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Losortan Potassium

Losartan Potassium Tablets, USP

FULL PRESCRIBING INFORMATION: CONTENTS*

LOSORTAN POTASSIUM DESCRIPTION
CLINICAL PHARMACOLOGY
LOSORTAN POTASSIUM INDICATIONS AND USAGE
- Hypertension:
- Hypertensive Patients with Left Ventricular Hypertrophy:
LOSORTAN POTASSIUM CONTRAINDICATIONS
WARNINGS
- Fetal/Neonatal Morbidity and Mortality:
- Hypotension — Volume-Depleted Patients:
PRECAUTIONS
LOSORTAN POTASSIUM ADVERSE REACTIONS
OVERDOSAGE
LOSORTAN POTASSIUM DOSAGE AND ADMINISTRATION
- Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension):
- Hypertensive Patients with Left Ventricular Hypertrophy:
HOW SUPPLIED
- Storage:
SPL PATIENT PACKAGE INSERT
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
Principal Display Panel
Principal Display Panel

FULL PRESCRIBING INFORMATION

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, losartan potassium tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

LOSORTAN POTASSIUM DESCRIPTION

Losartan potassium is an angiotensin II receptor (type AT₁) 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 C₂₂H₂₂ClKN₆O, and its structural formula is:

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

Each losartan potassium tablet 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 25 mg, 50 mg and 100 mg tablets 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.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT₂receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT₁ receptor and have much greater affinity (about 1000-fold) for the AT₁ receptor than for the AT₂ receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT₁ receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT₁ receptor.

Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacokinetics:

General:

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. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of ¹⁴C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.

The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.

Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. 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 of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its C_max but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).

The pharmacokinetics of losartan and its active metabolite were also determined after IV doses of each component separately in healthy volunteers. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. 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. 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 oral ¹⁴C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of ¹⁴C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.

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.

Special 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 1 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 1Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6-16 Following Multiple Dosing
	Adults given 50 mg once daily for 7days N=12		Age 6-16 given 0.7 mg/kg once daily for 7 days N=25
	Parent	Active Metabolite	Parent	Active Metabolite
AUC₀ _- ₂ ₄ Mean ± standard deviation(ng·h/mL)	442 ±173	1685 ± 452	368 ± 169	1866 ± 1076
C _M _A _X (ng/mL)Mean ± standard deviation	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
T_P _E _A _K(h)Median	0.9	3.5	2.0	4.1
CL_R _E _N (mL/min)Mean ± standard deviation	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, Preparation of Suspension).

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).

Race:

Pharmacokinetic differences due to race have not been studied (see also PRECAUTIONS, Race and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race).

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. No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted (see WARNINGS, Hypotension —Volume-Depleted Patients and DOSAGE AND ADMINISTRATION).

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 2-times higher. A lower starting dose is recommended for patients with a history of hepatic impairment (see DOSAGE AND ADMINISTRATION).

Drug Interactions:

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin. Losartan did not affect the pharmacokinetics of oral or intravenous digoxin. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide. Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite. A somewhat greater interaction (approximately 40% reduction in the AUC of active metabolite and approximately 30% reduction in the AUC of losartan) has been reported with rifampin. 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, another inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

Pharmacodynamics and Clinical Effects:

Adult Hypertension:

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours.

Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.

In a single-dose study in normal volunteers, losartan had no effects on glomerular filtration rate, renal plasma flow or filtration fraction. In multiple-dose studies in hypertensive patients, there were no notable effects on systemic or renal prostaglandin concentrations, fasting triglycerides, total cholesterol or HDL-cholesterol or fasting glucose concentrations. There was a small uricosuric effect leading to a minimal decrease in serum uric acid (mean decrease <0.4 mg/dL) during chronic oral administration.

The antihypertensive effects of losartan potassium tablets were demonstrated principally in 4 placebo-controlled, 6 to 12-week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparisons of two doses (50-100 mg/day) as once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.

The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The 10- and 25-mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100 and 150 mg once daily gave statistically significant systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5-10.5/3.5-7.5 mmHg, with the 150-mg dose giving no greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately, larger than trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50-95% and 60-90%, respectively.

Addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in placebo-adjusted blood pressure reductions of 15.5/9.2 mmHg.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, had generally similar responses. Losartan potassium tablets were effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).

The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.

Pediatric Hypertension:

The antihypertensive effect of losartan was studied in one trial enrolling 177 hypertensive pediatric patients aged 6 to 16 years old. Children who weighed <50 kg received 2.5, 25 or 50 mg of losartan daily and patients who weighed ≥ 50 kg received 5, 50 or 100 mg of losartan daily. Children in the lowest dose group were given losartan in a suspension formulation (see DOSAGE AND ADMINISTRATION, Preparation of Suspension). The majority of the children had hypertension associated with renal and urogenital disease. The sitting diastolic blood pressure (SiDBP) on entry into the study was higher than the 95^th percentile level for the patient’s age, gender, and height. At the end of three weeks, losartan reduced systolic and diastolic blood pressure, measured at trough, in a dose-dependent manner. Overall, the two higher doses (25 to 50 mg in patients < 50 kg; 50 to 100 mg in patients ≥ 50 kg) reduced diastolic blood pressure by 5 to 6 mmHg more than the lowest dose used (2.5 mg in patients < 50 kg; 5 mg in patients ≥ 50 kg). The lowest dose, corresponding to an average daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy. When patients were randomized to continue losartan at the two higher doses or to placebo after 3 weeks of therapy, trough diastolic blood pressure rose in patients on placebo between 5 and 7 mmHg more than patients randomized to continuing losartan. When the low dose of losartan was randomly withdrawn, the rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan, again suggesting that the lowest dose did not have significant antihypertensive efficacy. Overall, no significant differences in the overall antihypertensive effect of losartan were detected when the patients were analyzed according to age (<, ≥ 12 years old) or gender. While blood pressure was reduced in all racial subgroups examined, too few non-White patients were enrolled to compare the dose-response of losartan in the non-White subgroup.

Reduction in the Risk of Stroke:

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).

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.

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.

Table 2 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 (%)	RateRate per 1000 patient-years of follow-up
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 (nonfatalFirst report of an event, in some cases the patient died subsequently to the event reported)	209 (5)		286 (6)
Myocardial infarction (nonfatalFirst report of an event, in some cases the patient died subsequently to the event reported)	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 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

Symbols are proportional to sample size.

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

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

Losartan-K = Losartan Potassium.

Race:

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.

LOSORTAN POTASSIUM INDICATIONS AND USAGE

Hypertension:

Losartan potassium tablets are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics.

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 PRECAUTIONS, Race and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race).

LOSORTAN POTASSIUM CONTRAINDICATIONS

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

WARNINGS

Fetal/Neonatal Morbidity and Mortality:

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, losartan potassium tablets should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of losartan potassium tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, losartan potassium tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Hypotension — Volume-Depleted Patients:

In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with losartan potassium tablets. These conditions should be corrected prior to administration of losartan potassium tablets, or a lower starting dose should be used (see DOSAGE AND ADMINISTRATION).