Candesartan cilexetil

Warnings and Precautions (5.5) 02/2016

1 INDICATIONS AND USAGE Candesartan cilexetil tablets are an angiotensin II receptor blocker (ARB) indicated for: • Treatment of hypertension in adults and children 1 to < 17 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.1 ). • Treatment of heart failure (NYHA class II-IV); candesartan cilexetil tablets reduce cardiovascular death and heart failure hospitalization ( 1.2 ). 1.1 Hypertension Candesartan cilexetil tablets are indicated for the treatment of hypertension in adults and in children 1 to < 17 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal 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. 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. Candesartan cilexetil tablets may be used alone or in combination with other antihypertensive agents. 1.2 Heart Failure Candesartan cilexetil tablets are indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations [see Clinical Studies (14.2) ] . Candesartan cilexetil tablets also have an added effect on these outcomes when used with an ACE inhibitor [see Drug Interactions (7.4) ] .

2 DOSAGE AND ADMINISTRATION Starting Dose Target Dose Adult Hypertension (2.1) 16 mg tablet once daily 8 to 32 mg tablet total daily dose Pediatric Hypertension (1 to ˂6 years) (2.2) 0.2 mg/kg oral suspension once daily 0.05 to 0.4 mg/kg oral suspension once daily or consider divided dose Pediatric Hypertension (6 to ˂17 years) (2.2) 50 kg 8 to 16 mg tablet once daily 50 kg 4 to 32 mg tablet once daily or consider divided dose Adult Heart Failure (2.3) 4 mg tablet once daily 1 The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by patient 2.1 Adult Hypertension Dosage must be individualized. Blood pressure response is dose related over the range of 2 to 32 mg. The usual recommended starting dose of candesartan cilexetil tablet is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candesartan cilexetil tablets can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg. Larger doses do not appear to have a greater effect, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks, and maximal blood pressure reduction is generally obtained within 4 to 6 weeks of treatment with candesartan cilexetil tablets. Use in Hepatic Impairment: Initiate with 8 mg candesartan cilexetil tablets in patients with moderate hepatic insufficiency. Dosing recommendations cannot be provided for patients with severe hepatic insufficiency [see Clinical Pharmacology (12.3)] . Candesartan cilexetil tablets may be administered with or without food. If blood pressure is not controlled by candesartan cilexetil tablets alone, a diuretic may be added. Candesartan cilexetil tablets may be administered with other antihypertensive agents. 2.2 Pediatric Hypertension 1 to <17 Years of Age Candesartan cilexetil tablets may be administered once daily or divided into two equal doses. Adjust the dosage according to blood pressure response. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate candesartan cilexetil tablets under close medical supervision and consider administration of a lower dose [see Warnings and Precautions (5.3)]. Children 1 to <6 years of age: The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.2 mg/kg (oral suspension). Children 6 to <17 years of age: For those less than 50 kg, the dose range is 2 to 16 mg per day. The recommended starting dose is 4 to 8 mg. For those greater than 50 kg, the dose range is 4 to 32 mg per day. The recommended starting dose is 8 to 16 mg. Doses above 0.4 mg/kg (1 to <6 year olds) or 32 mg (6 to <17 year olds) have not been studied in pediatric patients [see Clinical Studies (14.1)]. An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with candesartan cilexetil tablets. Children <1 year of age must not receive candesartan cilexetil tablets for hypertension. All pediatric patients with a glomerular filtration rate less than 30 ml/min/1.73 m 2 should not receive candesartan cilexetil tablets since candesartan cilexetil tablets has not been studied in this population [see Use in Specific Populations (8.4)]. For children who cannot swallow tablets, an oral suspension may be substituted as described below: Preparation of Oral Suspension: Candesartan cilexetil oral suspension can be prepared in concentrations within the range of 0.1 to 2 mg/mL. Typically, a concentration of 1 mg/mL will be suitable for the prescribed dose. Any strength of candesartan cilexetil tablets can be used in the preparation of the suspension. Follow the steps below for preparation of the suspension. The number of tablets and volume of vehicle specified below will yield 160 mL of a 1 mg/mL suspension. · Prepare the vehicle by adding equal volume …

3 DOSAGE FORMS AND STRENGTHS Candesartan Cilexetil Tablets, USP are available containing 4 mg, 8 mg, 16 mg or 32 mg of candesartan cilexetil, USP. • The 4 mg tablets are white to off-white, round, scored tablets debossed with M on the left side of the score and C on the right side of the score on one side of the tablet and 24 on the other side of the tablet. • The 8 mg tablets are pink mottled, round, scored tablets debossed with M on the left side of the score and C on the right side of the score on one side of the tablet and 25 on the other side of the tablet. • The 16 mg tablets are pink mottled, round, scored tablets debossed with M on the left side of the score and C on the right side of the score on one side of the tablet and 31 on the other side of the tablet. • The 32 mg tablets are pink mottled, round, scored tablets debossed with MC above the score and 32 below the score on one side of the tablet and blank on the other side of the tablet. Tablets 4 mg, 8 mg, 16 mg, 32 mg ( 3 ).

4 CONTRAINDICATIONS Candesartan cilexetil tablets are contraindicated in patients who are hypersensitive to candesartan. Do not co-administer aliskiren with candesartan cilexetil tablets in patients with diabetes [see Drug Interactions (7.4) ] . Known hypersensitivity to product components ( 4 ). Do not co-administer aliskiren with candesartan cilexetil tablets in patients with diabetes ( 4 ).

6 ADVERSE REACTIONS • Most common adverse reactions which caused adult patients to discontinue therapy for: o Hypertension were headache (0.6%) and dizziness (0.3%) ( 6.1 ). o Heart Failure were hypotension (4.1%) ( 5.3 ), abnormal renal function (6.3%) ( 5.4 ), and hyperkalemia (2.4%) ( 5.5 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 Candesartan cilexetil tablets have been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with candesartan cilexetil tablets was well tolerated. The overall incidence of adverse events reported with candesartan cilexetil tablets was similar to placebo. The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (i.e., 108 of 3260) of patients treated with candesartan cilexetil tablets as monotherapy and 3.5% (i.e., 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (i.e., 57 of 2350) of patients treated with candesartan cilexetil tablets and 3.4% (i.e., 35 of 1027) of patients treated with placebo. The most common reasons for discontinuation of therapy with candesartan cilexetil tablets were headache (0.6%) and dizziness (0.3%). The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with candesartan cilexetil tablets and at a higher incidence in candesartan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%). Pediatric Hypertension Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded. Heart Failure The adverse event profile of candesartan cilexetil tablets in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing candesartan cilexetil tablets in total daily doses up to 32 mg once daily (n = 3803) with placebo (n = 3796), 21.0% of patients discontinued candesartan cilexetil tablets for adverse events vs. 16.1% of placebo patients. 6.2 Postmarketing Experience The following adverse reactions were identified during post-approval use of candesartan cilexetil tablets. 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. The following have been very rarely reported in post-marketing experience: Digestive: Abnormal hepatic function and hepatitis. Hematologic: Neutropenia, leukopenia, and agranulocytosis. Immunologic: Angioedema. Metabolic and Nutritional Disorders: Hyperkalemia, hyponatremia. Respiratory System Disorders: Cough. Skin and Appendages Disorders: Pruritus, rash and urticaria. Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

7 DRUG INTERACTIONS · Lithium: Increases in serum lithium concentrations and toxicity (7). · NSAIDs use may lead to increased risk of renal impairment and loss of antihypertensive effect (7). · Dual inhibition of the renin- angiotension system: Increased risk of renal impairment, hypotension, and hyperkalemia (7) . • Combined inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7). 7.1 Agents Increasing Serum Potassium Co-administration of candesartan cilexetil with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or 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 toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including candesartan cilexetil. Monitor serum lithium levels. 7.3 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, co­administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including candesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving candesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors. 7.4 Combination 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. Triple combination of candesartan cilexetil with an ACE-inhibitor and a mineralocorticoid receptor antagonist is generally not recommended. Closely monitor blood pressure, renal function and electrolytes in patients on candesartan cilexetil and other agents that affect the RAS. Do not co-administer aliskiren with candesartan cilexetil in patients with diabetes. Avoid use of aliskiren with candesartan cilexetil in patients with renal impairment (GFR <60 ml/min) [see Contraindications (4)].

8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Either nursing or drug should be discontinued ( 8.2 ). • Pediatrics: Children < 1 year of age must not receive candesartan cilexetil tablets for hypertension ( 5.2 ). Inhibitors of the renin-angiotensin system can cause renal abnormalities in neonatal animals ( 12.3 ). 8.1 Pregnancy Risk Summary Candesartan cilexetil 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. When pregnancy is detected, discontinue candesartan cilexetil tablets 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. 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. Pregnant women with chronic heart failure are at increased risk for preterm birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Heart failure may worsen with pregnancy and may lead to maternal death. Closely monitor pregnant patients for destabilization of their heart failure. 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. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe infants with histories of in utero exposure to candesartan for hypotension, oliguria, hyperkalemia or other symptoms of renal impairment [see Use in Specific Populations (8.4) ] . In neonates with a history of in utero exposure to candesartan, 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. Animal Data Oral doses ≥ 10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m 2 basis (comparison assumes human body weight of 50 kg). Candesartan cilexetil is toxic to rabbits. When given …

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. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. There is also an AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (> 10,000-fold) 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 widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. 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 angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.

11 DESCRIPTION Candesartan cilexetil tablets USP, a prodrug, are hydrolyzed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT 1 subtype angiotensin II receptor antagonist. Candesartan cilexetil, a nonpeptide, is chemically described as (±)2-Ethoxy-1-[[2’-(1 H -tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-1 H -benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester. Its molecular formula is C 33 H 34 N 6 O 6 , and its structural formula is: Candesartan cilexetil, USP is a white or off-white powder with a molecular weight of 610.66. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. Candesartan cilexetil is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil and the following inactive ingredients: carboxymethylcellulose calcium, corn starch, glyceryl stearate, hydroxypropyl cellulose, lactose monohydrate and magnesium stearate. The 8 mg, 16 mg and 32 mg tablets also contain red iron oxide. Candesartan Cilexetil Structural Formula

10 OVERDOSAGE No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. The most likely manifestation of overdosage with candesartan cilexetil tablets would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Candesartan cannot be removed by hemodialysis. Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.

16 HOW SUPPLIED/STORAGE AND HANDLING Candesartan cilexetil tablets USP, 4 mg are light pink, mottled, round, biconvex, uncoated scored tablets engraved with 'ZE' on one side and '58' on other side and are supplied as follows: NDC 72578-157-06 in bottle of 30 tablets NDC 72578-157-16 in bottle of 90 tablets NDC 72578-157-05 in bottle of 500 tablets Candesartan cilexetil tablets USP, 8 mg are pink, mottled, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '59' on other side and are supplied as follows: NDC 72578-158-06 in bottle of 30 tablets with child-resistant closure NDC 72578-158-16 in bottle of 90 tablets with child-resistant closure Candesartan cilexetil tablets USP, 16 mg are white, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '60' on other side and are supplied as follows: NDC 72578-159-06 in bottle of 30 tablets with child-resistant closure NDC 72578-159-16 in bottle of 90 tablets with child-resistant closure Candesartan cilexetil tablets USP, 32 mg are white to off-white, round, biconvex, uncoated tablets engraved with 'Z' & 'E' divided by score line on one side and '61' on other side and are supplied as follows: NDC 72578-160-06 in bottle of 30 tablets with child-resistant closure NDC 72578-160-16 in bottle of 90 tablets with child-resistant closure Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted at 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep in a tightly closed container. Dispense in a tight, light-resistant container as defined in the USP.