ARBLI

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 empirical formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium is a white to off-white free-flowing crystalline 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. Arbli is available as a white, translucent oral suspension with a peppermint odor. Each mL contains 10 mg losartan potassium (equivalent to 9.2 mg losartan), inactive ingredients are: hypromellose, methyl paraben, natural peppermint flavor, polyethylene glycol, povidone, propyl paraben, propylene glycol, purified water, simethicone, sodium phosphates, sucralose, and xanthan gum. structural formula

Arbli is 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 ) 1.1 Hypertension Arbli is 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. Arbli may be administered with other antihypertensive agents. 1.2 Hypertensive Patients with Left Ventricular Hypertrophy Arbli is 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 1.3 Nephropathy in Type 2 Diabetic Patients Arbli is 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, Arbli 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) [see Clinical Studies (14.3) ] .

Hypertension Usual adult dose: 50 mg orally once daily. ( 2.2 ) Usual pediatric starting dose: 0.7 mg per kg orally once daily (up to 50 mg). ( 2.2 ) Hypertensive Patients with Left Ventricular Hypertrophy Usual starting dose: 50 mg orally once daily. ( 2.3 ) Add hydrochlorothiazide 12.5 mg and/or increase Arbli to 100 mg orally followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed. ( 2.3 , 14.2 ) Nephropathy in Type 2 Diabetic Patients Usual dose: 50 mg orally once daily. ( 2.4 ) Increase dose to 100 mg orally once daily if further blood pressure response is needed. ( 2.4 ) 2.1 Important Administration Information Instruct patients or caregivers to use oral dosing syringe(s) or an oral dosing cup to measure the prescribed amount of medication. Inform patients that oral dosing syringe(s) or an oral dosing cup may be obtained from their pharmacy. 2.2 Hypertension Adult Hypertension The usual starting dose of Arbli is 50 mg orally once daily. The dosage can be increased to a maximum dose of 100 mg orally once daily as needed to control blood pressure [see Clinical Studies (14.1) ] . A starting dose of 25 mg once daily is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy). Pediatric Hypertension The usual recommended starting dose is 0.7 mg per kg orally once daily (up to 50 mg total) administered as 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 [see Clinical Pharmacology (12.3) , Clinical Studies (14.1) , and Warnings and Precautions (5.2) ] . Arbli is not recommended in pediatric patients less than 2 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m 2 [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . 2.3 Hypertensive Patients with Left Ventricular Hypertrophy The usual starting dose is 50 mg of Arbli orally once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Arbli should be increased to 100 mg orally once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response [see Clinical Studies (14.2) ] . 2.4 Nephropathy in Type 2 Diabetic Patients The usual starting dose is 50 mg orally once daily. The dose should be increased to 100 mg orally once daily based on blood pressure response [see Clinical Studies (14.3) ] . 2.5 Dosage Modifications in Patients with Hepatic Impairment In patients with mild-to-moderate hepatic impairment the recommended starting dose of Arbli is 25 mg orally once daily. Arbli has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3) ] .

Arbli is contraindicated: In patients who are hypersensitive to any component of this product. For co-administration with aliskiren in patients with diabetes. Hypersensitivity to any component. ( 4 ) Co-administration with aliskiren in patients with diabetes. ( 4 )

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 Scienture LLC at 1-833-754-4917 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypertension Arbli has been evaluated for safety in more than 3,300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1,200 patients were treated for over 6 months and more than 800 for over one year. Treatment with Arbli was well-tolerated with an overall incidence of adverse events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated with Arbli and 3.7% of patients given placebo. In 4 clinical trials involving over 1,000 patients on various doses (10 mg to 150 mg) of losartan potassium and over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with Arbli and more commonly than placebo were: dizziness (3% vs. 2%), upper respiratory infection (8% vs. 7%), nasal congestion (2% vs. 1%), and back pain (2% vs. 1%). The following less common adverse reactions have been reported: Blood and lymphatic system disorders: Anemia. Psychiatric disorders: Depression. Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine. Ear and labyrinth disorders: Vertigo, tinnitus. Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA. Respiratory, thoracic and mediastinal disorders: Dyspnea. Gastrointestinal disorders: Abdominal pain, constipation, nausea, vomiting. Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity. Musculoskeletal and connective tissue disorders: Myalgia, arthralgia. Reproductive system and breast disorders: Impotence. General disorders and administration site conditions: Edema. Cough Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown in Table 1 below. Table 1 Study 1 * HCTZ Losartan Lisinopril Cough 25% 17% 69% Study 2 † Placebo Losartan Lisinopril Cough 35% 29% 62% * Demographics = (89% Caucasian, 64% female) † Demographics = (90% Caucasian, 51% female) These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy. Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience. Hypertensive Patients with Left Ventricular Hypertrophy In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with losartan were similar to those reported previously for patients with hypertension. Nephropathy in Type 2 Diabetic Patients In the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study involving 1,513 patients treated with losartan or placebo, the overall incidences of reported adverse events were similar for the two groups. Discontinuations of losartan because of side effects were similar to placebo (19% for losartan, 24% for placebo). The adverse events, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with losartan and occurring with ≥2% difference in the losartan group vs. placebo on a background of conventional antihypertensive therapy, were asthenia/fatigue, chest pain, hypotension, orthostatic hypotension, diarrhea, anemia, hyperkalemia, hypoglycemia, back pain, muscular weakness, and urinary tract infection. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience with losartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure: Digestive: Hepatitis. General Disorders and Administration Site Conditions: Malaise. Hematologic: Thrombocytopenia. Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, tongue, and/or swelling of the intestine has been reported; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported. Anaphylactic reactions have been reported. Metabolic and Nutrition: Hyponatremia. Musculoskeletal: Rhabdomyolysis. Nervous System Disorders: Dysgeusia. Skin: Erythroderma.

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 ) 7.1 Agents Increasing Serum Potassium Co-administration of losartan with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. 7.2 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use. 7.3 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors. 7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1,448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end stage renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on losartan and other agents that affect the RAS. Do not co-administer aliskiren with losartan in patients with diabetes. Avoid use of aliskiren with losartan in patients with renal impairment (GFR <60 mL/min).