BENICAR HCT- olmesartan medoxomil and hydrochlorothiazide tablet, film coated
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue BENICAR HCT as soon as possible [see Warnings and Precautions (5.1)].
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
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 [see Dosage and Administration (2)].
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).
DOSAGE AND ADMINISTRATION
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.
3 DOSAGE FORMS AND STRENGTHS
BENICAR HCT (olmesartan / hydrochlorothiazide) is supplied as film-coated, non-scored tablets:
20 mg/12.5 mg reddish-yellow, circular, debossed with Sankyo on one side and C22 on the other side
40 mg/12.5 mg reddish-yellow, oval, debossed with Sankyo on one side and C23 on the other side
40 mg/25 mg pink, oval, debossed with Sankyo on one side and C25 on the other side
4 CONTRAINDICATIONS
BENICAR HCT is contraindicated:
In patients with hypersensitivity to any component of BENICAR HCT [see Adverse Reactions (6.1, 6.2)]
In patients with anuria [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]
For coadministration with aliskiren in patients with diabetes [see Drug Interactions (7.4)].
WARNINGS AND PRECAUTIONS
5.1 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 [see Use in Specific Populations (8.1)].
Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia [see Use in Specific Populations (8.1)].
5.2 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.
5.3 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 [see Drug Interactions (7)].
5.4 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.
5.6 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-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 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
7.1 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.
7.2 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.
7.4 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 [see Contraindications (4)]. Avoid use of aliskiren with BENICAR HCT in patients with renal impairment (GFR <60 ml/min).
7.5 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 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3)].
7.6 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 [see Clinical Pharmacology (12.3)].
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D
DESCRIPTION
BENICAR HCT (olmesartan medoxomil and hydrochlorothiazide) is a combination of an angiotensin II receptor antagonist (AT1 subtype), olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide (HCTZ).
Olmesartan medoxomil is 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p -(o -1H -tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.
Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.6. It is practically insoluble in water and sparingly soluble in methanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H -1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7 H8 ClN3 O4 S2
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.
BENICAR HCT is available for oral administration in tablets containing 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Inactive ingredients include: hydroxypropylcellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide and yellow iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Olmesartan medoxomil
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor.
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.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.
