USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended 8.2). Geriatric: Not recommended for initial therapy in patients >=75 years old 8.5) Hepatic Impairment: Not recommended for initial therapy 8.6). Lactation: Breastfeeding is not recommended 8.2). Geriatric: Not recommended for initial therapy in patients >=75 years old 8.5) Hepatic Impairment: Not recommended for initial therapy 8.6). 8.1 Pregnancy. Risk SummaryAzor can cause fetal harm when administered to 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 [see Clinical Considerations]. 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 Azor 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 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%-4% and 15%-20%, respectively.. Clinical Considerations. Disease-Associated Maternal and/or Embryo/Fetal RiskHypertension 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. Olmesartan medoxomilOligohydramnios 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. 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 for hypotension, oliguria, and hyperkalemia. In neonates with history of in utero exposure to olmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as means of reversing hypotension and supporting renal function [see Use in Specific Populations (8.4)]. Data. Animal DataNo reproductive studies have been conducted with the combination of olmesartan medoxomil, and amlodipine. However, these studies have been conducted for olmesartan medoxomil and amlodipine alone.. Olmesartan medoxomilNo 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 mg/m basis) or pregnant rabbits at oral doses up to mg/kg/day (half the MRHD on mg/m 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 auricular, 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 >= 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. Amlodipine No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on mg/m basis) during their respective periods of major organogenesis (calculations based on patient weight of 60 kg). However, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. 8.2 Lactation. Risk SummaryThere is limited information regarding the presence of Azor in human milk, the effects on the breastfed infant, or the effects on milk production. Amlodipine is present in human milk. Olmesartan is present in rat milk [see Data] Because of the potential for adverse effects on the nursing infant, advise nursing woman that breastfeeding is not recommended during treatment with Azor. DataPresence of olmesartan in milk was observed after single oral administration of mg/kg 14C] olmesartan medoxomil to lactating rats. 8.4 Pediatric Use. The safety and effectiveness of Azor in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of subjects in the double-blind clinical study of Azor, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients >=75 years old is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in patients >=75 years old.Amlodipine. Reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with resulting increase of AUC of approximately 40% to 60%, and lower initial dose may be required. Olmesartan medoxomil. Of the total number of hypertensive patients receiving olmesartan medoxomil in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment. There are no studies of Azor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment.The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, dose not available with Azor.Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 is 56 hours in patients with severely impaired hepatic function [see Warnings and Precautions 5.5 )]. Olmesartan medoxomil. Increases in AUC 0- and peak plasma concentration (C max) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%. 8.7 Renal Impairment. There are no studies of Azor in patients with renal impairment.Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Olmesartan medoxomil. Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). 8.8 Black Patients. Of the total number of subjects in the double-blind clinical study of Azor, 25% (481/1940) were black patients. Azor was effective in treating black patients (usually low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Anticipate hypotension in volume- or salt-depleted patients with treatment initiation. Start treatment under close supervision 5.2). Increased angina or myocardial infarction may occur upon dosage initiation or increase 5.3). Impaired renal function: changes in renal function may occur 5.4). Sprue-like enteropathy has been reported. Consider discontinuation of Azor in cases where no other etiology is found 5.6). Anticipate hypotension in volume- or salt-depleted patients with treatment initiation. Start treatment under close supervision 5.2). Increased angina or myocardial infarction may occur upon dosage initiation or increase 5.3). Impaired renal function: changes in renal function may occur 5.4). Sprue-like enteropathy has been reported. Consider discontinuation of Azor in cases where no other etiology is found 5.6). 5.1 Fetal Toxicity. Azor can cause fetal harm when administered to 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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Azor as soon as possible see Use in pecific Populations 8.1 ] . 5.2 Hypotension in Volume- or Salt-Depleted Patients. Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with Azor under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. transient hypotensive response is not contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely. 5.3 Increased Angina or Myocardial Infarction. Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.. 5.4 Impaired Renal Function. Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Azor because of the olmesartan medoxomil component s ee Drug Interactions 7 and Clinical Pharmacology 12.3 )]. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and Azor.. 5.5 Patients with Hepatic Impairment. Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients [see Use in Specific Populations 8.6 )]. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment. 5.6 Sprue-like Enteropathy. Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Azor in cases where no other etiology is identified.. 5.7 Electrolyte Imbalances. Azor contains olmesartan, drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Azor. Azor is combination of two antihypertensive drugs: dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, olmesartan medoxomil. The amlodipine component of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the vasoconstrictor effects of angiotensin II. Amlodipine. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by gradual rate of association and dissociation with the receptor binding site, resulting in gradual onset of effect. Amlodipine is peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause reduction in peripheral vascular resistance and reduction in blood pressure.Olmesartan medoxomil. Angiotensin II is formed from angiotensin in 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 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. An AT receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than 12,500-fold greater affinity for the AT receptor than for the AT receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, reaction also catalyzed by ACE. Because olmesartan 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.. 12.2 Pharmacodynamics. Amlodipine. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by significant change in heart rate or plasma catecholamine levels with chronic dosing. With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.Olmesartan medoxomil. Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours. Plasma concentrations of angiotensin and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium. 12.3 Pharmacokinetics. The pharmacokinetics of amlodipine and olmesartan medoxomil from Azor are equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when administered separately. The bioavailability of both components is well below 100%, but neither component is affected by food. The effective half-lives of amlodipine (45+-11 hours) and olmesartan (7+-1 hours) result in 2- to 3- fold accumulation for amlodipine and negligible accumulation for olmesartan with once-daily dosing.Amlodipine. After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between and 12 hours. Absolute bioavailability is estimated as between 64% and 90%. Olmesartan medoxomil. Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the peak plasma concentration (C max) of olmesartan is reached after to hours. Food does not affect the bioavailability of olmesartan medoxomil. DistributionAmlodipine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after to days of consecutive daily dosing. Olmesartan medoxomil. The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses. In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats. Metabolism and ExcretionAmlodipine. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine. Olmesartan medoxomil. Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. Olmesartan appears to be eliminated in biphasic manner with terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within to days and no accumulation in plasma occurs with once-daily dosing.Specific PopulationsGeriatric PatientsThe pharmacokinetic properties of Azor in the elderly are similar to those of the individual components.Amlodipine. Elderly patients have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%, and lower initial dose may be required. Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil were studied in the elderly (>=65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUC was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R. Pediatric PatientsAmlodipine. Sixty-two hypertensive patients aged to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults. Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil have not been investigated in patients <18 years of age. Male and Female PatientsPopulation pharmacokinetic analysis indicated that female patients had approximately 15% smaller clearances of olmesartan than male patients. Gender had no effect on the clearance of amlodipine.Olmesartan medoxomil. Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and max were 10% to 15% higher in women than in men.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.AzorThe data described below reflect exposure to Azor in more than 1600 patients including more than 1000 exposed for at least months and more than 700 exposed for year. Azor was studied in one placebo-controlled factorial trial [s ee Clinical Trials 14.1 ]. The population had mean age of 54 years and included approximately 55% males. Seventy-one percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily. The overall incidence of adverse reactions on therapy with Azor was similar to that seen with corresponding doses of the individual components of Azor, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for Azor and 6.8% for placebo).EdemaEdema is known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil.The placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil was added to the 10 mg amlodipine dose.Placebo-Subtracted Incidence of Edema During the Double-Blind Treatment PeriodOlmesartan MedoxomilPlacebo20 mg40 mgAmlodipinePlacebo- -2.4%6.2%5 mg0.7%5.7%6.2%10 mg24.5%13.3%11.2%12.3% actual placebo incidence Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine.There was greater decrease in hemoglobin and hematocrit in patients treated with Azor as compared to patients receiving either component. Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with Azor at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia. The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period.Initial TherapyAnalyzing the data described above specifically for initial therapy, it was observed that higher doses of Azor caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of Azor 5/20 mg. No increase in the incidence of syncope or near syncope was observed. The incidences of discontinuation because of any treatment emergent adverse events in the double-blind phase are summarized in the table below.Discontinuation for any Treatment Emergent Adverse Event1Olmesartan MedoxomilPlacebo10 mg20 mg40 mgAmlodipinePlacebo4.9%4.3%5.6%3.1%5 mg3.7%0.0%1.2%3.7%10 mg5.5%6.8%2.5%5.6%1 Hypertension is counted as treatment failure and not as treatment emergent adverse event. N=160-163 subjects per treatment group. Amlodipine.Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows:Adverse EventPlacebo N=520 2.5 mg N=275 5.0 mg N=296 10.0 mg N=268 Edema 0.61.83.010.8Dizziness 1.51.13.43.4Flushing 0.00.71.42.6Palpitation 0.60.71.44.5For several adverse experiences that appear to be drug- and dose-related, there was greater incidence in women than men associated with amlodipine treatment as shown in the following table:Adverse EventPlaceboAmlodipineMale=% (N=914) Female=% (N=336) Male=% (N=1218) Female=% (N=512) Edema 1.45.15.614.6Flushing 0.30.91.54.5Palpitation 0.90.91.43.3Somnolence0.80.31.31.6Olmesartan medoxomil.Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least months and more than 525 treated for at least year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.The overall frequency of adverse events was not dose related. Analysis of gender, age, and race groups demonstrated no differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reaction (incidence >=3%) is edema 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-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 drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.AzorThe data described below reflect exposure to Azor in more than 1600 patients including more than 1000 exposed for at least months and more than 700 exposed for year. Azor was studied in one placebo-controlled factorial trial [s ee Clinical Trials 14.1 ]. The population had mean age of 54 years and included approximately 55% males. Seventy-one percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily. The overall incidence of adverse reactions on therapy with Azor was similar to that seen with corresponding doses of the individual components of Azor, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for Azor and 6.8% for placebo).EdemaEdema is known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil.The placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil was added to the 10 mg amlodipine dose.Placebo-Subtracted Incidence of Edema During the Double-Blind Treatment PeriodOlmesartan MedoxomilPlacebo20 mg40 mgAmlodipinePlacebo- -2.4%6.2%5 mg0.7%5.7%6.2%10 mg24.5%13.3%11.2%12.3% actual placebo incidence Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine.There was greater decrease in hemoglobin and hematocrit in patients treated with Azor as compared to patients receiving either component. Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with Azor at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia. The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period.Initial TherapyAnalyzing the data described above specifically for initial therapy, it was observed that higher doses of Azor caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of Azor 5/20 mg. No increase in the incidence of syncope or near syncope was observed. The incidences of discontinuation because of any treatment emergent adverse events in the double-blind phase are summarized in the table below.Discontinuation for any Treatment Emergent Adverse Event1Olmesartan MedoxomilPlacebo10 mg20 mg40 mgAmlodipinePlacebo4.9%4.3%5.6%3.1%5 mg3.7%0.0%1.2%3.7%10 mg5.5%6.8%2.5%5.6%1 Hypertension is counted as treatment failure and not as treatment emergent adverse event. N=160-163 subjects per treatment group. Amlodipine.Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows:Adverse EventPlacebo N=520 2.5 mg N=275 5.0 mg N=296 10.0 mg N=268 Edema 0.61.83.010.8Dizziness 1.51.13.43.4Flushing 0.00.71.42.6Palpitation 0.60.71.44.5For several adverse experiences that appear to be drug- and dose-related, there was greater incidence in women than men associated with amlodipine treatment as shown in the following table:Adverse EventPlaceboAmlodipineMale=% (N=914) Female=% (N=336) Male=% (N=1218) Female=% (N=512) Edema 1.45.15.614.6Flushing 0.30.91.54.5Palpitation 0.90.91.43.3Somnolence0.80.31.31.6Olmesartan medoxomil.Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least months and more than 525 treated for at least year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.The overall frequency of adverse events was not dose related. Analysis of gender, age, and race groups demonstrated no differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%).. 6.2 Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of the individual components of Azor. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Amlodipine. The following post-marketing event has been reported infrequently where causal relationship is uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Postmarketing reporting has also revealed possible association between extrapyramidal disorder and amlodipine. Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience: Body as Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see Warnings and Precautions 5.6 )] 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=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 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 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. placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of nonfatal 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 in non-diabetic patients appeared to be associated with decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for 6 months.Overall, these data raise concern of possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for survival benefit in non-diabetics of magnitude similar to the adverse finding in diabetics.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m basis, similar to the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest dose was, on mg/m basis, about two and half times the MRHD. (Calculations based on 60 kg patient.) Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on mg/m basis). Olmesartan medoxomil. Olmesartan was not carcinogenic when administered by dietary administration to rats for up to years. The highest dose tested (2000 mg/kg/day) was, on mg/m basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, 6-month gavage study in the p53 knockout mouse and 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of carcinogenic effect of olmesartan. Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in study in which dosing was begun (female) or (male) weeks prior to mating.

DESCRIPTION SECTION.

11 DESCRIPTION. Azor provided as tablet for oral administration, is combination of the calcium channel blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker (ARB) olmesartan medoxomil.The amlodipine besylate component of Azor is chemically described as 3-ethyl-5-methyl (+-)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is 20H 25ClN 2O 5oC 6H 6O 3S. Olmesartan medoxomil, prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.The olmesartan medoxomil component of Azor is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ p-( o-1 H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is 29H 30N 6O 6. The structural formula for amlodipine besylate is:The structural formula for olmesartan medoxomil is:Azor contains amlodipine besylate, white to off-white crystalline powder, and olmesartan medoxomil, white to light yellowish-white powder or crystalline powder. The molecular weights of amlodipine besylate and olmesartan medoxomil are 567.1 and 558.59, respectively. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol.Each tablet of Azor also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coatings contain polyvinyl alcohol, macrogol/ polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (5/40 mg, 10/20 mg, 10/40 mg tablets), iron oxide red (10/20 mg and 10/40 mg tablets), and iron oxide black (10/20 mg tablets).. The structural formula for amlodipine besylate is chemically described as 3-ethyl-5-methyl (+-)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzene. The structural formula for olmesartan medoxomil is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, c.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Amlodipine 7.1): If simvastatin is co-administered with amlodipine, do not exceed 20 mg daily of simvastatin. Increased exposure of cyclosporine and tacrolimus. Increased exposure of amlodipine when coadministered with CYP3A inhibitors.Olmesartan medoxomil 7.2): Nonsteroidal anti-inflammatory drugs (NSAIDS) may lead to increased risk of renal impairment and loss of antihypertensive effect. Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. Colesevelam hydrochloride: Consider administering olmesartan at least hours before colesevelam hydrochloride dose. Lithium: Increases in serum lithium concentrations and lithium toxicity.. If simvastatin is co-administered with amlodipine, do not exceed 20 mg daily of simvastatin. Increased exposure of cyclosporine and tacrolimus. Increased exposure of amlodipine when coadministered with CYP3A inhibitors.. Nonsteroidal anti-inflammatory drugs (NSAIDS) may lead to increased risk of renal impairment and loss of antihypertensive effect. Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. Colesevelam hydrochloride: Consider administering olmesartan at least hours before colesevelam hydrochloride dose. Lithium: Increases in serum lithium concentrations and lithium toxicity.. 7.1 Drug Interactions with Amlodipine. Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology 12.3 )]. Immunosuppressants: Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)]. CYP3A Inhibitors: Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment .CYP3A Inducers: No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. 7.2 Drug Interactions with Olmesartan Medoxomil 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.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 Azor and other agents that affect the RAS.Do not co-administer aliskiren with Azor in patients with diabetes see Contraindications 4 ]. Avoid use of aliskiren with Azor in patients with renal impairment (GFR <60 ml/min). Use with 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 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least hours before the colesevelam hydrochloride dose [see Clinical Pharmacology 12.3 )]. Lithium:Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including AZOR. Monitor serum lithium levels during concomitant use.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Azor is indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Azor.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 Programs Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).Numerous antihypertensive drugs, from 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 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 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.Azor may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with combination compared to monotherapy. Individual blood pressure goals may vary based upon the patients risk.Data from an 8-week, placebo-controlled, parallel-group factorial study see Clinical Studies 14.1 ] provide estimates of the probability of reaching blood pressure goal with Azor compared to amlodipine or olmesartan medoxomil monotherapy. The figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with Azor 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. The right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures. Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) 140 mmHg at Week With LOCFFigure 2: Probability of Achieving Diastolic Blood Pressure (DBP) 90 mmHg at Week With LOCFFigure 3: Probability of Achieving Systolic Blood Pressure (SBP) 130 mmHg at Week With LOCFFigure 4: Probability of Achieving Diastolic Blood Pressure (DBP) 80 mmHg at Week With LOCFThe figures above provide an approximation of the likelihood of reaching targeted blood pressure goal (e.g., Week SBP <140 mmHg or <130 mmHg or DBP <90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study. Azor 5/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg.For example, patient with baseline blood pressure of 160/100 mmHg has about 48% likelihood of achieving goal of <140 mmHg (systolic) and 51% likelihood of achieving goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about 46% likelihood of achieving goal of <140 mmHg (systolic) and 60% likelihood of achieving goal of <90 mmHg (diastolic) on monotherapy with amlodipine 10 mg. The likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on Azor 5/20 mg, and to 68% (systolic) and 85% (diastolic) on Azor 10/40 mg.. Azor is combination of amlodipine besylate, dihydropyridine calcium channel blocker, and olmesartan medoxomil, an angiotensin II receptor blocker, indicated for the treatment of hypertension, 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). Azor may also be used as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals 1). Azor is combination of amlodipine besylate, dihydropyridine calcium channel blocker, and olmesartan medoxomil, an angiotensin II receptor blocker, indicated for the treatment of hypertension, 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). Azor may also be used as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals 1). Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) 140 mmHg at Week With LOCF. Figure 2: Probability of Achieving Diastolic Blood Pressure (DBP) 90 mmHg at Week With LOCF. Figure 3: Probability of Achieving Systolic Blood Pressure (SBP) 130 mmHg at Week With LOCF. Figure 4: Probability of Achieving Diastolic Blood Pressure (DBP) 80 mmHg at Week With LOCF.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Azor. Azor is combination of two antihypertensive drugs: dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, olmesartan medoxomil. The amlodipine component of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the vasoconstrictor effects of angiotensin II. Amlodipine. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by gradual rate of association and dissociation with the receptor binding site, resulting in gradual onset of effect. Amlodipine is peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause reduction in peripheral vascular resistance and reduction in blood pressure.Olmesartan medoxomil. Angiotensin II is formed from angiotensin in 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 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. An AT receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than 12,500-fold greater affinity for the AT receptor than for the AT receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, reaction also catalyzed by ACE. Because olmesartan 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m basis, similar to the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest dose was, on mg/m basis, about two and half times the MRHD. (Calculations based on 60 kg patient.) Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on mg/m basis). Olmesartan medoxomil. Olmesartan was not carcinogenic when administered by dietary administration to rats for up to years. The highest dose tested (2000 mg/kg/day) was, on mg/m basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, 6-month gavage study in the p53 knockout mouse and 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of carcinogenic effect of olmesartan. Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in study in which dosing was begun (female) or (male) weeks prior to mating.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Amlodipine. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by significant change in heart rate or plasma catecholamine levels with chronic dosing. With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.Olmesartan medoxomil. Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours. Plasma concentrations of angiotensin and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of amlodipine and olmesartan medoxomil from Azor are equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when administered separately. The bioavailability of both components is well below 100%, but neither component is affected by food. The effective half-lives of amlodipine (45+-11 hours) and olmesartan (7+-1 hours) result in 2- to 3- fold accumulation for amlodipine and negligible accumulation for olmesartan with once-daily dosing.Amlodipine. After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between and 12 hours. Absolute bioavailability is estimated as between 64% and 90%. Olmesartan medoxomil. Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the peak plasma concentration (C max) of olmesartan is reached after to hours. Food does not affect the bioavailability of olmesartan medoxomil. DistributionAmlodipine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after to days of consecutive daily dosing. Olmesartan medoxomil. The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses. In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats. Metabolism and ExcretionAmlodipine. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine. Olmesartan medoxomil. Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. Olmesartan appears to be eliminated in biphasic manner with terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within to days and no accumulation in plasma occurs with once-daily dosing.Specific PopulationsGeriatric PatientsThe pharmacokinetic properties of Azor in the elderly are similar to those of the individual components.Amlodipine. Elderly patients have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%, and lower initial dose may be required. Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil were studied in the elderly (>=65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUC was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R. Pediatric PatientsAmlodipine. Sixty-two hypertensive patients aged to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults. Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil have not been investigated in patients <18 years of age. Male and Female PatientsPopulation pharmacokinetic analysis indicated that female patients had approximately 15% smaller clearances of olmesartan than male patients. Gender had no effect on the clearance of amlodipine.Olmesartan medoxomil. Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and max were 10% to 15% higher in women than in men.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAzor can cause fetal harm when administered to 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 [see Clinical Considerations]. 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 Azor 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 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%-4% and 15%-20%, respectively.. Clinical Considerations. Disease-Associated Maternal and/or Embryo/Fetal RiskHypertension 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. Olmesartan medoxomilOligohydramnios 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. 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 for hypotension, oliguria, and hyperkalemia. In neonates with history of in utero exposure to olmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as means of reversing hypotension and supporting renal function [see Use in Specific Populations (8.4)]. Data. Animal DataNo reproductive studies have been conducted with the combination of olmesartan medoxomil, and amlodipine. However, these studies have been conducted for olmesartan medoxomil and amlodipine alone.. Olmesartan medoxomilNo 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 mg/m basis) or pregnant rabbits at oral doses up to mg/kg/day (half the MRHD on mg/m 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 auricular, 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 >= 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. Amlodipine No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on mg/m basis) during their respective periods of major organogenesis (calculations based on patient weight of 60 kg). However, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose.