ADVERSE REACTIONS

Hypertension

Losartan potassium has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year. In general, treatment with losartan potassium was well- tolerated. The overall incidence of adverse experiences reported with losartan potassium was similar to placebo.

In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 2.3 percent of patients treated with losartan potassium and 3.7 percent of patients given placebo.

The following table of adverse events is based on four 6 to 12 week, placebo- controlled trials involving over 1000 patients on various doses (10 to 150 mg) of losartan and over 300 patients given placebo. All doses of losartan are grouped because none of the adverse events appeared to have a dose-related frequency. The adverse experiences reported in ≥ 1% of patients treated with losartan potassium and more commonly than placebo are shown in the table below.

	Losartan (n = 1075) Incidence %	Placebo (n = 334) Incidence %
Musculoskeletal
Cramp, muscle	1	0
Pain, back	2	1
Pain, leg	1	0
Nervous System/Psychiatric
Dizziness	3	2
Respiratory
Congestion, nasal	2	1
Infection, upper respiratory	8	7
Sinusitis	1	0

The following adverse events were also reported at a rate of 1% or greater in patients treated with losartan, but were as, or more frequent, in the placebo group: asthenia/fatigue, edema/swelling, abdominal pain, chest pain, nausea, headache, pharyngitis, diarrhea, dyspepsia, myalgia, insomnia, cough, sinus disorder.

Adverse events occurred at about the same rates in men and women, older and younger patients, and Black and non-Black patients.

A patient with known hypersensitivity to aspirin and penicillin, when treated with losartan potassium, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.

Superficial peeling of palms and hemolysis were reported in one subject.

In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to losartan or other adverse events that occurred in < 1% of patients in clinical studies are listed below. It cannot be determined whether these events were causally related to losartan:

Body as a Whole: facial edema, fever, orthostatic effects, syncope;

Cardiovascular: angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation;

Digestive: anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting;

Hematologic: anemia;

Metabolic: gout;

Musculoskeletal: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness;

Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, decreased libido, memory impairment, migraine, nervousness, paresthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo;

Respiratory: dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion;

Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria;

Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity;

Urogenital: impotence, nocturia, urinary frequency, urinary tract infection.

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n = 97) or 25 mg hydrochlorothiazide (n = 135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown below.

Demographics = (89% caucasian, 64% female) † Demographics = (90% caucasian, 51% female)
Study 1*	HCTZ	Losartan	Lisinopril
Cough	25%	17%	69%
Study 2†	Placebo	Losartan	Lisinopril
Cough	35%	29%	62%

These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.

Pediatric Patients

No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.

Hypertensive Patients With Left Ventricular Hypertrophy

In the LIFE study, adverse events with losartan potassium were similar to those reported previously for patients with hypertension.

Nephropathy in Type 2 Diabetic Patients

In the RENAAL study involving 1513 patients treated with losartan potassium or placebo, the overall incidences of reported adverse experiences were similar for the two groups. Losartan potassium was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo (19% for losartan potassium, 24% for placebo). The adverse experiences, regardless of drug relationship, reported with an incidence of ≥ 4% of patients treated with losartan potassium and occurring more commonly than placebo, on a background of conventional antihypertensive therapy, are shown in the table below.

	Losartan and Conventional Antihypertensive Therapy Incidence	Placebo and Conventional Antihypertensive Therapy Incidence
%	%
(n = 751)	(n = 762)
Body as a Whole
Asthenia/Fatigue	14	10
Chest Pain	12	8
Fever	4	3
Infection	5	4
Influenza-like disease	10	9
Trauma	4	3
Cardiovascular
Hypotension	7	3
Orthostatic hypotension	4	1
Digestive
Diarrhea	15	10
Dyspepsia	4	3
Gastritis	5	4
Endocrine
Diabetic neuropathy	4	3
Diabetic vascular disease	10	9
Eyes, Ears, Nose and Throat
Cataract	7	5
Sinusitis	6	5
Hemic
Anemia	14	11
Metabolic and Nutrition
Hyperkalemia	7	3
Hypoglycemia	14	10
Weight gain	4	3
Musculoskeletal
Back pain	12	10
Leg pain	5	4
Knee pain	5	4
Muscular weakness	7	4
Nervous System
Hypesthesia	5	4
Respiratory
Bronchitis	10	9
Cough	11	10
Skin
Cellulitis	7	6
Urogenital
Urinary tract infection	16	13

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience:

Digestive: Hepatitis (reported rarely).

General Disorders and Administration Site Conditions: Malaise.

Hemic: Thrombocytopenia (reported rarely).

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE-inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported. Anaphylactic reactions have been reported.

Metabolic and Nutrition: Hyperkalemia, hyponatremia have been reported with losartan.

Musculoskeletal: Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Nervous system disorders: Dysgeusia.

Respiratory: Dry cough (see above).

Skin: Erythroderma.

Laboratory Test Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan potassium.

Creatinine, Blood Urea Nitrogen

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with losartan potassium alone (seePRECAUTIONS, Impaired Renal Function).

Hemoglobin and Hematocrit

Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred frequently in patients treated with losartan potassium alone, but were rarely of clinical importance. No patients were discontinued due to anemia.

Liver Function Tests

Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with losartan potassium alone, one patient (< 0.1%) was discontinued due to these laboratory adverse experiences.

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 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 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 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. These conditions should be corrected prior to administration of losartan potassium, or a lower starting dose should be used (seeDOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

Hypersensitivity

Angioedema. SeeADVERSE REACTIONS,Postmarketing Experience.

Impaired Hepatic Function

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with impaired liver function (seeDOSAGE AND ADMINISTRATION andCLINICAL****PHARMACOLOGY,Pharmacokinetics).

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with losartan potassium; in some patients, these changes in renal function were reversible upon discontinuation of therapy.

In patients whose renal function may depend on the activity of the renin- angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with losartan potassium.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with losartan potassium; in some patients, these effects were reversible upon discontinuation of therapy.

Electrolyte Imbalance

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with losartan potassium as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see ADVERSE REACTIONS).

Information for Patients

Pregnancy

Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin- angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Potassium Supplements

A patient receiving losartan potassium should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician (seePRECAUTIONS,Drug Interactions).

Drug Interactions

No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite. (SeeCLINICAL PHARMACOLOGY, Drug Interactions.) In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. 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.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Lithium

As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be coadministered with angiotensin II receptor antagonists.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective

Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day.

Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p < 0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Pregnancy

Teratogenic Effects

Pregnancy categories C (first trimester) and D (second and third

trimesters)

SeeWARNINGS,Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Antihypertensive effects of losartan potassium have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data on the effect of losartan potassium on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2 (seeCLINICAL PHARMACOLOGY,Pharmacokinetics, Special Populations andPharmacodynamics and****Clinical Effects, andDOSAGE AND ADMINISTRATION).

Geriatric Use

Of the total number of patients receiving losartan potassium in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Race

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on losartan potassium. 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 does not provide evidence that the benefits of losartan potassium on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients. (SeeCLINICAL PHARMACOLOGY, PharmacodynamicsandClinical Effects, Reduction in the Risk of Stroke.)

DOSAGE AND ADMINISTRATION

Adult Hypertensive Patients

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

Dosing must be individualized. The usual starting dose of losartan potassium tablets USP 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 (seePRECAUTIONS,General). Losartan potassium tablets USP 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 (seeCLINICAL PHARMACOLOGY,Pharmacodynamics and Clinical Effects, Hypertension).

If blood pressure is not controlled by losartan potassium tablets USP alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (seeCLINICAL 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 ≥ 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 (seePreparation 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. (SeeCLINICAL PHARMACOLOGY,Pharmacokinetics, Special Populations andPharmacodynamics and Clinical Effects, and WARNINGS,Hypotension – Volume-Depleted Patients.)

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

Preparation of Suspension (for 200 mL of a 2.5 mg/mL Suspension)

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg losartan potassium tablets USP. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus™* and Ora-Sweet SF™*. Add 190 mL of the 50/50 Ora-Plus™/Ora-Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2 to 8°C (36 to 46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

• Ora-Plus™ and Ora-Sweet SF™ are the trademarks of Paddock Laboratories, Inc.

Hypertensive Patients With Left Ventricular Hypertrophy

The usual starting dose is 50 mg of losartan potassium tablets USP once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of losartan potassium tablets USP should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response (seeCLINICAL PHARMACOLOGY,Pharmacodynamics and****Clinical Effects, Reduction in the Risk of Stroke).

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 (seeCLINICAL PHARMACOLOGY,Pharmacodynamics and Clinical Effects, Nephropathy in Type 2 Diabetic Patients). Losartan potassium tablets USP may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).