Losartan Potassium

WARNING: FETAL TOXICITY

•   When pregnancy is detected, discontinue losartan potassium as soon as possible.
•   Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS, Fetal Toxicity.      

Losartan potassium is an angiotensin II receptor (type AT ₁) antagonist. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt.

Its molecular formula is C ₂₂H ₂₂ClKN ₆O, and its structural formula is:

[image: img_1f919c57-4ae4-6f17-e054-00144ff88e88]

Losartan potassium, USP is white to off-white powder with a molecular weight of 461.01. It is freely soluble in water; soluble in isopropyl alcohol; slightly soluble in acetonitrile. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Each losartan potassium tablet, USP intended for oral administration contains 25 mg or 50 mg or 100 mg of losartan potassium. In addition, each tablet contains the following inactive ingredients: colloidal silica anhydrous, hydroxypropyl cellulose (low substituted), hypromellose, lactose monohydrate, magnesium stearate, maize starch (corn starch), microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

Losartan potassium tablets, USP 25 mg, 50 mg and 100 mg contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a multinational, double-blind study comparing losartan potassium tablets 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 tablets 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 tablets 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 tablets 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 non-fatal 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 tablets resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the atenolol group (see Figure 1 and Table 2); this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with losartan potassium tablets reduced the risk of stroke by 25% relative to atenolol (p=0.001) (see Figure 2 and Table 2).

[image: img_1f915bbb-9386-6cfd-e054-00144ff8d46c]

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 tablets and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

[image: img_1f915bbb-9387-6cfd-e054-00144ff8d46c]

Figure 2 Kaplan-Meier estimates of the time to fatal/nonfatal stroke in the groups treated with losartan potassium tablets and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

Table 2 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 intention-to-treat (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.

Table2Incidence of Primary Endpoint Events

*Rate per 1000 patient years of follow-up
†Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricularhypertrophy
‡ First report of an event, in some cases the patient died subsequently to the event reported
§ Death due to heart failure, non-coronary vascular disease, pulmonary embolism, or a cardiovascular cause other than stroke or coronary heart disease
	Losartan Potassium		Atenolol		Risk Reduction †	95 % CI	p - Value
	N (%)	Rate *	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
Other§	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 tablets and placebo. Although not measured directly, the difference between losartan potassium tablets 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 tablets and atenolol groups.

For the primary endpoint and stroke, the effects of losartan potassium tablets 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

[image: img_1f91c387-c720-0869-e054-00144ff88e88]

Symbols are proportional to sample size.

^* Other includes Asian, Hispanic, Asiatic, Multi-race, Indian, Native American, European.

^† Adjsuted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

Losartan-K = Losartan Potassium.

In the LIFE study, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with losartan potassium tablets. In the subgroup of Black patients (n=533; 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient years) on losartan potassium tablets. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of losartan potassium tablets on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.

Nephropathy in Type 2 Diabetic Patients:

The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a randomized, placebo controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3 mg/dl in females or males ≤60 kg and 1.5 to 3 mg/dl in males >60 kg and proteinuria [urinary albumin to creatinine ratio ≥300 mg/g]).

Patients were randomized to receive losartan potassium tablet 50 mg once daily or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. After one month, investigators were instructed to titrate study drug to 100 mg once daily if the trough blood pressure goal (140/90 mmHg) was not achieved. Overall, 72% of patients received the 100 mg daily dose more than 50% of the time they were on study drug. Because the study was designed to achieve equal blood pressure control in both groups, other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups. Patients were followed for a mean duration of 3.4 years.

The study population was diverse with regard to race (Asian 16.7%, Black 15.2%, Hispanic 18.3%, White 48.6%). Overall, 63.2% of the patients were men, and 66.4% were under the age of 65 years. Almost all of the patients (96.6%) had a history of hypertension, and the patients entered the trial with a mean serum creatinine of 1.9 mg/dl and mean proteinuria (urinary albumin/creatinine) of 1808 mg/g at baseline.

The primary endpoint of the study was the time to first occurrence of any one of the following events: doubling of serum creatinine, end-stage renal disease (ESRD) (need for dialysis or transplantation), or death. Treatment with losartan potassium tablets resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 3). Treatment with losartan potassium tablets also reduced the occurrence of sustained doubling of serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality (see Table 3).

The mean baseline blood pressures were 152/82 mmHg for losartan potassium tablets plus conventional antihypertensive therapy and 153/82 mmHg for placebo plus conventional antihypertensive therapy. At the end of the study, the mean blood pressures were 143/76 mmHg for the group treated with losartan potassium tablets and 146/77 mmHg for the group treated with placebo.

[image: img_1f915bbb-9389-6cfd-e054-00144ff8d46c]

Figure 4. Kaplan-Meier curve for the primary composite endpoint of doubling of serum creatinine, end stage renal disease (need for dialysis or transplantation) or death.

Table 3Incidence of Primary Endpoint Events

	Incidence	Risk Reduction	95 % C . I .	p - Value
	Losartan	Placebo
Primary Composite Endpoint	43 . 5 %	47 . 1 %	16 . 1 %	2 . 3 % to 27 . 9 %	0 . 22
Doubling of Serum Creatinine, ESRD and Death Occurring as a First Event
Doubling of Serum Creatinine	21.6%	26%
ESRD	8.5%	8.5%
Death	13.4%	12.6%
Overall Incidence of Doubling of Serum Creatinine, ESRD and Death
Doubling of Serum Creatinine	21.6%	26%	25.3%	7.8% to 39.4%	0.006
ESRD	19.6%	25.5%	28.6%	11.5% to 42.4%	0.002
Death	21%	20.3%	-1.7%	-26.9% to 18.6%	0.884

The secondary endpoints of the study were change in proteinuria, change in the rate of progression of renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or cardiovascular death). Compared with placebo, losartan significantly reduced proteinuria by an average of 34%, an effect that was evident within 3 months of starting therapy, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13%, as measured by the reciprocal of the serum creatinine concentration. There was no significant difference in the incidence of the composite endpoint of cardiovascular morbidity and mortality.

The favorable effects of losartan were seen in patients also taking other anti-hypertensive medications (angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors were not allowed), oral hypoglycemic agents and lipid-lowering agents.

For the primary endpoint and ESRD, the effects of losartan in patient subgroups defined by age, gender and race are shown in Table 4 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

Table 4Efficacy Outcomes within Demographic Subgroups

	No . of Patients	Primary Composite Endpoint			ESRD
		Losartan Potassium Tablets Event Rate %	Placebo Event Rate %	Hazard Ratio ( 95 % CI )	Losartan Potassium Tablets Event Rate %	Placebo Event Rate %	Hazard Ratio ( 95 % CI )
Overall Results	1513	43.5	47.1	0.839 (0.721, 0.977)	19.6	25.5	0.714 (0.576, 0.885)
Age
<65 years	1005	44.1	49	0.784 (0.653, 0.941)	21.1	28.5	0.670 (0.521, 0.863)
≥65 years	508	42.3	43.5	0.978 (0.749, 1.277)	16.5	19.6	0.847 (0.560, 1.281)
Gender
Female	557	47.8	54.1	0.762 (0.603, 0.962)	22.8	32.8	0.601 (0.436, 0.828)
Male	956	40.9	43.3	0.892 (0.733, 1.085)	17.5	21.5	0.809 (0.605, 1.081)
Race
Asian	252	41.9	54.8	0.655 (0.453, 0.947)	18.8	27.4	0.625 (0.367, 1.066)
Black	230	40	39	0.983 (0.647, 1.495)	17.6	21	0.831 (0.456, 1.516)
Hispanic	277	55	54	1.003 (0.728, 1.380)	30	28.5	1.024 (0.661, 1.586)
White	735	40.5	43.2	0.809 (0.645, 1.013)	16.2	23.9	0.596 (0.427, 0.831)

Losartan potassium tablets are contraindicated in patients who are hypersensitive to any component of this product.

Do not co-administer aliskiren with losartan potassium tablets in patients with diabetes.

Significant lethality was observed in mice and rats after oral administration of   1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m ² basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor its active metabolite can be removed by hemodialysis.

Adult Hypertensive Patients:

Losartan potassium tablets may be administered with other antihypertensive agents, and with or without food.

Dosing must be individualized. The usual starting dose of losartan potassium tablets is 50 mg once daily, with 25 mg used in patients with possible depletion of intravascular volume (e.g., patients treated with diuretics) (see WARNINGS, Hypotension — Volume-Depleted Patients ) and patients with a history of hepatic impairment (see PRECAUTIONS, General ). Losartan potassium tablets can be administered once or twice daily with total daily doses ranging from 25 mg to 100 mg.

If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 weeks (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension ).

If blood pressure is not controlled by losartan potassium tablets alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension ).

No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.

Pediatric Hypertensive Patients greater than or equal to 6 years of age:

The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total) administered as a tablet or a suspension (see Preparation of Suspension). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics,  Special Populations and Pharmacodynamics and Clinical Effects and WARNINGS, Hypotension — Volume-Depleted Patients, ).

Losartan potassium tablets are not recommended in pediatric patients <6 years of age or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics,  Special Populations, Pharmacodynamics and Clinical Effects, and PRECAUTIONS ).

Losartan Potassium Tablets USP, 25 mg are white to off-white, capsule-shaped, film-coated tablets debossed with the logo of "Z" on one side and "2"on other side and are supplied as follows:

NDC 68382-135-06 in bottle of 30 tablets

NDC 68382-135-16 in bottle of 90 tablets

NDC 68382-135-01 in bottle of 100 tablets

NDC 68382-135-10 in bottle of 1,000 tablets

NDC 68382-135-24 in bottle of 10,000 tablets

Losartan Potassium Tablets USP, 50 mg are white to off-white, capsule-shaped, film-coated tablets debossed with the logo of "Z16" on one side and lip type breakline on other side and are supplied as follows:

NDC 68382-136-06 in bottle of 30 tablets

NDC 68382-136-16 in bottle of 90 tablets

NDC 68382-136-01 in bottle of 100 tablets

NDC 68382-136-10 in bottle of 1,000 tablets

NDC 68382-136-24 in bottle of 10,000 tablets

Losartan Potassium Tablets USP, 100 mg are white to off-white, capsule-shaped, film-coated tablets debossed with the logo of "Z18" on one side and plain on other side and are supplied as follows:

NDC 68382-137-06 in bottle of 30 tablets

NDC 68382-137-16 in bottle of 90 tablets

NDC 68382-137-01 in bottle of 100 tablets

NDC 68382-137-10 in bottle of 1,000 tablets

NDC 68382-137-24 in bottle of 10,000 tablets

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 10/14