Benicar Hct Drug Information

Uses of Benicar Hct

(olmesartan medoxomil and hydrochlorothiazide) is indicated for the treatment of hypertension, to lower blood pressure. BENICAR HCT is not indicated for the initial therapy of hypertension . Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

There are no controlled trials demonstrating risk reduction with BENICAR HCT. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. BENICAR HCT may be used alone, or in combination with other antihypertensive drugs. BENICAR HCT is a combination of olmesartan, an angiotensin II receptor blocker and hydrochlorothiazide, a thiazide diuretic indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Dosage & Administration of Benicar Hct

The recommended starting dose of BENICAR HCT is 40/12.5 mg once daily in patients whose blood pressure is not adequately controlled with olmesartan monotherapy. Dose can be titrated up to 40 /25 mg if necessary. The recommended starting dose of BENICAR HCT is 20/12.5 mg once daily in patients whose blood pressure is not adequately controlled with HCT monotherapy or who experience dose-limiting adverse reactions with hydrochlorothiazide.

Dose can be titrated up to 40 /25 mg if necessary. Patients titrated to the individual components (olmesartan and hydrochlorothiazide) may instead receive the corresponding dose of BENICAR HCT. Recommended starting dose in patients not adequately controlled with olmesartan monotherapy, 40/12.5 mg Recommended starting dose in patients not adequately controlled with hydrochlorothiazide monotherapy, 20/12.5 mg Adjust dose after 2 to 4 weeks, as needed, to a maximum of 40 mg / 25 mg olmesartan / hydrochlorothiazide

Side Effects of Benicar Hct

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. Olmesartan medoxomil and hydrochlorothiazide The concomitant use of olmesartan medoxomil and hydrochlorothiazide was evaluated for safety in 1243 hypertensive patients. Treatment with olmesartan medoxomil and hydrochlorothiazide was well tolerated, with an incidence of adverse events similar to that of placebo.

Adverse reactions were generally mild, transient and not dependent on the dose of olmesartan medoxomil and hydrochlorothiazide. The rate of withdrawals for adverse events in all trials of hypertensive patients was 2.0% (25/1243) on olmesartan medoxomil plus hydrochlorothiazide and 2.0% (7/342) on placebo. In a placebo-controlled, factorial clinical trial of olmesartan medoxomil (2.5 mg to 40 mg) and hydrochlorothiazide (12.5 mg to 25 mg), the following adverse reactions reported in Table 1 occurred in >2% of patients, and more often on the olmesartan medoxomil and hydrochlorothiazide combination than on placebo.

Table 1: Adverse Reactions in a Factorial Trial of Patients with Hypertension Olmesartan/HCTZ (N=247) (%) Olmesartan (N=125) (%) HCTZ (N=88) (%) Placebo (N=42) (%) Nausea 3 2 1 0 Hyperuricemia 4 0 2 2 Dizziness 9 1 8 2 Upper Respiratory Infection 7 6 7 0 Other adverse reactions 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 and 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, ALT increased Metabolic and Nutritional: creatine phosphokinase increased 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 and hydrochlorothiazide. Angioedema has been reported with angiotensin II receptor antagonists, including BENICAR HCT. Hydrochlorothiazide Other adverse reactions that have been reported with hydrochlorothiazide 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: glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Clinical Laboratory Test Findings Creatinine/ b lood u rea n itrogen (BUN): Minor elevations in creatinine and BUN occurred in 1.7% and 2.5% respectively, of patients taking BENICAR HCT and 0% and 0% respectively, given placebo in controlled clinical trials.

Post- m arketing Experience

The following adverse reactions have been identified during post-approval use of BENICAR HCT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Body as a Whole: Asthenia Gastrointestinal: Vomiting Metabolic: Hyperkalemia Musculoskeletal: Rhabdomyolysis Skin and Appendages: Alopecia, pruritus 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 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval, 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18). The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years.

In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a 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 a concern of a 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 a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics. Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer.

In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Warnings & Cautions for Benicar Hct

Fetal Toxicity Pregnancy Category D 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 BENICAR HCT as soon as possible. Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia .

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. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. When electrolyte and fluid imbalances have been corrected, BENICAR HCT usually can be continued without difficulty. A transient hypotensive response is not a contraindication to further treatment.

Impaired Renal Function Changes in renal function including acute renal failure can

be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system ( e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on BENICAR HCT. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on BENICAR HCT .

Hypersensitivity Reactions 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. 5. 5 Electrolyte and Metabolic Imbalances BENICAR HCT contains hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. BENICAR HCT also contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia.

Monitor serum electrolytes periodically. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an

idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. 5. 7 Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5. 8 Sprue-L ike 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 a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of BENICAR HCT in cases where no other etiology is identified.

Drug Interactions with Benicar Hct

Agents Increasing Serum Potassium Coadministration of

BENICAR HCT with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

Lithium Increases in serum lithium concentrations and lithium toxicity have been reported

during concomitant administration of lithium with angiotensin II receptor antagonists or hydrochlorothiazide. Monitor serum lithium levels during concomitant use. 7. 3 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) Olmesartan medoxomil 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. Hydrochlorothiazide In some patients the administration of a NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics.

Therefore, monitor blood pressure closely.

Dual Blockade of the Renin Angiotensin System 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 BENICAR HCT and other agents that affect the RAS. Do not co-administer aliskiren with BENICAR HCT in patients with diabetes. Avoid use of aliskiren with BENICAR HCT in patients with renal impairment (GFR <60 ml/min).

Colesevelam H ydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride

reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose . 7. 6 The Use of Hydrochlorothiazide with Other Drugs When administered concurrently the following drugs may interact with thiazide diuretics: Antidiabetic drugs (oral agents and insulin) : Dosage adjustment of the antidiabetic drug may be required.

Ion exchange resins: Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 – 6 hours after the administration of resins would potentially minimize the interaction . Corticosteroids, ACTH : Intensified electrolyte depletion, particularly hypokalemia.

Pregnancy Safety for Benicar Hct

Pregnancy Pregnancy Category D 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 BENICAR HCT as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment.

If oligohydramnios is observed, discontinue BENICAR HCT, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to BENICAR HCT for hypotension, oliguria, and hyperkalemia.

Pediatric Use of Benicar Hct

Pediatric Use Neonates with a history of in utero exposure to BENICAR HCT: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function. Safety and effectiveness of BENICAR HCT in pediatric patients have not been established.

Contraindications for Benicar Hct

is contraindicated: In patients with hypersensitivity to any component of BENICAR HCT In patients with anuria For coadministration with aliskiren in patients with diabetes. Hypersensitivity to any component of BENICAR HCT Anuria Do not co-administer aliskiren with BENICAR HCT in patients with diabetes.

Overdosage Information for Benicar Hct

Olmesartan medoxomil Limited data are available related to overdosage of olmesartan medoxomil in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension should occur, supportive treatment should be initiated.

The dialyzability of olmesartan is unknown. No lethality was observed in acute toxicity studies in mice and rats given single oral doses up to 2000 mg/kg olmesartan medoxomil. The minimum lethal oral dose of olmesartan medoxomil in dogs was greater than 1500 mg/kg.

Hydrochlorothiazide The most common signs and symptoms of hydrochlorothiazide overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Clinical Studies of Benicar Hct

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. Olmesartan medoxomil and hydrochlorothiazide The concomitant use of olmesartan medoxomil and hydrochlorothiazide was evaluated for safety in 1243 hypertensive patients. Treatment with olmesartan medoxomil and hydrochlorothiazide was well tolerated, with an incidence of adverse events similar to that of placebo.

Adverse reactions were generally mild, transient and not dependent on the dose of olmesartan medoxomil and hydrochlorothiazide. The rate of withdrawals for adverse events in all trials of hypertensive patients was 2.0% (25/1243) on olmesartan medoxomil plus hydrochlorothiazide and 2.0% (7/342) on placebo. In a placebo-controlled, factorial clinical trial of olmesartan medoxomil (2.5 mg to 40 mg) and hydrochlorothiazide (12.5 mg to 25 mg), the following adverse reactions reported in Table 1 occurred in >2% of patients, and more often on the olmesartan medoxomil and hydrochlorothiazide combination than on placebo.

Table 1: Adverse Reactions in a Factorial Trial of Patients with Hypertension Olmesartan/HCTZ (N=247) (%) Olmesartan (N=125) (%) HCTZ (N=88) (%) Placebo (N=42) (%) Nausea 3 2 1 0 Hyperuricemia 4 0 2 2 Dizziness 9 1 8 2 Upper Respiratory Infection 7 6 7 0 Other adverse reactions 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 and 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, ALT increased Metabolic and Nutritional: creatine phosphokinase increased 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 and hydrochlorothiazide. Angioedema has been reported with angiotensin II receptor antagonists, including BENICAR HCT. Hydrochlorothiazide Other adverse reactions that have been reported with hydrochlorothiazide 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: glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Clinical Laboratory Test Findings Creatinine/ b lood u rea n itrogen (BUN): Minor elevations in creatinine and BUN occurred in 1.7% and 2.5% respectively, of patients taking BENICAR HCT and 0% and 0% respectively, given placebo in controlled clinical trials.