Losartan

Losartan is an oral medication that belongs to a class of drugs called angiotensin receptor blockers (ARBs). Other ARBs include irbesartan (Avapro), valsartan (Diovan), and candesartan (Atacand). Angiotensin formed in the blood by the action of angiotensin converting enzyme (ACE) is a powerful chemical that attaches to angiotensin receptors found in many tissues but primarily on smooth muscle cells of blood vessels. Angiotensin's attachment to the receptors causes the muscle cells to contract and the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Losartan (more specifically, the chemical formed when the liver converts the inactive losartan into its active form) blocks the angiotensin receptor. By blocking the action of angiotensin, losartan relaxes muscle cells and dilates blood vessels thereby reducing blood pressure.

Losartan was approved by the FDA in April 1995.

Losartan is part of the drug class:

• ANGIOTENSIN II ANTAGONISTS, PLAIN

Your doctor will determine the best dose for you. Follow the directions on your prescription label carefully. Your doctor will probably start you on a low dose of losartan and gradually increase your dose. Losartan can be given once or twice daily with total daily doses ranging from 25 mg to 100 mg.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Signs of a common cold.
• Dizziness.
• Loose stools (diarrhea).
• Feeling tired or weak.
• Back pain.
• Stuffy nose.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• If a liquid (suspension) is made from the tablets, store in a refrigerator. Do not freeze. Throw away any part not used after 28 days.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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.

Treatment with Losartan potassium was well-tolerated with an overall incidence of adverse events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated with Losartan potassium and 3.7% of patients given placebo. In 4 clinical trials involving over 1000 patients on various doses (10 to 150 mg) of Losartan potassium and over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with Losartan potassium and more commonly than placebo were: dizziness (3% vs. 2%), upper respiratory infection (8% vs. 7%), nasal congestion (2% vs. 1%), and back pain (2% vs. 1%).

The following less common adverse reactions have been reported:

Blood and lymphatic system disorders: Anemia.

Psychiatric disorders: Depression.

Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine.

Ear and labyrinth disorders: Vertigo, tinnitus.

Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA.

Respiratory, thoracic and mediastinal disorders: Dyspnea.

Gastrointestinal disorders: Abdominal pain, constipation, nausea, vomiting.

Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

Reproductive system and breast disorders: Impotence.

General disorders and administration site conditions: Edema.

Cough

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 in Table 1 below.

Table 1:

* Demographics = (89% Caucasian, 64% female)

† Demographics = (90% Caucasian, 51% female)

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.

Hypertensive Patients with Left Ventricular Hypertrophy

In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with Losartan potassium were similar to those reported previously for patients with hypertension.

Nephropathy in Type 2 Diabetic Patients

In the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study involving 1513 patients treated with Losartan potassium or placebo, the overall incidences of reported adverse events were similar for the two groups. Discontinuations of Losartan potassium because of side effects were similar to placebo (19% for Losartan potassium, 24% for placebo). The adverse events, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with Losartan potassium and occurring with ≥2% difference in the Losartan group vs. placebo on a background of conventional antihypertensive therapy, were asthenia/fatigue, chest pain, hypotension, orthostatic hypotension, diarrhea, anemia, hyperkalemia, hypoglycemia, back pain, muscular weakness, and urinary tract infection.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience with Losartan potassium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure:

Digestive: Hepatitis.

General Disorders and Administration Site Conditions: Malaise.

Hematologic: Thrombocytopenia.

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: Hyponatremia.

Musculoskeletal: Rhabdomyolysis.

Nervous system disorders: Dysgeusia.

Skin: Erythroderma.

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.

Hypertension

Adult H ypertension

The antihypertensive effects of Losartan potassium 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 to 115. The studies allowed comparisons of two doses (50 to 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 mg 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 to 10.5/3.5 to 7.5 mmHg, with the 150 mg dose giving no greater effect than 50 to 100 mg. Twice-daily dosing at 50 to 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 to 95% and 60 to 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 was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).

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 ( 2.1)]. 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 95th 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.

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 50 mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) w as 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 o f 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

*Rate per 1000 patient-years of follow-up

†Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy

‡Death due to heart failure, non-coronary vascular disease, pulmonary embolism, or a cardiovascular cause other than stroke or coronary heart disease

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

The 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 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 resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 4). Treatment with Losartan potassium 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 4).

The mean baseline blood pressures were 152/82 mmHg for Losartan potassium 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 and 146/77 mmHg for the group treated with placebo.

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 4: Incidence of Primary Endpoint Events

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 potassium 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 potassium 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 potassium in patient subgroups defined by age, gender and race are shown in Table 5 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

Table 5: Efficacy Outcomes within Demographic Subgroups

• Angiotensin II Receptor Blocker
• Antihypertensive

Plasma concentrations of losartan are increased 5 times and active metabolite increased 1.7 times in patients with mild to moderate alcoholic cirrhosis. Total plasma clearance of losartan is reduced ~50% and oral bioavailability is about doubled.

Refer to adult dosing.

Hypertension: Oral: Children ≥6 years and Adolescents ≤16 years:

US labeling: Initial: 0.7 mg/kg once daily (maximum initial dose: 50 mg/day); adjust dose to blood pressure response; doses >1.4 mg/kg (>100 mg) once daily have not been studied

Canadian labeling:

≥20 kg to <50 kg: Initial: 25 mg once daily; adjust dose to blood pressure response (maximum: 50 mg/day)

≥50 kg: Initial: 50 mg once daily; adjust dose to blood pressure response (maximum: 100 mg/day)

Aortic-root dilation with Marfan’s syndrome (off-label use): Children 14 months to 16 years: Initial: 0.6 mg/kg/day; can be increased to a maximum of 1.4 mg/kg/day (not to exceed adult maximum of 100 mg daily) (Brooke, 2008)

Some products may contain potassium.

Store at 25°C (77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Concerns related to adverse effects:

• Angioedema: Angioedema has been reported rarely with some angiotensin II receptor antagonists (ARBs) and may occur at any time during treatment (especially following first dose). It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with angiotensin-converting enzyme (ACE) inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Discontinue therapy immediately if angioedema occurs. Aggressive early management is critical. Intramuscular (IM) administration of epinephrine may be necessary. Do not readminister to patients who have had angioedema with ARBs.

• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypotension: Symptomatic hypotension may occur upon initiation in patients who are salt or volume depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration. This transient hypotensive response is not a contraindication to further treatment with losartan.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.

• Hepatic impairment: Use with caution in patients with hepatic impairment or a history of hepatic impairment; dose adjustment needed.

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution with preexisting renal insufficiency.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Black patients: When used to reduce the risk of stroke in patients with HTN and LVH, may not be effective in the black population.

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

• Surgical patients: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis, 2011).

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. The use of drugs which act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Use is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed in utero should be monitored for hyperkalemia, hypotension, and oliguria (exchange transfusions or dialysis may be needed). These adverse events are generally associated with maternal use in the second and third trimesters.

Untreated chronic maternal hypertension is also associated with adverse events in the fetus, infant, and mother. The use of angiotensin II receptor blockers is not recommended to treat chronic uncomplicated hypertension in pregnant women and should generally be avoided in women of reproductive potential (ACOG, 2013).

Get emergency medical help if you have any of these signs of an allergic reaction to losartan: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

In rare cases, losartan can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Call your doctor at once if you have:

• a feeling that you might pass out;

• pain or burning when you urinate;

• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• wheezing, chest pain;

• drowsiness, confusion, mood changes, increased thirst, loss of appetite, nausea and vomiting;

• swelling, weight gain, feeling short of breath, urinating less than usual or not at all; or

• high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling).

Common losartan side effects may include:

• cold or flu symptoms such as stuffy nose, sneezing, sore throat, fever;

• dry cough;

• muscle cramps;

• pain in your legs or back;

• stomach pain, diarrhea;

• headache, dizziness;

• tired feeling; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to losartan: oral tablet

Along with its needed effects, losartan may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking losartan:

• Abdominal or stomach pain
• anxiety
• bladder pain
• bloody or cloudy urine
• blurred vision
• chills
• cold sweats
• coma
• confusion
• cool, pale skin
• depression
• difficult breathing
• difficult, burning, or painful urination
• dizziness
• fast heartbeat
• frequent urge to urinate
• headache
• increased hunger
• irregular heartbeat
• lower back or side pain
• nausea or vomiting
• nightmares
• numbness or tingling in the hands, feet, or lips
• pale skin
• seizures
• shakiness
• shortness of breath
• slurred speech
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• weakness or heaviness of the legs

• Arm, back, or jaw pain
• chest pain or discomfort
• chest tightness or heaviness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, irregular, pounding, or racing heartbeat or pulse
• inability to speak
• pain or discomfort in the arms, jaw, back, or neck
• severe or sudden headache
• sweating
• swelling or puffiness of the face
• temporary blindness
• unsteadiness or awkwardness
• weakness in the arm or leg on one side of the body, sudden and severe
• weakness in the arms, hands, legs, or feet

• Black, tarry stools
• bleeding gums
• cough
• dark urine
• difficulty with swallowing
• general tiredness and weakness
• hives
• itching
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• muscle cramps or spasms
• muscle pain or stiffness
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• skin rash
• upper right abdominal or stomach pain
• yellow eyes and skin

Some side effects of losartan may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blindness
• body aches or pain
• decreased vision
• dry cough
• ear congestion
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat

• Acid or sour stomach
• back pain
• belching
• difficulty with moving
• heartburn
• increased sensitivity to pain
• increased sensitivity to touch
• indigestion
• joint pain
• lack or loss of strength
• pain in the knees or legs
• pain or tenderness around the eyes and cheekbones
• stomach discomfort or upset
• swollen joints
• trouble sleeping
• weight gain

• Ankle, knee, or great toe joint pain
• bloated
• change or loss of taste
• depression
• difficulty having a bowel movement (stool)
• dry skin
• excess air or gas in the stomach or intestines
• full feeling
• hair loss or thinning of the hair
• hearing loss
• increased sensitivity of the skin to sunlight
• loss of appetite
• passing gas
• redness or other discoloration of the skin
• severe sunburn
• weight loss

Applies to losartan: oral tablet

General

The most common adverse reactions were upper respiratory infection and dizziness.[Ref]

Respiratory

Common (1% to 10%): Nasal congestion, upper respiratory infection, sinusitis, pharyngitis, cough, sinus disorder
Uncommon (0.1% to 1%): Dyspnea
Frequency not reported: Bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion[Ref]

Gastrointestinal

Common (1% to 10%): Abdominal pain, nausea, diarrhea, dyspepsia
Uncommon (0.1% to 1%): Obstipation, vomiting
Frequency not reported: Constipation, dental pain, dry mouth, flatulence, gastritis[Ref]

Musculoskeletal

Common (1% to 10%): Muscle cramp, back pain, leg pain, myalgia
Frequency not reported: Arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness
Postmarketing reports: Rhabdomyolysis[Ref]

Renal

Common (1% to 10%): Renal impairment, renal failure, BUN increased, serum creatinine increased[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache, vertigo
Uncommon (0.1% to 1%): Somnolence
Rare (less than 0.1%): Paresthesia, syncope, cerebrovascular accident
Frequency not reported: Ataxia, hypesthesia, memory impairment, migraine, peripheral neuropathy, tremor, taste perversion, tinnitus[Ref]

Other

Common (1% to 10%): Asthenia/fatigue, edema/swelling, chest pain
Frequency not reported: Facial edema, fever, orthostatic effects
Postmarketing reports: Malaise[Ref]

Metabolic

Common (1% to 10%): Hyperkalemia, serum potassium increased, hypoglycemia
Frequency not reported: Anorexia, gout
Postmarketing reports: Hyponatremia[Ref]

Cardiovascular

Common (1% to 10%): Orthostatic hypotension
Uncommon (0.1% to 1%): Palpitation, angina pectoris
Rare (less than 0.1%): Atrial fibrillation
Frequency not reported: Second degree atrioventricular block, hypotension, myocardial infarction, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation, flushing
Postmarketing reports: Vasculitis[Ref]

Psychiatric

Common (1% to 10%): Insomnia
Uncommon (0.1% to 1%): Sleep disorder
Frequency not reported: Anxiety, anxiety disorder, confusion, depression, dream abnormality, libido decreased, nervousness, panic disorder[Ref]

Hematologic

Common (1% to 10%): Anemia
Rare (less than 0.1%): Hemolysis
Postmarketing reports: Thrombocytopenia, hemoglobin decreased, hematocrit decreased[Ref]

Dermatologic

Uncommon (0.1% to 1%): Urticaria, pruritus, rash
Rare (less than 0.1%): Angioedema, superficial peeling of palms
Frequency not reported: Alopecia, dermatitis, dry skin, ecchymosis, erythema, photosensitivity, sweating
Postmarketing reports: Erythroderma[Ref]

Hepatic

Rare (less than 0.1%): ALT increased
Postmarketing reports: Hepatitis, liver enzymes increased, serum bilirubin increased, pancreatitis, liver function abnormalities[Ref]

Genitourinary

Frequency not reported: Impotence, nocturia, urinary frequency, urinary tract infection[Ref]

Ocular

Frequency not reported: Blurred vision, burning/stinging in the eye, conjunctivitis, visual acuity decreased[Ref]

Immunologic

Frequency not reported: Flu-like symptoms
Postmarketing reports: Anaphylactic reactions, hypersensitivity reactions[Ref]

Some side effects of losartan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

US BOXED WARNING:
-FETAL TOXICITY: If pregnancy is detected, discontinue this drug as soon as possible. Drugs that act directly on the renin angiotensin system (RAS) can cause injury and death to the developing fetus.

Safety and efficacy have not been established in patients younger than 6 years.

Consult WARNINGS section for additional precautions.