CO-NORTA

Losartan potassium is 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 white to off-white powder with a molecular weight of 461.01.

It is freely soluble in water; soluble in isopropyl alcohol; slightly soluble in acetonitrile.

Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

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.

Each losartan potassium tablet, USP intended for oral administration contains 25 mg or 50 mg or 100 mg of losartan potassium.

In addition, each tablet contains the following inactive ingredients: colloidal silica anhydrous, hydroxypropyl cellulose (low substituted), hypromellose, lactose monohydrate, magnesium stearate, maize starch (corn starch), microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

• 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.

• 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.

• Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. 1.1 Hypertension 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. 1.2 Hypertensive Patients with Left Ventricular Hypertrophy Losartan potassium tablets are indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. 1.3 Nephropathy in Type 2 Diabetic Patients Losartan potassium tablets are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type 2 diabetes and a history of hypertension.

In this population, losartan potassium reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation) .

Lactation History of hepatic impairment History of edema of Quincke Obstructive Cardiomyopathy Child under 50 kg Child under 6 years of age Female likely to be pregnant Primary hyperaldosteronism Hyponatremia Hypovolaemia Heart failure Hepatic impairment Renal impairment Myocardial Ischemia Cerebrovascular pathology Aortic rectification Mitral shrinkage Subject at risk of hyperkalaemia Subject over 75 years Black subject Renal transplant, recent history (de).

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 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. 12.2 Pharmacodynamics 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 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 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. 12.3 Pharmacokinetics 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 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.

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.

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.

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 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.

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 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 to 16 Following Multiple Dosing Adults given 50 mg once daily for 7 days N=12 Age 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) Mean ± standard deviation 442 ± 173 1685 ± 452 368 ± 169 1866 ± 1076 C MAX (ng/mL) 224 ± 82 212 ± 73 141 ± 88 222 ± 127 T 1/2 (h) Harmonic mean and standard deviation 2.1 ± 0.70 7.4 ± 2.4 2.3 ± 0.8 5.6 ± 1.2 T PEAK (h) Median 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.

Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders.

Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives.

Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females.

No dosage adjustment is necessary.

Pharmacokinetic differences due to race have not been studied.

Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by to 90% in patients with mild (creatinine clearance of to 74 mL/min) or moderate (creatinine clearance to 49 mL/min) renal insufficiency.

In this study, renal clearance was reduced by 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.

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.

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.

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.

The active substance is an angiotensin

II, a potent vasoconstrictor, the main active hormone in the renin-angiotensin system and an important determinant of hypertension physiopathology.

Angiotensin II also binds to the

AT1 receptors present in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and heart) and exercises several important biological actions, including vasoconstriction and the release of aldosterone.

II also stimulates the proliferation of smooth muscle cells.

Losartan selectively inhibits the

AT1 receptors.

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• Uremia (increase) (Common)
• Hyperkalaemia (Common)
• Hyponatremia (Common)
• Hypoglycaemia (Common)
• Blood creatinine (increase) (Common)
• ALT (increase) (Rare)
• Urticaria (Uncommon)
• Rash (Uncommon)
• Pruritus (Uncommon)
• Photosensitivity Asthenia (Common)
• Edema (Uncommon)
• Fatigue (Common)
• Swelling of the face Irflu pseudo-influenza syndrome Anemia (Common)
• Thrombocytopenia
• Hepatitis (Rare)
• Hypersensitivity (Rare)
• Angioedema (Rare)
• Anaphylactic reaction (Rare)
• Vertigo (Common)
• Feeling dizzy (Common)
• Dysgueusia Tinnitus Pharyngeal edema Swelling of the larynx
• Swelling of the glots Sleep disorder (Uncommon)
• Depression Angor (Uncommon)
• Hypotension (Common)
• Palpitation (Uncommon)
• Syncope (Rare)
• Atrial fibrillation (Rare)
• Vasculitis (Rare)
• Orthostatic hypotension Malaise Dose-related orthostatic effect Constipation (Uncommon)
• Nausea (Uncommon)
• Abdominal pain (Uncommon)
• Vomiting (Uncommon)
• Diarrhoea (Uncommon)
• Intestinal angioedema (Rare)
• Pancreatitis Abnormal liver function Swelling of lips
• Swelling of the language Muscle pain Joint pain Sleeping Rheumatoid purpura Rhabdomyolysis
• Headache (Uncommon)
• Somnolence (Uncommon)
• Stroke (Rare)
• Paraesthesia (Rare)
• Migraine
• Dyspnoea (Uncommon)
• Cough (Uncommon)
• Airway obstruction Renal impairment (Common)
• Renal impairment (Common)
• Urinary tract infection Erection disorder Impower.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 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.

• In patients who are hypersensitive to any component of this product.

• For coadministration with aliskiren in patients with diabetes.

• Hypersensitivity to any component.

• Coadministration with aliskiren in patients with diabetes.

• Usual adult dose: 50 mg once daily.

• Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg).

• Usual starting dose: 50 mg once daily.

• Add hydrochlorothiazide 12.5 mg and/or increase losartan potassium to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed.

Nephropathy in

Type 2 Diabetic Patients.

• Usual dose: 50 mg once daily.

• Increase dose to 100 mg once daily if further blood pressure response is needed. 2.1 Hypertension Adult Hypertension The usual starting dose of losartan potassium tablets is 50 mg once daily.

The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure.

A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension.

Dosage should be adjusted according to blood pressure response.

Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

Losartan potassium tablets are not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m 2. 2.2 Hypertensive Patients with Left Ventricular Hypertrophy The usual starting dose is 50 mg of losartan potassium tablets once daily.

Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of losartan potassium should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response. 2.3 Nephropathy in Type 2 Diabetic Patients The usual starting dose is 50 mg once daily.

The dose should be increased to 100 mg once daily based on blood pressure response. 2.4 Dosage Modifications in Patients with Hepatic Impairment In patients with mild-to-moderate hepatic impairment the recommended starting dose of losartan potassium is 25 mg once daily.

Losartan potassium has not been studied in patients with severe hepatic impairment. 2.5 Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension) Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg losartan potassium tablets.

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 to 8°C (36 to 46°F) and can be stored for up to 4 weeks.

Shake the suspension prior to each use and return promptly to the refrigerator.

USP, 25 mg are white to off-white, capsule-shaped, film-coated tablets debossed with the logo of "Z" on one side and "2" on other side and are supplied as follows: Overbagged with 10 film-coated per bag, NDC 55154-4783-0 Losartan Potassium Tablets USP, 50 mg are white to off-white, capsule-shaped, film-coated tablets debossed with the logo of "Z16" on one side and lip type breakline on other side and are supplied as follows: Overbagged with 10 film-coated per bag, NDC 55154-2089-0 Losartan Potassium Tablets USP, 100 mg are white to off-white, capsule-shaped, film-coated tablets debossed with the logo of "Z18" on one side and plain on other side and are supplied as follows: Overbagged with 10 film-coated per bag, NDC 55154-6643-0 WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only.

Keep this and all drugs out of the reach of children.

Store at 20°C to 25°C (68°F to 77°F) .

Protect from light.

Do not use if blister is torn or broken.

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.

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.

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, 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 infants 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.

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 mg/kg/day, 25 mg/kg/day, 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.

Antihypertensive effects of losartan potassium have been established in hypertensive pediatric patients aged 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.

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.