Olmesartan Medoxomil

RECENT MAJOR CHANGES Warnings and Precautions ( 5.3 , 5.6 ) 10/2019

1 INDICATIONS AND USAGE Olmesartan medoxomil tablets are indicated for the treatment of hypertension in adults and children six years of age and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with olmesartan medoxomil tablets. 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 one 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. It may be used alone or in combination with other antihypertensive agents. Olmesartan medoxomil tablets are an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension in adult and pediatric patients six years of age and older, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1 ).

2 DOSAGE & ADMINISTRATION Indication Starting Dose Dose Range Adult Hypertension (2.1) 20 mg once daily 20 to 40 mg once daily Pediatric Hypertension (6 years of age and older) ( 2.2 ) 20 to <35 kg 10 mg once daily ≥35 kg 20 mg once daily 20 to <35 kg 10 to 20 mg once daily ≥35 kg 20 to 40 mg once daily. 2.1 Adult Hypertension Dosage must be individualized. The usual recommended starting dose of olmesartan medoxomil tablets is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan medoxomil tablets may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect. Twice-daily dosing offers no advantage over the same total dose given once daily. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate olmesartan medoxomil tablets under close medical supervision and give consideration to use of a lower starting dose [see Warnings and Precautions ( 5.3 )] 2.2 Pediatric Hypertension (6 Years of Age and Older) Dosage must be individualized. For children who can swallow tablets, the usual recommended starting dose of olmesartan medoxomil tablets is 10 mg once daily for patients who weigh 20 to <35 kg (44 to 77 lb), or 20 mg once daily for patients who weigh ≥35 kg. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan medoxomil tablets may be increased to a maximum of 20 mg once daily for patients who weigh <35 kg or 40 mg once daily for patients who weigh ≥35 kg. Use of olmesartan medoxomil tablets in children less than 1 year of age is not recommended [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.4 )] . For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see Clinical Pharmacology ( 12.3 ) ]. Follow the suspension preparation instructions below to administer olmesartan medoxomil tablets as a suspension. Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty olmesartan medoxomil tablets 20 mg and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of ORA-Sweet ® and 50 mL of ORA-Plus ®* to the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2 to 8°C (36 to 46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator. * ORA-Sweet ® and ORA-Plus ® are registered trademarks of Paddock Laboratories, Inc.

3 DOSAGE FORMS AND STRENGTHS 5 mg: Yellow, film coated circular shaped, biconvex tablet, debossed "065" on one side and plain on other side. 20 mg: White to off-white, film coated circular shaped, biconvex tablet, debossed "066" on one side and plain on other side. 40 mg: White to off-white, film coated oval shaped, biconvex tablet, debossed "067" on one side and plain on other side. Tablets: 5 mg, 20 mg, and 40 mg ( 3 )

4 CONTRAINDICATIONS Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes [see Drug Interactions ( 7.3 )]. Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes ( 4 ).

6 ADVERSE REACTIONS The most common adverse reaction in adults was dizziness (3%) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact to Cadila Pharmaceuticals Limited at 1-202-355-9785 (fax 1-202-355-9784) or FDA at 1-800-332-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adult Hypertension Olmesartan medoxomil tablets has been evaluated for safety in more than 3,825 patients/subjects, including more than 3,275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil tablets. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil tablets and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3,278) of patients treated with olmesartan medoxomil tablets and 2.7% (i.e., 32/1,179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with olmesartan medoxomil tablets and at a higher incidence versus placebo was dizziness (3% vs. 1%). Facial edema was reported in five patients receiving olmesartan medoxomil tablets. Angioedema has been reported with angiotensin II antagonists. Pediatric Hypertension No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to 16 years and that previously reported for adult patients. 6.2 Post-Marketing Experience The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole : Asthenia, angioedema, anaphylactic reactions Gastrointestinal : Vomiting, sprue-like enteropathy [see Warnings and Precautions ( 5.5 )] Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal : Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4,447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18). The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use …

7 DRUG INTERACTIONS • Agents increasing potassium levels may lead to increase in serum potassium ( 7.1 ). • NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.2 ). • Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.3 ). • Lithium: Increases in serum lithium concentrations and lithium toxicity ( 7.4 ). • Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose ( 7.5 ). 7.1 Agents Increasing Serum Potassium Concomitant use of olmesartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium. If co-medication is considered necessary, monitoring of serum potassium is advisable. 7.2 Non-Steroidal Anti-Inflammatory Agents 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 olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil, may be attenuated by NSAIDs including selective COX-2 inhibitors. 7.3 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, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on olmesartan medoxomil tablets and other agents that affect the RAS. Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes [see Contraindications (4)]. Avoid use of aliskiren with olmesartan medoxomil tablets in patients with renal impairment (GFR less than 60 ml/min). 7.4 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including olmesartan medoxomil tablets. Monitor serum lithium levels during concomitant use. 7.5 Colesevelam Hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS • Lactation: Choose to discontinue nursing or drug (8.2 ). 8.1 Pregnancy Risk Summary Olmesartan medoxomil tablets 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. In animal reproduction studies, olmesartan medoxomil tablets treatment during organogenesis resulted in increased embryofetal toxicity in rats at doses lower than maternally toxic doses. When pregnancy is detected, discontinue olmesartan medoxomil tablets as soon as possible. Consider alternative antihypertensive therapy during pregnancy. 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 and 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 patients taking olmesartan medoxomil tablets during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. 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 olmesartan medoxomil tablets for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to olmesartan medoxomil tablets, if oliguria or hypotension occurs, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function. Data Animal Data No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day. 8.2 Lactation Risk Summary There is no information regarding the presence of olmesartan in human milk, th …

12.1 Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. An AT 2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT 1 receptor than for the AT 2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

11 DESCRIPTION Olmesartan medoxomil,USP a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C 29 H 30 N 6 O 6 and its structural formula is: Olmesartan medoxomil, USP is a white to off-white crystalline powder with a molecular weight of 558.59. It is practically insoluble in water and in heptanes,slightly soluble in ethanol (96%),sparingly soluble in methanol. Olmesartan medoxomil tablets is available for oral use as film-coated tablets containing 5 mg, 20 mg, or 40 mg of olmesartan medoxomil,USP and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy propyl cellulose ,stearic acid,magnesium stearate, talc, titanium dioxide, and (5 mg only) yellow iron oxide. If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6. olmesartan-structure

10 OVERDOSAGE Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension occurs, initiate supportive treatment. The dialyzability of olmesartan is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING Olmesartan medoxomil tablets, USP is supplied as yellow coloured round shape film coated tablets containing 5 mg of olmesartan medoxomil USP, as white to off-white coloured, round shape film coated tablets containing 20 mg of olmesartan medoxomil USP, and as white to off-white coloured,oval shape film coated tablets containing 40 mg of olmesartan medoxomil USP. Tablets are debossed with OLM on one side and 5,20 & 40 on the other side of the 5, 20, and 40 mg tablets, respectively. Tablets are supplied as follows: 5mg 20mg 40mg Bottle of 30's 67877-445-30 67877-446-30 67877-447-30 Bottle of 90's 67877-445-90 67877-446-90 67877-447-90 Bottle of 500's 67877-445-05 67877-446-05 67877-447-05 Bottle of 1000's 67877-445-10 67877-446-10 67877-447-10 Carton pack of 10's (1x10's) -- 67877-446-33 -- Carton pack of 30's (3x10's) -- 67877-446-84 -- Carton pack of 50's (5x10's) -- 67877-446-74 -- Carton pack of 100's (10x10's) -- 67877-446-38 -- Storage Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature].