Patient Information

  When pregnancy is detected, discontinue losartan potassium as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ].

Losartan potassium tablets are an angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension, to lower blood pressure in adults and children greater than 6 years old. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients. ( 1.2 ) Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. ( 1.3 )

Hypertension •  Usual adult dose: 50 mg once daily. ( 2.1 ) •  Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg). ( 2.1 ) Hypertensive Patients with Left Ventricular Hypertrophy •  Usual starting dose: 50 mg once daily. ( 2.2 ) •  Add hydrochlorothiazide 12.5 mg and/or increase losartan potassium tablets to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed. ( 2.2 , 14.2 ) Nephropathy in Type 2 Diabetic Patients •  Usual dose: 50 mg once daily. ( 2.3 ) •  Increase dose to 100 mg once daily if further blood pressure response is needed. ( 2.3 )

Losartan potassium tablets USP are supplied as follows: Losartan Potassium Tablets USP, 25 mg are green colored, oval shaped, biconvex film-coated tablets debossed with ‘E’ on one side and ‘45’ on other side. NDC: 70518-0959-00 PACKAGIGN: 30 in 1 BLISTER PACK Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Losartan potassium tablets are contraindicated: In patients who are hypersensitive to any component of this product. For coadministration with aliskiren in patients with diabetes.

Losartan potassium tablets are an angiotensin II receptor blocker acting on the AT 1 receptor subtype. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p -( o -1 H- tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its molecular formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium USP is a white to off-white powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Losartan potassium is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch (maize), low substituted hydroxypropyl cellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose 6 cP, titanium dioxide, FD & C blue #2/indigo carmine aluminum lake, D & C yellow #10 aluminum lake, and purified water. Losartan potassium tablets USP, 25 mg, 50 mg and 100 mg contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively.

Agents Increasing Serum Potassium: Risk of hyperkalemia. ( 7.1 ) Lithium: Risk of lithium toxicity. ( 7.2 ) NSAIDs: Increased risk of renal impairment and reduced diuretic, natriuretic, and antihypertensive effects. ( 7.3 ) Dual Inhibition of the Renin-Angiotensin System: Increased risk of renal impairment, hypotension, syncope, and hyperkalemia. ( 7.4 )

Advise the patient to read the FDA-approved patient labeling (Patient Information). Pregnancy Advise female patients of childbearing age about the consequences of exposure to losartan potassium during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see  Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Potassium Supplements Advise patients receiving losartan potassium not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider [see Drug Interactions (7.1) ] . Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

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

Antihypertensive effects of losartan potassium have been established in hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m 2 [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] .

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

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day. Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays. Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p < 0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Most common adverse reactions (incidence ≥2% and greater than placebo) are: dizziness, upper respiratory infection, nasal congestion, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m 2 basis. Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor its active metabolite can be removed by hemodialysis.

Risk Summary Losartan potassium can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue losartan potassium as soon as possible (see Clinical Considerations). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk   Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. In patients taking losartan potassium during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue losartan potassium, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to losartan potassium for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to losartan potassium, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data Losartan potassium was administered orally to rats during the period of late gestation through lactation (Gestation Day 15 through Lactation Day 20) at doses of 10, 25, and 100 mg/kg/day. Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m 2 basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Losartan potassium tablets are indicated for the treatment of hypertension in adults and pediatric patients 6 years of age and older, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Losartan potassium tablets may be administered with other antihypertensive agents.

Losartan Potassium (loe sar' tan poe tas' ee um) Tablets USP 25 mg, 50 mg, 100 mg Rx only Read the Patient Information that comes with losartan potassium tablets before you start taking them and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition and treatment. What is the most important information I should know about losartan potassium tablets? Losartan potassium tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking losartan potassium tablets, tell your doctor right away. What are losartan potassium tablets? Losartan potassium tablets is a prescription medicine called an angiotensin receptor blocker (ARB). It is used: alone or with other blood pressure medicines to lower high blood pressure (hypertension). to lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy. Losartan potassium tablets may not help Black patients with this problem. to slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who have or had high blood pressure. Losartan potassium tablets have not been studied in children less than 6 years old or in children with certain kidney problems. High Blood Pressure (hypertension). Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Losartan potassium tablets can help your blood vessels relax so your blood pressure is lower. Left Ventricular Hypertrophy (LVH) is an enlargement of the walls of the left chamber of the heart (the heart’s main pumping chamber). LVH can happen from several things. High blood pressure is the most common cause of LVH. Type 2 Diabetes with Nephropathy. Type 2 diabetes is a type of diabetes that happens mainly in adults. If you have diabetic nephropathy it means that your kidneys do not work properly because of damage from the diabetes. Who should not take losartan potassium tablets? Do not take losartan potassium tablets if you are allergic to any of the ingredients in losartan potassium tablets. See the end of this leaflet for a complete list of ingredients in losartan potassium tablets. Do not take losartan potassium tablets if you have diabetes and are taking a medicine called aliskiren to reduce blood pressure. What should I tell my doctor before taking losartan potassium tablets? Tell your doctor about all of your medical conditions including if you: are pregnant or planning to become pregnant. See “What is the most important information I should know about losartan potassium tablets?” are breastfeeding. It is not known if losartan potassium passes into your breast milk. You should choose either to take losartan potassium tablets or breastfeed, but not both. are vomiting a lot or having a lot of diarrhea have liver problems have kidney problems Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Losartan potassium tablets and certain other medicines may interact with each other. Especially tell your doctor if you are taking: potassium supplements salt substitutes containing potassium other medicines that may increase serum potassium water pills (diuretics) lithium (a medicine used to treat a certain kind of depression) medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors other medicines to reduce blood pressure How should I take losartan potassium tablets? Take losartan potassium tablets exactly as prescribed by your doctor. Your doctor may change your dose if needed. Losartan potassium tablets can be taken with or without food. If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Just take the next dose at your regular time. If you take too much losartan potassium, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away. What are the possible side effects of losartan potassium tablets? Losartan potassium tablets may cause the following side effects that may be serious: Injury or death of unborn babies. See “What is the most important information I should know about losartan potassium tablets?” Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat or tongue. Get emergency medical help right away and stop taking losartan potassium tablets. Low blood pressure (hypotension). Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. Call your doctor right away. For people who already have kidney problems, you may see a worsening in how well your kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain. High blood levels of potassium The most common side effects of losartan potassium tablets in people with high blood pressure are: “colds” (upper respiratory infection) dizziness stuffy nose back pain The most common side effects of losartan potassium tablets in people with type 2 diabetes with diabetic kidney disease are: diarrhea tiredness low blood sugar chest pain high blood potassium low blood pressure Tell your doctor if you get any side effect that bothers you or that won’t go away. This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist. How do I store losartan potassium tablets? Store losartan potassium tablets at 59°F to 86°F (15°C to 30°C). Keep losartan potassium tablets in a tightly closed container that protects the medicine from light. Keep losartan potassium tablets and all medicines out of the reach of children. General information about losartan potassium tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use losartan potassium tablets for a condition for which it was not prescribed. Do not give losartan potassium tablets to other people, even if they have the same symptoms that you have. They may harm them. This leaflet summarizes the most important information about losartan potassium tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about losartan potassium tablets that is written for health professionals. What are the ingredients in losartan potassium tablets? Active ingredient: losartan potassium Inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch (maize), low substituted hydroxypropyl cellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose 6 cP, titanium dioxide, FD & C blue #2/indigo carmine aluminum lake, D & C yellow #10 aluminum lake, and purified water. Ora-Plus™ and Ora-Sweet SF™ are the trademarks of Paddock Laboratories, Inc. Revised: 08/2025 Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Losartan Potassium Tablets USP, 25 mg are green colored, oval shaped, biconvex film-coated tablets debossed with ‘E’ on one side and ‘45’ on other side.

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)] is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT 1 receptor, and both have much greater affinity (about 1000-fold) for the AT 1 receptor than for the AT 2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT 1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT 1 receptor. Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25 to 40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.

Absorption : Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its C max   but has only minor effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Distribution : The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all. Metabolism: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Elimination: Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6 to 9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14 C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14 C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing. Specific Populations Pediatric: Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below. Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6 to 16 Following Multiple Dosing * Mean ± standard deviation † Harmonic mean and standard deviation ‡ Median   Adults given 50 mg once daily for 7 days N=12 Age 6   to 16 given 0.7 mg/kg once daily for 7 days N=25   Parent Active Metabolite Parent Active Metabolite AUC 0-24 (ng•hr/mL)* 442 ± 173 1685 ± 452 368 ± 169 1866 ± 1076 C MAX (ng/mL)* 224 ± 82 212 ± 73 141 ± 88 222 ± 127 T 1/2 (h) † 2.1 ± 0.70 7.4 ± 2.4 2.3 ± 0.8 5.6 ± 1.2 T PEAK (h) ‡ 0.9 3.5 2.0 4.1 CL REN (mL/min)* 56 ± 23 20 ± 3 53 ± 33 17 ± 8 The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both losartan and the active metabolite [see Dosage and Administration (2.5) ] . Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65 to 75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary [see Dosage and Administration (2.1) ] . Race: Pharmacokinetic differences due to race have not been studied [see Use in Specific Populations (8.6) ]. Renal Insufficiency: Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50 to 90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55 to 85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis [see  Warnings and Precautions (5.3) and Use in Specific Populations (8.7) ] . Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment. Losartan potassium has not been studied in patients with severe hepatic impairment [see  Dosage and Administration (2.4) and Use in Specific Populations (8.8) ]. Drug Interactions No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

Losartan potassium is not recommended in pediatric patients less than 6 years of age or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m 2 . ( 2.1 , 8.4 ) Hepatic Impairment: Recommended starting dose 25 mg once daily. ( 2.4 , 8.8 , 12.3 )

Hypotension: Correct volume or salt depletion prior to administration of losartan potassium. ( 5.2 ) Monitor renal function and potassium in susceptible patients. ( 5.3 , 5.4 )

DRUG: Losartan Potassium GENERIC: Losartan Potassium DOSAGE: TABLET, FILM COATED ADMINSTRATION: ORAL NDC: 70518-0959-0 COLOR: green SHAPE: OVAL SCORE: No score SIZE: 8 mm IMPRINT: E;45 PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): LOSARTAN POTASSIUM 25mg in 1 INACTIVE INGREDIENT(S): MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE STARCH, CORN LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE FD & C BLUE NO. 2 D & C YELLOW NO. 10 WATER

  When pregnancy is detected, discontinue losartan potassium as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ].

Losartan potassium tablets are an angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension, to lower blood pressure in adults and children greater than 6 years old. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients. ( 1.2 ) Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. ( 1.3 )

Hypertension •  Usual adult dose: 50 mg once daily. ( 2.1 ) •  Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg). ( 2.1 ) Hypertensive Patients with Left Ventricular Hypertrophy •  Usual starting dose: 50 mg once daily. ( 2.2 ) •  Add hydrochlorothiazide 12.5 mg and/or increase losartan potassium tablets to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed. ( 2.2 , 14.2 ) Nephropathy in Type 2 Diabetic Patients •  Usual dose: 50 mg once daily. ( 2.3 ) •  Increase dose to 100 mg once daily if further blood pressure response is needed. ( 2.3 )

Losartan potassium tablets USP are supplied as follows: Losartan Potassium Tablets USP, 25 mg are green colored, oval shaped, biconvex film-coated tablets debossed with ‘E’ on one side and ‘45’ on other side. NDC: 70518-0959-00 PACKAGIGN: 30 in 1 BLISTER PACK Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Losartan potassium tablets are contraindicated: In patients who are hypersensitive to any component of this product. For coadministration with aliskiren in patients with diabetes.

Agents Increasing Serum Potassium: Risk of hyperkalemia. ( 7.1 ) Lithium: Risk of lithium toxicity. ( 7.2 ) NSAIDs: Increased risk of renal impairment and reduced diuretic, natriuretic, and antihypertensive effects. ( 7.3 ) Dual Inhibition of the Renin-Angiotensin System: Increased risk of renal impairment, hypotension, syncope, and hyperkalemia. ( 7.4 )

Advise the patient to read the FDA-approved patient labeling (Patient Information). Pregnancy Advise female patients of childbearing age about the consequences of exposure to losartan potassium during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see  Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Potassium Supplements Advise patients receiving losartan potassium not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider [see Drug Interactions (7.1) ] . Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

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

Antihypertensive effects of losartan potassium have been established in hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m 2 [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] .

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

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day. Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays. Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p < 0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Most common adverse reactions (incidence ≥2% and greater than placebo) are: dizziness, upper respiratory infection, nasal congestion, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m 2 basis. Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor its active metabolite can be removed by hemodialysis.

Losartan potassium tablets are an angiotensin II receptor blocker acting on the AT 1 receptor subtype. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p -( o -1 H- tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its molecular formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium USP is a white to off-white powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Losartan potassium is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch (maize), low substituted hydroxypropyl cellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose 6 cP, titanium dioxide, FD & C blue #2/indigo carmine aluminum lake, D & C yellow #10 aluminum lake, and purified water. Losartan potassium tablets USP, 25 mg, 50 mg and 100 mg contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively.

Risk Summary Losartan potassium can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue losartan potassium as soon as possible (see Clinical Considerations). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk   Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. In patients taking losartan potassium during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue losartan potassium, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to losartan potassium for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to losartan potassium, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data Losartan potassium was administered orally to rats during the period of late gestation through lactation (Gestation Day 15 through Lactation Day 20) at doses of 10, 25, and 100 mg/kg/day. Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m 2 basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Losartan potassium tablets are indicated for the treatment of hypertension in adults and pediatric patients 6 years of age and older, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Losartan potassium tablets may be administered with other antihypertensive agents.

Losartan Potassium (loe sar' tan poe tas' ee um) Tablets USP 25 mg, 50 mg, 100 mg Rx only Read the Patient Information that comes with losartan potassium tablets before you start taking them and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition and treatment. What is the most important information I should know about losartan potassium tablets? Losartan potassium tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking losartan potassium tablets, tell your doctor right away. What are losartan potassium tablets? Losartan potassium tablets is a prescription medicine called an angiotensin receptor blocker (ARB). It is used: alone or with other blood pressure medicines to lower high blood pressure (hypertension). to lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy. Losartan potassium tablets may not help Black patients with this problem. to slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who have or had high blood pressure. Losartan potassium tablets have not been studied in children less than 6 years old or in children with certain kidney problems. High Blood Pressure (hypertension). Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Losartan potassium tablets can help your blood vessels relax so your blood pressure is lower. Left Ventricular Hypertrophy (LVH) is an enlargement of the walls of the left chamber of the heart (the heart’s main pumping chamber). LVH can happen from several things. High blood pressure is the most common cause of LVH. Type 2 Diabetes with Nephropathy. Type 2 diabetes is a type of diabetes that happens mainly in adults. If you have diabetic nephropathy it means that your kidneys do not work properly because of damage from the diabetes. Who should not take losartan potassium tablets? Do not take losartan potassium tablets if you are allergic to any of the ingredients in losartan potassium tablets. See the end of this leaflet for a complete list of ingredients in losartan potassium tablets. Do not take losartan potassium tablets if you have diabetes and are taking a medicine called aliskiren to reduce blood pressure. What should I tell my doctor before taking losartan potassium tablets? Tell your doctor about all of your medical conditions including if you: are pregnant or planning to become pregnant. See “What is the most important information I should know about losartan potassium tablets?” are breastfeeding. It is not known if losartan potassium passes into your breast milk. You should choose either to take losartan potassium tablets or breastfeed, but not both. are vomiting a lot or having a lot of diarrhea have liver problems have kidney problems Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Losartan potassium tablets and certain other medicines may interact with each other. Especially tell your doctor if you are taking: potassium supplements salt substitutes containing potassium other medicines that may increase serum potassium water pills (diuretics) lithium (a medicine used to treat a certain kind of depression) medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors other medicines to reduce blood pressure How should I take losartan potassium tablets? Take losartan potassium tablets exactly as prescribed by your doctor. Your doctor may change your dose if needed. Losartan potassium tablets can be taken with or without food. If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Just take the next dose at your regular time. If you take too much losartan potassium, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away. What are the possible side effects of losartan potassium tablets? Losartan potassium tablets may cause the following side effects that may be serious: Injury or death of unborn babies. See “What is the most important information I should know about losartan potassium tablets?” Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat or tongue. Get emergency medical help right away and stop taking losartan potassium tablets. Low blood pressure (hypotension). Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. Call your doctor right away. For people who already have kidney problems, you may see a worsening in how well your kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain. High blood levels of potassium The most common side effects of losartan potassium tablets in people with high blood pressure are: “colds” (upper respiratory infection) dizziness stuffy nose back pain The most common side effects of losartan potassium tablets in people with type 2 diabetes with diabetic kidney disease are: diarrhea tiredness low blood sugar chest pain high blood potassium low blood pressure Tell your doctor if you get any side effect that bothers you or that won’t go away. This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist. How do I store losartan potassium tablets? Store losartan potassium tablets at 59°F to 86°F (15°C to 30°C). Keep losartan potassium tablets in a tightly closed container that protects the medicine from light. Keep losartan potassium tablets and all medicines out of the reach of children. General information about losartan potassium tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use losartan potassium tablets for a condition for which it was not prescribed. Do not give losartan potassium tablets to other people, even if they have the same symptoms that you have. They may harm them. This leaflet summarizes the most important information about losartan potassium tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about losartan potassium tablets that is written for health professionals. What are the ingredients in losartan potassium tablets? Active ingredient: losartan potassium Inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch (maize), low substituted hydroxypropyl cellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose 6 cP, titanium dioxide, FD & C blue #2/indigo carmine aluminum lake, D & C yellow #10 aluminum lake, and purified water. Ora-Plus™ and Ora-Sweet SF™ are the trademarks of Paddock Laboratories, Inc. Revised: 08/2025 Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Losartan Potassium Tablets USP, 25 mg are green colored, oval shaped, biconvex film-coated tablets debossed with ‘E’ on one side and ‘45’ on other side.

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)] is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT 1 receptor, and both have much greater affinity (about 1000-fold) for the AT 1 receptor than for the AT 2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT 1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT 1 receptor. Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25 to 40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.

Absorption : Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its C max   but has only minor effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Distribution : The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all. Metabolism: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Elimination: Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6 to 9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14 C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14 C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing. Specific Populations Pediatric: Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below. Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6 to 16 Following Multiple Dosing * Mean ± standard deviation † Harmonic mean and standard deviation ‡ Median   Adults given 50 mg once daily for 7 days N=12 Age 6   to 16 given 0.7 mg/kg once daily for 7 days N=25   Parent Active Metabolite Parent Active Metabolite AUC 0-24 (ng•hr/mL)* 442 ± 173 1685 ± 452 368 ± 169 1866 ± 1076 C MAX (ng/mL)* 224 ± 82 212 ± 73 141 ± 88 222 ± 127 T 1/2 (h) † 2.1 ± 0.70 7.4 ± 2.4 2.3 ± 0.8 5.6 ± 1.2 T PEAK (h) ‡ 0.9 3.5 2.0 4.1 CL REN (mL/min)* 56 ± 23 20 ± 3 53 ± 33 17 ± 8 The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both losartan and the active metabolite [see Dosage and Administration (2.5) ] . Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65 to 75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary [see Dosage and Administration (2.1) ] . Race: Pharmacokinetic differences due to race have not been studied [see Use in Specific Populations (8.6) ]. Renal Insufficiency: Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50 to 90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55 to 85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis [see  Warnings and Precautions (5.3) and Use in Specific Populations (8.7) ] . Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment. Losartan potassium has not been studied in patients with severe hepatic impairment [see  Dosage and Administration (2.4) and Use in Specific Populations (8.8) ]. Drug Interactions No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

Losartan potassium is not recommended in pediatric patients less than 6 years of age or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m 2 . ( 2.1 , 8.4 ) Hepatic Impairment: Recommended starting dose 25 mg once daily. ( 2.4 , 8.8 , 12.3 )

Hypotension: Correct volume or salt depletion prior to administration of losartan potassium. ( 5.2 ) Monitor renal function and potassium in susceptible patients. ( 5.3 , 5.4 )

DRUG: Losartan Potassium GENERIC: Losartan Potassium DOSAGE: TABLET, FILM COATED ADMINSTRATION: ORAL NDC: 70518-0959-0 COLOR: green SHAPE: OVAL SCORE: No score SIZE: 8 mm IMPRINT: E;45 PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): LOSARTAN POTASSIUM 25mg in 1 INACTIVE INGREDIENT(S): MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE STARCH, CORN LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE FD & C BLUE NO. 2 D & C YELLOW NO. 10 WATER