FDA label 94cc0af7-0516-4ef0-8bfe-39f2708ef22e

Azor ® (amlodipine and olmesartan medoxomil) tablets USE IN PREGNANCY When pregnancy is detected, discontinue Azor as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus [see Warning and Precautions (5.1) ] . USE IN PREGNANCY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue Azor as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus (5.1) .

<table border="0" cellpadding="3" cellspacing="1" ID="ide7d86c4-9f54-4faa-8c5b-a571bcad8ade"> <tbody> <tr> <td> <content styleCode="bold">USE IN PREGNANCY</content> <content>See full prescribing information for complete boxed warning.</content> <content styleCode="bold">When pregnancy is detected, discontinue Azor as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus <linkHtml href="#a7a554a0-7034-11dc-95c5-0002a5d5c51b">(5.1)</linkHtml>.</content> </td> </tr> <tr> <td> </td> </tr> </tbody> </table>

5 WARNINGS AND PRECAUTIONS Enter section text here Hypotension in volume- or salt-depleted patients with treatment initiation may be anticipated. Start treatment under close supervision (5.2) . Increased angina or myocardial infarction with calcium channel blockers may occur upon dosage initiation or increase (5.4) . Impaired renal function: changes in renal function may be anticipated in susceptible individuals (5.6) . 5.1 Fetal/Neonatal Morbidity and Mortality Olmesartan medoxomil . Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. There have been several dozen cases reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue Azor as soon as possible. During the second and third trimesters of pregnancy, these drugs have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Azor as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Azor unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear 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 ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day. 5.2 Hypotension in Volume- or Salt-Depleted Patients Olmesartan medoxomil . Symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. 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) may be particularly vulnerable. 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. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.3 Vasodilation Amlodipine . Since the vasodilation attributable to amlodipine in Azor is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution, as with any other peripheral vasodilator, when administering Azor, particularly in patients with severe aortic stenosis. 5.4 Patients with Severe Obstructive Coronary Artery Disease 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. 5.5 Patients with Congestive Heart Failure Amlodipine . In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. 5.6 Patients with Impaired Renal Function Azor. There are no studies of Azor in patients with renal impairment. Olmesartan medoxomil . Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a 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 [See 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. 5.7 Patients with Hepatic Impairment Amlodipine . 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, exercise caution when administering Azor to patients with severe 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) ]. 5.8 Laboratory Tests Azor . There was a greater decrease in hemoglobin and hematocrit in the combination product compared to either component. Other laboratory changes can usually be attributed to either monotherapy component. Amlodipine . In post-marketing experience, hepatic enzyme elevations have been reported (6.2) . Olmesartan medoxomil . In post-marketing experience, increased blood creatinine levels and hyperkalemia have been reported.

6 ADVERSE REACTIONS Enter section text here Most common adverse reaction (incidence ≥3%) is edema (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 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 a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Azor The data described below reflect exposure to Azor in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Azor was studied in one placebo-controlled factorial trial (see Section 14.1 ). The population had a 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). Edema Edema is a 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 Period Olmesartan Medoxomil Placebo 20 mg 40 mg Amlodipine Placebo –% * -2.4% 6.2% 5mg 0.7% 5.7% 6.2% 10 mg 24.5% 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. 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 Therapy Analyzing 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 Event 1 Olmesartan Medoxomil Placebo 10 mg 20 mg 40 mg Amlodipine Placebo 4.9% 4.3% 5.6% 3.1% 5mg 3.7% 0.0% 1.2% 3.7% 10 mg 5.5% 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 Event Placebo N=520 2.5 mg N=275 5.0 mg N=296 10.0 mg N=268 Edema 0.6 1.8 3.0 10.8 Dizziness 1.5 1.1 3.4 3.4 Flushing 0.0 0.7 1.4 2.6 Palpitation 0.6 0.7 1.4 4.5 For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table; Adverse Event Placebo Amlodipine Male=% (N=914) Female=% (N=336) Male=% (N=1218) Female=% (N=512) Edema 1.4 5.1 5.6 14.6 Flushing 0.3 0.9 1.5 4.5 Palpitation 0.9 0.9 1.4 3.3 Somnolence 0.8 0.3 1.3 1.6 Olmesartan 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 6 months and more than 525 for at least 1 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 a 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Amlodipine. The following post-marketing event has been reported infrequently where a 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. Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience: Body as a Whole: asthenia, angioedema Gastrointestinal: vomiting Musculoskeletal: rhabdomyolysis Urogenital System: acute renal failure Skin and Appendages: alopecia, pruritus, urticaria

<table width="380" ID="ibc450d8f-55a7-4ea5-89d1-5953f1f01eeb"> <caption>Placebo-Subtracted Incidence of Edema during the Double-Blind Treatment Period</caption> <tbody> <tr> <td> </td> <td> <content styleCode="bold">Olmesartan Medoxomil </content> </td> </tr> <tr> <td> </td> <td> <content styleCode="bold">Placebo</content> </td> <td> <content styleCode="bold">20 mg</content> </td> <td> <content styleCode="bold">40 mg</content> </td> </tr> <tr> <td> <content styleCode="bold">Amlodipine</content> </td> <td> <content styleCode="bold">Placebo </content> </td> <td>&#x2013;%^* </td> <td>-2.4%</td> <td>6.2%</td> </tr> <tr> <td> <content styleCode="bold">5mg</content> </td> <td>0.7%</td> <td>5.7%</td> <td>6.2%</td> </tr> <tr> <td> <content styleCode="bold">10 mg</content> </td> <td>24.5%</td> <td>13.3%</td> <td>11.2%</td> </tr> </tbody> </table>

<table width="460" ID="i99ead42a-c85f-4bfd-85c0-0d57ca30df67"> <caption>Discontinuation for any Treatment Emergent Adverse Event¹ </caption> <tbody> <tr> <td> </td> <td> <content styleCode="bold">Olmesartan Medoxomil </content> </td> </tr> <tr> <td> </td> <td> <content styleCode="bold">Placebo</content> </td> <td> <content styleCode="bold">10 mg</content> </td> <td> <content styleCode="bold">20 mg</content> </td> <td> <content styleCode="bold">40 mg</content> </td> </tr> <tr> <td> <content styleCode="bold">Amlodipine</content> </td> <td> <content styleCode="bold">Placebo </content> </td> <td>4.9%</td> <td>4.3%</td> <td>5.6%</td> <td>3.1%</td> </tr> <tr> <td> <content styleCode="bold">5mg</content> </td> <td>3.7%</td> <td>0.0%</td> <td>1.2%</td> <td>3.7%</td> </tr> <tr> <td> <content styleCode="bold">10 mg</content> </td> <td>5.5%</td> <td>6.8%</td> <td>2.5%</td> <td>5.6%</td> </tr> </tbody> </table>

<table width="350" ID="i42c1d7b4-1763-4166-8afb-98b12591775f"> <tbody> <tr> <td> <paragraph> <content styleCode="bold">Adverse Event</content> </paragraph> </td> <td> <paragraph> <content styleCode="bold">Placebo N=520</content> </paragraph> </td> <td> <paragraph> <content styleCode="bold">2.5 mg N=275</content> </paragraph> </td> <td> <paragraph> <content styleCode="bold">5.0 mg N=296</content> </paragraph> </td> <td> <paragraph> <content styleCode="bold">10.0 mg N=268</content> </paragraph> </td> </tr> <tr> <td>Edema</td> <td>0.6</td> <td>1.8</td> <td>3.0</td> <td>10.8</td> </tr> <tr> <td>Dizziness</td> <td>1.5</td> <td>1.1</td> <td>3.4</td> <td>3.4</td> </tr> <tr> <td>Flushing</td> <td>0.0</td> <td>0.7</td> <td>1.4</td> <td>2.6</td> </tr> <tr> <td>Palpitation</td> <td>0.6</td> <td>0.7</td> <td>1.4</td> <td>4.5</td> </tr> </tbody> </table>