FDA label a55f325d-2d36-4f85-b22c-2add48e91aab

USE IN PREGNANCY 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. When pregnancy is detected, BENICAR HCT ® should be discontinued as soon as possible. See WARNINGS , Fetal/Neonatal Morbidity and Mortality.

WARNINGS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, BENICAR HCT ® should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal 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 BENICAR HCT ® 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, BENICAR HCT ® should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress 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. There is no clinical experience with the use of BENICAR HCT ® in pregnant women. No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) or pregnant rats at oral doses up to 1625 mg/kg/day (280 times the MRHD on a mg/m 2 basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats, 162.5 mg/kg/day, is about 28 times, on a mg/m 2 basis, the MRHD of BENICAR HCT ® (40 mg olmesartan medoxomil /25 mg hydrochlorothiazide/day). Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults. Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients ( e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with BENICAR HCT ® , as with any angiotensin receptor blocker. Treatment should start under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline (See DOSAGE AND ADMINISTRATION ). When electrolyte and fluid imbalances have been corrected, therapy usually can be continued without difficulty. A transient hypotensive response is not a contraindication to further treatment. Hydrochlorothiazide Hepatic Impairment Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Hypersensitivity Reaction Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Lithium Interaction Lithium generally should not be given with thiazides (see PRECAUTIONS: Drug Interactions ; Hydrochlorothiazide, Lithium ).

ADVERSE REACTIONS Olmesartan medoxomil-hydrochlorothiazide Olmesartan medoxomil-hydrochlorothiazide has been evaluated for safety in 1243 hypertensive patients. Treatment with olmesartan medoxomil-hydrochlorothiazide was well tolerated, with an incidence of adverse events similar to placebo. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil-hydrochlorothiazide. In the clinical trials, the overall frequency of adverse events was not dose-related. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil-hydrochlorothiazide and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.0% (25/1243) of patients treated with olmesartan medoxomil-hydrochlorothiazide and 2.0% (7/342) of patients treated with placebo. In a placebo-controlled clinical trial, the following adverse events reported with olmesartan medoxomil-hydrochlorothiazide occurred in >2% of patients, and more often on the olmesartan medoxomil-hydrochlorothiazide combination than on placebo, regardless of drug relationship: Olmesartan/HCTZ (N=247) (%) Placebo (N=42) (%) Olmesartan (N=125) (%) HCTZ (N=88) (%) Gastrointestinal Nausea 3 0 2 1 Metabolic Hyperuricemia 4 2 0 2 Nervous System Dizziness 9 2 1 8 Respiratory Upper Respiratory Tract Infection 7 0 6 7 The following adverse events were also reported at a rate of >2%, but were as, or more, common in the placebo group: headache and urinary tract infection. Other adverse events that have been reported with an incidence of greater than 1.0%, whether or not attributed to treatment, in the more than 1200 hypertensive patients treated with olmesartan medoxomil-hydrochlorothiazide in controlled or open-label trials are listed below. Body as a Whole: chest pain, back pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, diarrhea Liver and Biliary System: SGOT increased, GGT increased, SGPT increased Metabolic and Nutritional: hyperlipemia, creatine phosphokinase increased, hyperglycemia Musculoskeletal: arthritis, arthralgia, myalgia Respiratory System: coughing Skin and Appendages Disorders: rash Urinary System: hematuria Facial edema was reported in 2/1243 patients receiving olmesartan medoxomil-hydrochlorothiazide. Angioedema has been reported with angiotensin II receptor antagonists. Olmesartan medoxomil Other adverse events that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in more than 3100 hypertensive patients treated with olmesartan medoxomil monotherapy in controlled or open-label trials are tachycardia and hypercholesterolemia. Hydrochlorothiazide Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body as a Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Laboratory Test Findings In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of olmesartan medoxomil-hydrochlorothiazide. Creatinine, Blood Urea Nitrogen: Increases in blood urea nitrogen (BUN) and serum creatinine of >50% were observed in 1.3% of patients. No patients were discontinued from clinical trials of olmesartan medoxomil-hydrochlorothiazide due to increased BUN or creatinine. Hemoglobin and Hematocrit: A greater than 20% decrease in hemoglobin and hematocrit was observed in 0.0 % and 0.4% (one patient), respectively, of olmesartan medoxomil-hydrochlorothiazide patients, compared with 0.0% and 0.0%, respectively, in placebo-treated patients. No patients were discontinued due to anemia. Post-Marketing Experience : The following adverse reactions have been reported in post-marketing experience: Body as a Whole: Asthenia, angioedema Gastrointestinal: Vomiting Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal: Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria

<table ID="L8daf287a-6798-4f1d-a529-f3c88af6f7ee" width="100%"> <colgroup> <col width="25%"/> <col width="24%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> </colgroup> <thead> <tr> <td/> <td align="center">Olmesartan/HCTZ (N=247) (%)</td> <td align="center">Placebo (N=42) (%)</td> <td align="center">Olmesartan (N=125) (%)</td> <td align="center">HCTZ (N=88) (%)</td> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Gastrointestinal</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Nausea</td> <td align="center">3</td> <td align="center">0</td> <td align="center">2</td> <td align="center">1</td> </tr> <tr> <td/> <td align="center"/> <td align="center"/> <td align="center"/> <td align="center"/> </tr> <tr> <td> <content styleCode="bold">Metabolic</content> </td> <td align="center"/> <td align="center"/> <td align="center"/> <td align="center"/> </tr> <tr> <td>Hyperuricemia</td> <td align="center">4</td> <td align="center">2</td> <td align="center">0</td> <td align="center">2</td> </tr> <tr> <td/> <td align="center"/> <td align="center"/> <td align="center"/> <td align="center"/> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td align="center"/> <td align="center"/> <td align="center"/> <td align="center"/> </tr> <tr> <td>Dizziness</td> <td align="center">9</td> <td align="center">2</td> <td align="center">1</td> <td align="center">8</td> </tr> <tr> <td/> <td align="center"/> <td align="center"/> <td align="center"/> <td align="center"/> </tr> <tr> <td> <content styleCode="bold">Respiratory</content> </td> <td align="center"/> <td align="center"/> <td align="center"/> <td align="center"/> </tr> <tr> <td>Upper Respiratory Tract Infection</td> <td align="center">7</td> <td align="center">0</td> <td align="center">6</td> <td align="center">7</td> </tr> </tbody> </table>