautions (5.2)].

  Losartan potassium tablets are not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m²

  [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14)].
  )

Hypertensive Patients with Left Ventricular Hypertrophy

• Usual starting dose: 50 mg once daily. (
  2.2 Hypertensive Patients with Left Ventricular Hypertrophy

  The usual starting dose is 50 mg of losartan potassium tablets once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of losartan potassium tablets should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response

  [see Clinical Studies (14.2)]

  .
  )
• Add hydrochlorothiazide 12.5 mg and/or increase losartan Potassium to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed. (
  2.2 Hypertensive Patients with Left Ventricular Hypertrophy

  The usual starting dose is 50 mg of losartan potassium tablets once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of losartan potassium tablets should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response

  [see Clinical Studies (14.2)]

  .
  ,
  14.2 Hypertensive Patients with Left Ventricular Hypertrophy

  The LIFE study was a multinational, double-blind study comparing losartan potassium and atenolol in 9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within six months prior to randomization were excluded. Patients were randomized to receive once daily losartan potassium tablets 50 mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan potassium or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e.g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.

  Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67 with 5704 (62%) age ≥65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure was 174/98 mmHg in both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the last visit before a primary endpoint, 77% of the group treated with losartan potassium and 73% of the group treated with atenolol were still taking study medication. Of the patients still taking study medication, the mean doses of losartan potassium and atenolol were both about 80 mg/day, and 15% were taking atenolol or losartan as monotherapy, while 77% were also receiving hydrochlorothiazide (at a mean dose of 20 mg/day in each group). Blood pressure reduction measured at trough was similar for both treatment groups but blood pressure was not measured at any other time of the day. At the end of study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the group treated with losartan potassium and 145.4/80.9 mmHg for the group treated with atenolol; the difference in systolic blood pressure (SBP) of 1.3 mmHg was significant (p<0.001), while the difference of 0.4 mmHg in diastolic blood pressure (DBP) was not significant (p=0.098).

  The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Patients with nonfatal events remained in the trial, so that there was also an examination of the first event of each type even if it was not the first event (e.g., a stroke following an initial myocardial infarction would be counted in the analysis of stroke). Treatment with losartan potassium resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the atenolol group (see Figure 1 and Table 3); this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with losartan potassium reduced the risk of stroke by 25% relative to atenolol (p=0.001) (see Figure 2 and Table 3).

  

  Figure 1:

  Kaplan-Meier estimates of the primary endpoint of time to cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction in the groups treated with losartan potassium and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy

  

  Figure 2:

  Kaplan-Meier estimates of the time to fatal/nonfatal stroke in the groups treated with losartan potassium and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

  Table 3 shows the results for the primary composite endpoint and the individual endpoints. The primary endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an ITT approach. The table shows the number of events for each component in two different ways. The Components of Primary Endpoint (as a first event) counts only the events that define the primary endpoint, while the Secondary Endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.

  Table 3: Incidence of Primary Endpoint Events

  	Losartan potassium			Atenolol			Risk ReductionAdjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.					95% CI	p-Value
  	N (%)	RateRate per 1000 patient-years of follow-up		N (%)	Rate
  Primary Composite Endpoint	508 (11)	23.8		588 (13)	27.9		13%					2% to 23%	0.021
  Components of Primary Composite Endpoint (as a first event)
  Stroke (nonfatal)	209 (5)			286 (6)
  Myocardial infarction (nonfatal)	174 (4)			168 (4)
  Cardiovascular mortality	125 (3)			134 (3)
  Secondary Endpoints (any time in study)
  Stroke (fatal/nonfatal)	232 (5)	10.8		309 (7)	14.5		25%					11% to 37%	0.001
  Myocardial infarction (fatal/nonfatal)	198 (4)	9.2		188 (4)	8.7		-7%					-13% to 12%	0.491
  Cardiovascular mortality	204 (4)	9.2		234 (5)	10.6		11%					-7% to 27%	0.206
  Due to CHD	125 (3)	5.6		124 (3)	5.6		-3%					-32% to 20%	0.839
  Due to Stroke	40 (1)	1.8		62 (1)	2.8		35%					4% to 67%	0.032
  OtherDeath due to heart failure, non-coronary vascular disease, pulmonary embolism, or a cardiovascular cause other than stroke or coronary heart disease.	39 (1)	1.8		48 (1)	2.2		16%					-28% to 45%	0.411

  Although the LIFE study favored losartan potassium over atenolol with respect to the primary endpoint (p=0.021), this result is from a single study and, therefore, is less compelling than the difference between losartan potassium and placebo. Although not measured directly, the difference between losartan potassium and placebo is compelling because there is evidence that atenolol is itself effective (vs. placebo) in reducing cardiovascular events, including stroke, in hypertensive patients.

  Other clinical endpoints of the LIFE study were: total mortality, hospitalization for heart failure or angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac arrest. There were no significant differences in the rates of these endpoints between the losartan potassium and atenolol groups.

  For the primary endpoint and stroke, the effects of losartan potassium in patient subgroups defined by age, gender, race and presence or absence of isolated systolic hypertension (ISH), diabetes, and history of cardiovascular disease (CVD) are shown in Figure 3 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

  Figure 3: Primary Endpoint Events^†within Demographic Subgroups

  
  )

Nephropathy in Type 2 Diabetic Patients

• Usual dose: 50 mg once daily. (
  2.3 Nephropathy in Type 2 Diabetic Patients

  The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response

  [see Clinical Studies (14.3)]

  .
  )
• Increase dose to 100 mg once daily if further blood pressure response is needed. (
  2.3 Nephropathy in Type 2 Diabetic Patients

  The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response

  [see Clinical Studies (14.3)]

  .
  )

Tablets: 25 mg; 50 mg; and 100 mg. (

• Losartan potassium is not recommended in pediatric patients less than 6 years of age or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m². (
  2.1 Hypertension

  Adult Hypertension

  The usual starting dose of losartan potassium tablets is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure

  [see Clinical Studies (14.1)].

  A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

  Pediatric Hypertension

  The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension

  [see Dosage and Administration (2.5)]

  . Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients

  [see Clinical Pharmacology (12.3), Clinical Studies (14.1), and Warnings and Precautions (5.2)].

  Losartan potassium tablets are not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m²

  [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14)].
  ,
  8.4 Pediatric Use

  Antihypertensive effects of losartan potassium have been established in hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m²

  [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]

  .
  )
• Hepatic Impairment: Recommended starting dose 25 mg once daily. (
  2.4 Dosage Modifications in Patients with Hepatic Impairment

  In patients with mild-to-moderate hepatic impairment the recommended starting dose of losartan potassium tablets is 25 mg once daily. Losartan potassium tablets has not been studied in patients with severe hepatic impairment

  [see Use in Specific Populations (8.8)and Clinical Pharmacology (12.3)]

  .
  ,
  8.8 Hepatic Impairment

  The recommended starting dose of losartan potassium is 25 mg in patients with mild-to-moderate hepatic impairment. Following oral administration in patients with mild-to-moderate hepatic impairment, plasma concentrations of losartan and its active metabolite were, respectively, 5 times and 1.7 times those seen in healthy volunteers. Losartan potassium has not been studied in patients with severe hepatic impairment

  [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

  .
  ,
  12.3 Pharmacokinetics

  Absorption

  : Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.

  Distribution

  : The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

  Metabolism:

  Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed.

  In vitro

  studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

  Elimination:

  Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral¹⁴C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of¹⁴C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.

  Specific Populations

  Pediatric:

  Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below.

  Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6-16 Following Multiple Dosing

  + standard deviation
  	Adults given 50 mg once daily for 7 days N=12			Age 6-16 given 0.7 mg/kg once daily for 7 days N=25
  	Parent	Active Metabolite		Parent	Active Metabolite
  AUC0-24(ng•hr/mL)Mean	442 + 173	1685 + 452		368 + 169	1866 + 1076
  CMAX (ng/mL)	224 + 82	212 + 73		141 + 88	222 + 127
  T1/2(h)Harmonic mean and standard deviation	2.1 + 0.70	7.4 + 2.4		2.3 + 0.8	5.6 + 1.2
  TPEAK(h)Median	0.9	3.5		2.0	4.1
  CLREN(mL/min)	56 + 23	20 + 3		53 + 33	17 + 8

  The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both losartan and the active metabolite

  [see Dosage and Administration (2.5)]

  .

  Geriatric and Gender:

  Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary

  [see Dosage and Administration (2.1)]

  .

  Race:

  Pharmacokinetic differences due to race have not been studied

  [see Use in Specific Populations (8.6)].

  Renal Insufficiency

  : Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50-90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis

  [see Warnings and Precautions (5.3)and Use in Specific Populations (8.7)]

  .

  Hepatic Insufficiency:

  Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment. Losartan potassium has not been studied in patients with severe hepatic impairment

  [see Dosage and Administration (2.4)and Use in Specific Populations (8.8)].

  Drug Interactions

  No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

  The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.
  )