LOSARTAN POTASSIUM (Generic for COZAAR)

Losartan is the first of a unique class of oral antihypertensive agents called angiotensin II (AG II) receptor antagonists. Losartan and its longer acting active metabolite (E-3174) are specific and selective AT1 receptor antagonists. Losartan is indicated to treat essential hypertension, diabetic nephropathy, and proteinuria, and has also been used off-label to treat congestive heart failure. Compared with the angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalapril), losartan is associated with a lower incidence of drug-induced cough, rash, and/or taste disturbances. Because losartan does not inhibit ACE, it does not result in bradykinin accumulation which is theorized to cause the cough and angioedema associated with ACE inhibitors. However, angioedema has been rarely associated with losartan or other angiotensin II antagonists. Because AT1 receptors are nearly saturated at the starting dose for most angiotensin II antagonists, the antihypertensive dose-response curve of these drugs are nonlinear, with proportionally small decreases in blood pressure attained with increased dosage; greater antihypertensive efficacy is achieved by adding a small dose of a diuretic. The LIFE outcome trial (conducted in patients with hypertension and left ventricular hypertrophy) shows that losartan is more effective than atenolol in reducing total mortality and cardiovascular morbidity and mortality, and is associated with less drug-related adverse events. The results of the long-term (mean 3.4 years) RENAAL study reported that losartan (50-100 mg/day) is renoprotective (endpoints: doubling of serum creatinine, development of end-stage renal disease) in patients with type 2 diabetes and nephropathy. Although it is not FDA approved for the treatment of heart failure, losartan has been shown to lower all-cause mortality and hospitalization to a greater extent than captopril in elderly patients with chronic heart failure (ELITE I trial). Losartan (Cozaar(R)) was approved by the FDA for the treatment of hypertension in April 1995 and for the treatment of nephropathy in patients with type 2 diabetes mellitus in September 2002.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations:
-Tablets: May administer without regard to food.

Oral Liquid Formulations:
-Preparation of Suspension: To prepare 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 losartan 50 mg tablets. 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 2-8 degrees C (36-46 degrees F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

Losartan is generally well-tolerated. The overall incidence of adverse reactions in adult treatment groups are similar to placebo. Losartan has been evaluated in over 4,000 patients, many of whom received the drug for greater than 6-12 months. No relevant differences between the adverse experience profile for pediatric patients compared to adults have been identified.

In July 2010, the FDA released a Medwatch alert announcing the possibility of an increased risk of malignancy in patients taking angiotensin receptor blockers (ARBs), such as losartan, for the treatment of hypertension. This announcement was based on results of a meta-analysis including data from over 1000 patients in several long-term, randomized, controlled clinical trials evaluating ARBs. Frequencies of new cancer occurrence was 7.2% for patients receiving ARBs compared to 6% for those not receiving ARBs (RR = 1.08, 95% CI, 1.01-1.15). In June 2011, the FDA announced that the use of ARBs for hypertension does not increase the risk for cancer. The FDA analyzed data from 31 randomized controlled trials (including 155,000 patients) comparing ARBs to other treatments. Based on these data, the FDA concluded that there is no evidence of an increased risk of new cancer, cancer-related death, breast cancer, lung cancer, or prostate cancer in patients receiving ARBs.

Gastrointestinal adverse events reported in controlled clinical trials for hypertension in >= 1% of losartan-treated patients and as frequent or more frequently than placebo include abdominal pain, diarrhea, dyspepsia, and nausea. Anorexia, constipation, dental pain, xerostomia, flatulence, gastritis, and vomiting occurred in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies; a causal relationship has not been determined. Dysgeusia has been reported during post-marketing experience with losartan.

Edema/swelling and chest pain (unspecified) were reported in >= 1% of losartan-treated patients and as frequent or more frequently than placebo in clinical trials. Angina pectoris, second degree AV block, CVA (stroke), hypotension, myocardial infarction, arrhythmia exacerbation (including atrial fibrillation, palpitations, sinus bradycardia, sinus tachycardia, ventricular tachycardia, and ventricular fibrillation), orthostatic effects (e.g., orthostatic hypotension) and syncope occurred in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies; a causal relationship has not been determined.

Musculoskeletal adverse reactions reported in controlled clinical trials of losartan for hypertension and more frequently than placebo include: muscle cramps (1% vs. 0%), back pain (2% vs. 1%), and leg pain (1% vs. 0%). Myalgia was reported in >= 1% of losartan-treated patients but as frequent or more frequently than placebo. Events that occurred in at least 2 losartan-treated patients or other adverse events that occurred in < 1% of patients in clinical studies include: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, and muscle weakness. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Dizziness was reported in 3% of losartan-treated patients compared to 2% of placebo-treated patients in controlled clinical trials for hypertension. Asthenia, fatigue, headache, and insomnia were reported in >= 1% of losartan-treated patients and as frequent or more frequently than in placebo-treated patients. Anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypoesthesia, libido decrease, memory impairment, migraine, nervousness, paresthesias, peripheral neuropathy, panic disorder, sleep disorder, drowsiness, tremor, and vertigo occurred in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies.

Respiratory adverse reactions reported in controlled clinical trials of losartan and more frequently than placebo include: nasal congestion (2% vs 1%), sinusitis (1% vs 0%) and upper respiratory infection (8% vs 7%). The incidence of cough appears to be lower with losartan than with the angiotensin converting enzyme inhibitors (ACEIs); losartan does not inhibit angiotensin converting enzyme (kinase II), which is thought to be responsible for the ACEI-induced cough. In comparative studies, the incidence of cough in losartan-treated patients with a prior history of ACEI-induced cough was similar to that associated with hydrochlorothiazide or placebo therapy. Cough was reported in >= 1% of losartan-treated patients and as frequent or more frequently than in placebo-treated patients. Cases of cough, including positive re-challenges, have been reported with the use of losartan in post-marketing experience. Pharyngitis and sinus disorder were also reported in >= 1% of losartan-treated patients and as frequent or more frequently than in placebo-treated patients. Dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, fever and respiratory congestion occurred in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies.

Anaphylactic reactions (anaphylactoid reactions) and angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue have been reported rarely in patients treated with losartan. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Facial edema occurred in < 1% of losartan-treated patients in clinical studies; a causal relationship has not been determined. One patient with known hypersensitivity to aspirin and penicillin was withdrawn from a clinical trial due to swelling of the lips and eyelids and facial rash, reported as angioedema after treatment with losartan. The patient returned to normal within 5 days of discontinuing therapy. Theoretically, angiotensin II receptor antagonists (ARBs) should be less likely than angiotensin converting enzyme inhibitors (ACEIs) to precipitate angioedema because ARBs do not cause accumulation of kinins.

Vasculitis, including Henoch-Schoenlein purpura, has been reported during post-marketing experience with losartan.

Impotence (erectile dysfunction) occurred in < 1% of patients in clinical studies.

Anemia occurred in < 1% of patients in clinical trials of losartan. Small decreases in hemoglobin (0.11 grams percent) and hematocrit (0.09 volume percent) occurred frequently during losartan therapy, but therapy was not discontinued due to anemia. Thrombocytopenia has been reported rarely during post-marketing experience.

General malaise has been reported during post-marketing experience with losartan.

Treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure (unspecified) and/or death in patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure). Similar outcomes have been reported with losartan. Minor increases in BUN or serum creatinine were observed in < 0.1% of losartan-treated patients with essential hypertension in clinical trials. In the ELITE study, renal dysfunction (defined as a persistent increase in serum creatinine of 0.3 mg/dl) occurred in 10.5% of elderly heart failure patients treated with losartan and in 10.5% of patients treated with an ACE inhibitor (captopril).

Due to the potential for teratogenesis, losartan should not be used during pregnancy. Drugs that affect the renin-angiotensin system have been associated with fetal and neonatal abnormalities when administered to women during the second or third trimesters of pregnancy. Adverse fetal and neonatal effects have included hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, oligohydramnios, and death. Oligohydramnios has been associated with craniofacial deformation and hypoplastic lung development. If oliguria or hypotension occurs in a neonate with a history of in utero exposure to losartan, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function.

Clinically significant laboratory abnormalities are rarely reported with losartan. Elevated hepatic enzymes and hyperbilirubinemia have been reported during therapy with losartan; only one patient was withdrawn from clinical trials due to these effects. Hepatitis has been rarely reported during postmarketing experience. Hyperkalemia and hyponatremia have also been reported during post-marketing experience with losartan.

Superficial peeling of the palms and hemolysis has been reported in one patient receiving losartan. Erythroderma (exfoliative dermatitis) has been reported during post-marketing experience. The possibility of severe skin reactions should be considered. Alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash (unspecified), diaphoresis, and urticaria occurred in at least 2 losartan-treated patients or in < 1% of patients in clinical studies.

According to the manufacturer, gout has been reported in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies. However, in a single dose study of losartan, there was a small uricosuric effect leading to a mean decrease in serum uric acid of < 0.4 mg/dL during chronic oral administration. Nocturia, increased urinary frequency, and urinary tract infection also occurred in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies; a causal relationship has not been determined.

Blurred vision, ocular irritation (burning/stinging in the eye), conjunctivitis, taste perversion, tinnitus, and visual impairment (decrease in visual acuity) occurred in at least 2 losartan-treated patients or in < 1% of losartan-treated patients in clinical studies; a causal relationship has not been determined.

Losartan and active metabolite plasma concentrations are similar in elderly and young adults with hypertension. Plasma losartan concentrations are about twice as high in females versus males, but the plasma concentrations of the active metabolite are unchanged. However, blood pressure responses are similar, regardless of age or gender. According to the manufacturer, no dosage adjustment is necessary.

Losartan should be used with caution in patients with hepatic disease. Losartan requires dosage adjustment in patients with hepatic disease. Patients with mild to moderate alcoholic cirrhosis demonstrated significantly increased losartan and active metabolite plasma concentrations which were 5 and 1.7 times higher, respectively, compared to normal subjects.

Losartan should be used with caution in patients whose renal function is critically dependent on the activity of the renin-angiotensin-aldosterone system (RAS) (e.g., patients with heart failure). To minimize hypotensive effects in patients with heart failure, initial doses of losartan are lower than those used for hypertension. Changes in renal function have been reported in susceptible individuals receiving losartan, with these changes reversible upon discontinuation of therapy in some patients. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists affect the RAS system and have caused increases in serum creatinine in susceptible individuals. Although serum creatinine returns to baseline or stabilizes in most patients with continued use, oliguria, progressive azotemia, and rarely, acute renal failure have occurred in this patient population. ACEIs have also been associated with azotemia in patients with unilateral or bilateral renal artery stenosis. Although losartan has not been studied in renal artery stenosis, similar effects to the ACEIs might be anticipated due to losartan's pharmacology. Renal function should be monitored in patients receiving losartan.

Losartan should be used with caution in patients who have hypovolemia. Intravascular volume depletion increases the risk of symptomatic hypotension during therapy. When initiating therapy in these patients, lower doses are recommended (see Dosage). Losartan should be used with great care in patients who exhibit signs of hypotension. Volume depletion should be corrected prior to the administration of losartan.

Losartan should be used with caution patients with hyperkalemia. Although hyperkalemia is infrequent with losartan, angiotensin II blockade can elevate serum potassium concentrations by blocking aldosterone secretion and could worsen pre-existing hyperkalemia. Monitor serum potassium periodically and treat appropriately. Dosage reduction or discontinuation of losartan may be required. Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia.

Anaphylactic reactions (anaphylactoid reactions) and angioedema have been reported with angiotensin II receptor antagonists, such as losartan. Theoretically, angiotensin II receptor antagonists should be less likely than angiotensin converting enzyme inhibitors (ACEIs) to precipitate angioedema because angiotensin II receptor antagonists do not cause accumulation of kinins. However, angioedema (swelling of lips and eyelids, facial rash) has been rarely reported in patients receiving angiotensin II receptor antagonists, including in patients with a prior history of ACE-inhibitor induced angioedema. While angiotensin II receptor antagonists have been suggested as potential alternatives to ACE inhibitors for patients who experience angioedema due to a lower frequency of associated angioedema , the safety of angiotensin II receptor antagonists in patients with a prior history of ACE-inhibitor induced angioedema has not been definitively established. It is prudent to use substantial caution when prescribing angiotensin II receptor antagonists in patients with a history of ACE-inhibitor induced angioedema. Some authors have recommended that angiotensin II receptor antagonists should be avoided in patients with a history of angioedema, especially in those with ACE-inhibitor induced angioedema.

Although angiotensin II receptor antagonists, such as losartan, are effective in reducing blood pressure in Black patients (a low renin population), there is generally a smaller antihypertensive response compared to other ethnic populations. A greater proportion of Black patients will attain blood pressure goals when angiotensin II receptor antagonists are combined with a diuretic. The overall antihypertensive response to the combination of losartan and hydrochlorothiazide is similar for Black and non-Black patients. Although losartan is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, there is evidence that this benefit may not apply to Black patients. In the LIFE study, Black patients treated with atenolol were at a lower risk of experiencing cardiovascular events compared with Black patients receiving losartan. This finding could not be explained on any imbalances between the treatment groups or on the basis of differences in the populations, other than race. Blood pressure reductions in both treatment groups were consistent between Black and non-Black patients in this trial. The explanation for these findings has not been established.

Losartan is not recommended for use in infants and children younger than 6 years or in pediatric patients with an estimated glomerular filtration rate less than 30 mL/minute/1.73 m2.

Losartan can cause fetal harm when administered to a pregnant patient. Once pregnancy is detected, discontinue losartan therapy as soon as possible. Women of child-bearing age should be made aware of the potential risk and losartan should only be given after careful counseling and consideration of individual risks and benefits. When used during the second and third trimesters, medications that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase fetal and neonatal morbidity and death. Use of drugs that affect the renin-angiotensin system during pregnancy can cause fetal death or injury such as hypotension, neonatal skull hypoplasia, reversible or irreversible renal failure, and death. Anhydramnios and oligohydramnios have also been reported. Development of oligohydramnios may be associated with decreased fetal renal function leading to anuria and renal failure and results in fetal limb contractures, craniofacial deformation, hypotension, hypoplastic lung development, and death. Retrospective data indicate that first-trimester use of ACE inhibitors has been associated with a potential risk of birth defects. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Infants born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. An observational cohort study evaluating the outcomes of angiotensin receptor blockers (ARBs) use during the first trimester of pregnancy found an increased rate of major birth defects compared to non-hypertensive pregnancies, 5.4% and 3%, respectively; the difference did not reach statistical significance. The authors noted that there was a higher risk of major birth defects with ARB therapy beyond 6 weeks of gestation compared to discontinuation of ARBs before week 6, 7.3% and 2.8%, respectively. The rates of prematurity and reduced birth weight were also increased in the ARB group. There were no statistically significant differences in the rates of major birth defects, spontaneous abortions, or preterm births between women with chronic hypertension treated with an ARB versus methyldopa. In rare cases, when another antihypertensive agent cannot be used to treat a pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, discontinue losartan unless it is considered life-saving for the mother. Oligohydramnios may not appear until after the fetus has sustained an irreversible injury. Closely observe neonates with histories of in utero exposure to losartan for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function.

According to the manufacturer, it is not known whether losartan is excreted into human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made to discontinue breast-feeding or discontinue losartan therapy, taking into account the importance of the medication to the mother. The ACE inhibitors captopril and enalapril are considered usually compatible with breast-feeding and may represent preferable alternatives in some patients. In addition, benazepril and quinapril are excreted in human breast milk in very small quantities; therefore, a clinically significant risk to a breast-feeding infant is not expected.

Greater sensitivity to the hypotensive effects of losartan is possible in geriatric patients due to an age-related decline in renal function. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Angiotensin receptor blockers (ARBs) may cause angioedema, chronic persistent non-productive cough, and may worsen renal failure. There are many drug interactions that can potentiate the effects of antihypertensives. Combination therapy of an ARB with a potassium-sparing diuretic or potassium supplementation has the potential for life-threatening elevations of serum potassium.

In patients undergoing major surgery or during anesthesia with agents that lower blood pressure, losartan may enhance hypotensive effects via angiotensin II blockade. Therefore, losartan should be used with caution prior to surgery. If hypotension occurs during surgery and/or anesthesia and is considered to be due to blockade of angiotensin II formation, it can be corrected by volume expansion.

For the treatment of hypertension:
Oral dosage:
Adults: 50 mg PO once daily, initially. May increase dose to 100 mg/day in 1 to 2 divided doses if further control is needed.
Children and Adolescents 6 to 17 years: 0.7 mg/kg/dose PO once daily (Max: 50 mg/day), initially. May increase dose if further control is needed. Max: 1.4 mg/kg/day (up to 100 mg/day).

For stroke prophylaxis in hypertensive patients with left ventricular hypertrophy (LVH):
NOTE: There is evidence that this benefit does not apply to Black patients.
Oral dosage:
Adults: Initially, 50 mg PO once daily. Maximal antihypertensive effects generally occur within 3 to 6 weeks. If needed for blood pressure (BP) reduction, add hydrochlorothiazide (HCTZ) 12.5 mg PO once daily and/or increase the losartan dosage to 100 mg PO once daily. If further BP control is needed, increase the HCTZ dosage to 25 mg PO once daily. This FDA-approved indication is based on the findings of the LIFE trial which compared losartan vs. atenolol in patients with hypertension and LVH. In this trial, losartan reduced the risk of stroke (nonfatal and fatal) by 25% compared to atenolol. The overall findings demonstrate that losartan is more effective than atenolol in reducing total mortality and cardiovascular morbidity and mortality, and is associated with less drug-related adverse events. In a pre-specified subanalysis of the LIFE study in diabetic hypertensives with LVH, similar findings are reported.
Geriatric: See adult dosage. No dosage adjustment is necessary.
Adolescents and Children: Safety and efficacy have not been established.

For the treatment of heart failure*:
Oral dosage:
Adults: 25 to 50 mg PO once daily, initially. Increase the dose every 2 weeks as tolerated up to 50 to 150 mg/day. Max: 150 mg/day. Guidelines recommend an angiotensin receptor blocker (ARB) in combination with an evidence-based beta blocker and aldosterone antagonist, in select patients, for patients with chronic reduced ejection fraction heart failure (HFrEF) NYHA class I to IV to reduce morbidity and mortality. In patients with prior or current symptoms of chronic HFrEF who are intolerant to angiotensin-converting enzyme (ACE) inhibitors because of cough or angioedema, use of an ARB is recommended. Continued use of an ARB is recommended for those patients for whom subsequent angiotensin receptor-neprilysin inhibitor (ARNI) use is inappropriate. Use of an ARB may be considered to decrease hospitalizations for patients with preserved ejection fraction heart failure (HFpEF) and is reasonable to control blood pressure in HFpEF patients with hypertension.

For the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (persistent albuminuria) in patients with type 2 diabetes and a history of hypertension:
Oral dosage:
Adults: 50 mg PO once daily, initially. Increase dose to 100 mg PO once daily based on blood pressure response. Guidelines recommend the use of an angiotensin receptor blocker as an alternative to an ACE inhibitor to slow the progression of renal disease in selected diabetic patients.

For the treatment of diabetic cardiovascular autonomic neuropathy*:
Oral dosage:
Adults: 100 mg PO once daily. Early initiation of losartan, either alone or in combination with quinapril, improved both diabetic cardiovascular autonomic neuropathy (DCAN) and left ventricular diastolic dysfunction in asymptomatic patients with type 1 or 2 diabetes mellitus after 1 year. Losartan has also been used to treat supine hypertension in DCAN patients with neurogenic orthostatic hypotension.

Maximum Dosage Limits:
-Adults
100 mg/day PO.
-Geriatric
100 mg/day PO.
-Adolescents
1.4 mg/kg/day (Max: 100 mg/day) PO.
-Children
6 to 12 years: 1.4 mg/kg/day (Max: 100 mg/day) PO.
1 to 5 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Initiate therapy with 25 mg PO once daily.

Patients with Renal Impairment Dosing
CrCl >= 30 ml/min: No dosage adjustment is needed.
CrCl < 30 ml/min: For adults, no dosage adjustment needed, unless the patient is also volume-depleted. Losartan is not recommended in children with glomerular filtration rate < 30 ml/min/1.73 m2.

Intermittent hemodialysis
Neither losartan or its active metabolite are removed by hemodialysis. No dosage adjustment is necessary, unless the patient is also volume-depleted (see Dosage).

*non-FDA-approved indication

Acarbose: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.

Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Adagrasib: (Moderate) Closely monitor blood pressure during coadministration of losartan and adagrasib; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Aldesleukin, IL-2: (Moderate) Angiotensin II receptor antagonists may potentiate the hypotension seen with aldesleukin, IL 2.

Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.

Aliskiren: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Aliskiren; Amlodipine: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Aliskiren; Valsartan: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.

Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Alpha-glucosidase Inhibitors: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as angiotensin II receptor antagonists (angiotensin receptor blockers, or ARBs), may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.

Amifostine: (Major) Patients receiving angiotensin II receptor antagonists should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine.

Amiloride: (Major) Potassium-sparing diuretics, such as amiloride, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.

Amiloride; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as amiloride, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.

Amiodarone: (Moderate) Closely monitor blood pressure during coadministration of losartan and amiodarone; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.

Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.

Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Angiotensin II: (Moderate) Angiotensin II receptor antagonists (angiotensin receptor blockers, or ARBs) may decrease the response to angiotensin II. Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. ARBs block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the angiotensin receptor in many tissues.

Angiotensin-converting enzyme inhibitors: (Major) In general, avoid combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) due to lack of benefit with concomitant use in most patients. Closely monitor blood pressure, renal function, and electrolytes in patients on ACE inhibitors and ARBs. Dual blockade of the renin-angiotensin system with ACE inhibitors and ARBs is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function, including acute renal failure, compared to monotherapy.

Apomorphine: (Moderate) Use of angiotensin II receptor antagonists and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.

Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.

Aprepitant, Fosaprepitant: (Moderate) Use caution if losartan and aprepitant, fosaprepitant are used concurrently, and monitor for an increase in losartan-related adverse effects for several days after administration of a multi-day aprepitant regimen. Losartan is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of losartan. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and losartan is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.

Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Articaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.

Asciminib: (Moderate) Closely monitor blood pressure during coadministration of losartan and asciminib at doses greater than or equal to 200 mg BID; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; asciminib at doses greater than or equal to 200 mg BID is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.

Atazanavir: (Minor) Caution is warranted when atazanavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4.

Atazanavir; Cobicistat: (Minor) Caution is warranted when atazanavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4.

Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.

Benzphetamine: (Minor) Benzphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.

Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.

Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Brompheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Bupivacaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.

Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including angiotensin II receptor antagonists. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.

Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin II receptor antagonists, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.

Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.

Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.

Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Carbinoxamine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.

Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.

Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.

Cobicistat: (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4.

Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.

Codeine; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Codeine; Phenylephrine; Promethazine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.

Cyclosporine: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like losartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with losartan.

Dabrafenib: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer and losartan, a CYP2C9 substrate, may result in decreased levels of losartan; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of losartan efficacy.

Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Darunavir: (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.

Darunavir; Cobicistat: (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4. (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4. (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.

Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

Delavirdine: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as delavirdine, have potential to inhibit the conversion of losartan to its active metabolite E-3174. The importance of theoretical CYP2C9 interactions has not been established; monitor therapeutic response to individualize losartan dosage.

Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Dexbrompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.

Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving beta-blockers, hydralazine, methyldopa, minoxidil, nitrites, prazosin, reserpine, or other antihypertensive agents.

Diethylpropion: (Moderate) Diethylpropion has vasopressor effects and may limit the benefit of angiotensin II receptor antagonists. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.

Digoxin: (Moderate) Monitor for signs and symptoms of digoxin toxicity during concomitant losartan use. A decline in GFR or tubular secretion, as from angiotensin receptor blockers, may impair the excretion of digoxin.

Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Losartan is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.

Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Estetrol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.

Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.

Efavirenz: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.

Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.

Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.

Elbasvir; Grazoprevir: (Minor) Administering losartan with grazoprevir may result in elevated losartan plasma concentrations. Losartan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.

Elexacaftor; tezacaftor; ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as losartan. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; losartan is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as losartan, can theoretically increase losartan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when elvitegravir is administered with losartan as there is a potential for decreased losartan concentrations. Losartan is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer. (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when elvitegravir is administered with losartan as there is a potential for decreased losartan concentrations. Losartan is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer. (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4.

Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Ephedrine: (Moderate) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.

Ephedrine; Guaifenesin: (Moderate) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.

Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.

Eplerenone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.

Epoprostenol: (Moderate) Angiotensin II receptor antagonists can enhance the hypotensive effects of antihypertensive agents if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.

Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Erythromycin: (Minor) Losartan is metabolized to an active metabolite E-3174. The AUC of this active metabolite of oral losartan is not affected by erythromycin, a CYP3A4 inhibitor; however, the AUC of losartan is increased by 30%.

Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.

Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.

Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Etravirine: (Moderate) Closely monitor blood pressure during coadministration of losartan and etravirine; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; etravirine is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as losartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of losartan during coadministration with fenofibric acid.

Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Finerenone: (Moderate) Monitor serum potassium concentrations closely if finerenone and angiotensin II receptor antagonists are used together. Concomitant use may increase the risk of hyperkalemia.

Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.

Fluconazole: (Moderate) Closely monitor blood pressure during coadministration of losartan and fluconazole; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; fluconazole is a moderate CYP2C9 inhibitor. Coadministration with fluconazole in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Fluorouracil, 5-FU: (Moderate) Closely monitor blood pressure during coadministration of losartan and fluorouracil; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; fluorouracil is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Fluoxetine: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.

Fluvoxamine: (Moderate) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluvoxamine, have the potential to inhibit the conversion of losartan, a prodrug, to its active metabolite. No specific management recommendations are currently available. Monitor therapeutic response to individualize losartan dosage to desired blood pressure or other therapeutic goals.

Fosphenytoin: (Minor) In a study of 16 healthy volunteers, phenytoin inhibited the CYP2C9-mediated conversion of losartan to its active metabolite. The clinical significance of this interaction is not known; however, a reduced clinical effect of losartan is possible via reduced formation of a metabolite which significantly contributes to the efficacy of losartan. A similar interaction might be expected with fosphenytoin.

General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during losartan treatment due to the risk for decreased exposure to the active metabolite of losartan and decreased losartan efficacy. Losartan is converted to a more active metabolite via CYP2C9 and grapefruit juice is a CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Haloperidol: (Moderate) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.

Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and angiotensin II receptor antagonists as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.

Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with losartan, a CYP3A substrate, as losartan toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.

Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.

Iloprost: (Moderate) Angiotensin II receptor antagonists can enhance the hypotensive effects of antihypertensive agents if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.

Imatinib: (Minor) Imatinib, STI-571 is a potent inhibitor of the hepatic CYP2C9 isoenzyme and may inhibit the conversion of losartan to its more active metabolite E-3174. Monitor patients response to therapy closely if imatinib is added or discontinued in a patient receiving losartan.

Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Indapamide: (Moderate) The effects of indapamide may be additive when administered with other antihypertensive agents or diuretics. In some patients, this may be desirable, but orthostatic hypotension may occur. Angiotensin II receptor antagonists tend to reverse the potassium loss, but not the serum uric acid rise associated with thiazide diuretic monotherapy.

Insulins: (Moderate) Monitor blood glucose during concomitant insulin and angiotensin II receptor blocker use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.

Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with losartan may result in increased serum concentrations of losartan. Losartan is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.

Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when isocarboxazid is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during concurrent therapy of isocarboxazid with angiotensin II receptor antagonists. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of isocarboxazid and an angiotensin II receptor antagonist.

Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin significantly induces the metabolism of losartan and its more potent metabolite, E-3174, resulting in a decrease in the AUC and half-life of both compounds; monitor for potential loss of losartan activity.

Isoniazid, INH; Rifampin: (Moderate) Rifampin significantly induces the metabolism of losartan and its more potent metabolite, E-3174, resulting in a decrease in the AUC and half-life of both compounds; monitor for potential loss of losartan activity.

Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.

Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as losartan. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; losartan is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as losartan, can theoretically increase losartan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.

Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.

Lidocaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.

Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Lisdexamfetamine: (Minor) Lisdexamfetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.

Lithium: (Moderate) Monitor serum lithium concentrations during concomitant angiotensin II receptor blocker use; reduce the lithium dose based on serum lithium concentration and clinical response. Concomitant use may increase steady-state lithium concentrations.

Loop diuretics: (Moderate) Coadministration of furosemide and Angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists may result in severe hypotension and deterioration in renal function, including renal failure. Hyponatremia or hypovolemia predisposes patients to acute hypotensive episodes following initiation of ACE inhibitor therapy. While ACE inhibitors and loop diuretics are routinely administered together in the treatment of heart failure, if an ACE inhibitor is to be administered to a patient receiving furosemide, initial doses should be conservative.

Lopinavir; Ritonavir: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.

Lumacaftor; Ivacaftor: (Moderate) Concomitant use of losartan and lumacaftor; ivacaftor may alter the therapeutic effects of losartan; caution and close monitoring of blood pressure are advised if these drugs are used together. Losartan is primarily metabolized by CYP2C9 and is also a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer; in vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. Although induction of losartan through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased losartan efficacy or increased or prolonged therapeutic effects and adverse events.

Lumacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as losartan. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; losartan is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as losartan, can theoretically increase losartan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.

Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.

Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists.

Meglitinides: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.

Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Repaglinide: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Rosiglitazone: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Methamphetamine: (Minor) Methamphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.

Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.

Methylphenidate Derivatives: (Moderate) Monitor blood pressure and adjust the dose of the angiotensin II blockers as needed during coadministration with methylphenidate. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.

Mifepristone: (Moderate) Closely monitor blood pressure during coadministration of losartan and mifepristone; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; mifepristone is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Miglitol: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.

Mitotane: (Major) Use caution if mitotane and losartan are used concomitantly, and monitor for decreased efficacy of losartan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and losartan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of losartan. Another strong CYP3A inducer, rifampin, decreased the AUC and half-life of losartan by 35% and 50%, respectively. In addition, rifampin decreased the AUC and half-life for the active metabolite of losartan, E-3174, by 40% and 50%, respectively.

Naproxen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Nateglinide: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.

Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.

Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.

Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.

Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.

Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.

Nonsteroidal antiinflammatory drugs: (Moderate) Monitor blood pressure and renal function periodically during concomitant angiotensin II blocker and nonsteroidal anti-inflammatory drug (NSAID) use. The antihypertensive effect of angiotensin II blockers may be diminished by NSAIDs. In persons who are elderly, volume-depleted, or with compromised renal function, coadministration of angiotensin II blockers and NSAIDs may result in deterioration of renal function, including possible acute renal failure; these effects are usually reversible.

Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.

Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. If these drugs are used together, closely monitor for changes in blood pressure.

Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and angiotensin II receptor antagonists who are susceptible to hypotension.

Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and losartan, a CYP3A4 substrate, may cause an increase in systemic concentrations of losartan. Use caution when administering these drugs concomitantly.

Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.

Phenelzine: (Moderate) Additive hypotensive effects may be seen when phenelzine is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during concurrent therapy of phenelzine with angiotensin II receptor antagonists. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of phenelzine and angiotensin II receptor antagonists.

Phenobarbital: (Moderate) Phenobarbital causes a reduction of approximately 20 percent in the AUC of losartan and its metabolite. The clinical significance of this interaction is unknown.

Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Phenobarbital causes a reduction of approximately 20 percent in the AUC of losartan and its metabolite. The clinical significance of this interaction is unknown.

Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Phenytoin: (Minor) Phenytoin may inhibit the CYP2C9-mediated conversion of losartan to its active metabolite. A reduced clinical effect of losartan is possible via reduced formation of a metabolite which significantly contributes to the efficacy of losartan.

Pioglitazone; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Polyethylene Glycol; Electrolytes: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists.

Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists.

Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin II receptor antagonists as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.

Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin II receptor antagonists as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.

Potassium: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and angiotensin II receptor antagonists are used together. Concomitant use may increase the risk of hyperkalemia.

Pramlintide: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of pramlintide by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with pramlintide should be monitored for changes in glycemic control.

Prazosin: (Moderate) razosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.

Prilocaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine.

Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.

Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.

Promethazine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.

Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Pseudoephedrine; Triprolidine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure.

Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.

Rasagiline: (Moderate) Additive hypotensive effects may be seen when rasagiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.

Repaglinide: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

Rifampin: (Moderate) Rifampin significantly induces the metabolism of losartan and its more potent metabolite, E-3174, resulting in a decrease in the AUC and half-life of both compounds; monitor for potential loss of losartan activity.

Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of angiotensin II receptor antagonists. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving angiotensin II receptor antagonists concomitantly.

Ritonavir: (Moderate) Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.

SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.

Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin II receptor antagonists, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.

Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists. In addition, use caution in patients receiving drugs where hypokalemia is a particular risk.

Sparsentan: (Contraindicated) Concomitant use of sparsentan and angiotensin receptor blockers (ARBs) is contraindicated due to the additive risk for serious adverse effects such as hypotension, syncope, hypokalemia, and renal dysfunction.

Spironolactone: (Moderate) Monitor serum potassium concentrations closely if angiotensin II receptor antagonists and spironolactone are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.

Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if angiotensin II receptor antagonists and spironolactone are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.

Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Avoid concomitant use and consider alternative antibiotic therapy in patients with additional risk factors for hyperkalemia, including patients older than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim. Amongst patients older than 65 years, concomitant use has been associated with a 2- to 7-fold increased risk of significant hyperkalemia compared to other antibiotics. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.

Sulfonamides: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as sulfonamides, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.

Sulfonylureas: (Moderate) Monitor blood glucose during concomitant sulfonylurea and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.

Tezacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as losartan. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; losartan is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as losartan, can theoretically increase losartan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.

Thiazolidinediones: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.

Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.

Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.

Tolvaptan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.

Tranylcypromine: (Contraindicated) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.

Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.

Triamterene: (Moderate) Monitor serum potassium concentrations in patients receiving angiotensin II receptor antagonists concomitantly with triamterene. Concomitant use may result in hyperkalemia.

Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations in patients receiving angiotensin II receptor antagonists concomitantly with triamterene. Concomitant use may result in hyperkalemia.

Trimethoprim: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Avoid concomitant use and consider alternative antibiotic therapy in patients with additional risk factors for hyperkalemia, including patients older than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim. Amongst patients older than 65 years, concomitant use has been associated with a 2- to 7-fold increased risk of significant hyperkalemia compared to other antibiotics. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.

Valproic Acid, Divalproex Sodium: (Moderate) Closely monitor blood pressure during coadministration of losartan and valproic acid; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; valproic acid is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Vemurafenib: (Moderate) Concomitant use of vemurafenib and losartan may result in altered concentrations of losartan. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Losartan is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.

Vigabatrin: (Minor) Vigabatrin is not significantly metabolized; however, it is an inducer of CYP2C9. In theory, decreased exposure of drugs that are extensively metabolized by CYP2C9, such as losartan, may occur during concurrent use of vigabatrin.

Voriconazole: (Moderate) Closely monitor blood pressure during coadministration of losartan and voriconazole; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; voriconazole is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.

Zafirlukast: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as losartan.

Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

Losartan and its longer acting active metabolite (E-3174) are specific and selective AT1 receptor antagonists. While ACE inhibitors inhibit the actions of angiotensin II by preventing its formation from angiotensin I, losartan interferes with the binding of formed angiotensin II to its endogenous receptor. The active metabolite, E-3174, is 10-40 times more potent than losartan and is primarily responsible for the therapeutic effects of losartan. E-3174 directly antagonizes the actions of angiotensin II by reversibly and non-competitively binding to the AT1 receptor. Losartan and its metabolite have no agonist activity at the AT1 receptor. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system and plays an important role in the pathophysiology of hypertension. Besides being a potent vasoconstrictor, Angiotensin II stimulates aldosterone secretion by the adrenal gland. Thus, by blocking the effects of angiotensin II, losartan decreases systemic vascular resistance without a marked change in heart rate. Type 1 angiotensin (AT1) receptors are found in many tissues, including vascular smooth muscle and the adrenal gland. AT2 receptors are also found in many tissues, although their relationship to cardiovascular hemostasis is not known. The affinity of losartan and its metabolite is about 1000-fold greater for the AT1 receptor than for the AT2 receptor. Neither losartan or its metabolite inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels. Losartan is associated with dose-related antiproteinuric effects. Losartan, but not its metabolite, has modest dose-related uricosuric properties.

Losartan is administered orally. Losartan and its active metabolite are highly protein bound, mainly to albumin. The free fraction in plasma of losartan is 1.3% and 0.2% for its metabolite. Losartan does not readily penetrate the blood-brain barrier. Approximately 35% an oral dose is renally excreted; overall 4% is excreted unchanged and 6% as the active metabolite (E-3174) is excreted in the urine. Approximately 60% of a dose is excreted in the feces. The terminal half-life is 2 hours for losartan and 6 hours for its active metabolite. The maximal effects usually occur within the first week of therapy, although in some studies maximal effect has occurred after 3-6 weeks of treatment.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2C19
Losartan is primarily metabolized by CYP2C9, and to a lesser extent by CYP3A4. It has also been reported to have some inhibitory affinity for CYP2C19. Metabolism results in both active and inactive metabolites. In 1% of patients, less than 1% of the active drug is metabolized to its active metabolite, compared to 14% in the majority of patients.


-Route-Specific Pharmacokinetics
Oral Route
Losartan is well absorbed, but undergoes substantial first-pass metabolism. The systemic bioavailability for losartan tablets is approximately 35%; about 14% of an oral dose is carboxylated in the liver to its active metabolite. Oral bioavailability is approximately 2 times higher in patients with hepatic impairment. The pharmacokinetics of losartan and its active metabolite (E-3174) are linear over the dose range up to 200 mg; however, the antihypertensive dose-response curve is nonlinear, with proportionally small decreases in blood pressure attained with increased dosage. Peak serum concentrations occur at 1 hour and 3-4 hours, respectively for the parent drug and metabolite. Maximum serum concentrations are similar for losartan and its metabolite, but the AUC for the metabolite is approximately 4 times greater. Food decreases the maximum concentration and slightly (approximately 10%) decreases the AUC. The bioavailability of losartan and its active metabolite in adults are similar for the tablets and a extemporaneously compounded suspension (see Administration section).


-Special Populations
Hepatic Impairment
Total plasma clearance of losartan was 50% lower in patients with hepatic impairment, requiring dosage adjustment. Patients with mild to moderate alcoholic cirrhosis demonstrated significantly increased losartan and active metabolite plasma concentrations which were 5 and 1.7 times higher, respectively, compared to normal subjects.

Renal Impairment
In patients with renal impairment (creatinine clearances < 30 ml/minute), AUCs are about 50% greater, and AUCs are doubled in hemodialysis patients. Neither losartan or its active metabolite are removed by hemodialysis.

Geriatric
Losartan and active metabolite plasma concentrations are similar in elderly and young hypertensive adults.

Gender Differences
Plasma losartan concentrations are about twice as high in female vs. male hypertensives, but the plasma concentrations of active metabolite are similar. The pharmacokinetic values for losartan and its metabolite are similar to those obtained previously in adults.