Olmesartan Medoxomil and Hydrochlorothiazide: Package Insert and Label Information

OLMESARTAN MEDOXOMIL AND HYDROCHLOROTHIAZIDE — olmesartan medoxomil and hydrochlorothiazide tablet, film coated
Aurobindo Pharma Limited

1 INDICATIONS AND USAGE

Olmesartan medoxomil and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Olmesartan medoxomil and hydrochlorothiazide tablets are 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 olmesartan medoxomil and hydrochlorothiazide tablets.

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.
Olmesartan medoxomil and hydrochlorothiazide tablets may be used alone, or in combination with other antihypertensive drugs.

2 DOSAGE AND ADMINISTRATION

The recommended starting dose of olmesartan medoxomil and hydrochlorothiazide tablets is 40 mg/12.5 mg once daily in patients whose blood pressure is not adequately controlled with olmesartan monotherapy. Dose can be titrated up to 40 mg/25 mg if necessary.
The recommended starting dose of olmesartan medoxomil and hydrochlorothiazide tablets is 20 mg/12.5 mg once daily in patients whose blood pressure is not adequately controlled with hydrochlorothiazide monotherapy or who experience dose-limiting adverse reactions with hydrochlorothiazide. Dose can be titrated up to 40 mg/25 mg if necessary.
Patients titrated to the individual components (olmesartan and hydrochlorothiazide) may instead receive the corresponding dose of olmesartan medoxomil and hydrochlorothiazide tablets.

3 DOSAGE FORMS AND STRENGTHS

• Olmesartan medoxomil and hydrochlorothiazide tablets 20 mg/12.5 mg are reddish-yellow, round shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘23’ on the other side.
• Olmesartan medoxomil and hydrochlorothiazide tablets 40 mg/12.5 mg are reddish-yellow, oval shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘53’ on the other side.
• Olmesartan medoxomil and hydrochlorothiazide tablets 40 mg/25 mg are pink, oval shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘54’ on the other side.

4 CONTRAINDICATIONS

Olmesartan medoxomil and hydrochlorothiazide tablets are contraindicated:

• In patients with hypersensitivity to any component of olmesartan medoxomil and hydrochlorothiazide tablets [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)].

5 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 olmesartan medoxomil and hydrochlorothiazide 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 olmesartan medoxomil and hydrochlorothiazide. 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, olmesartan medoxomil and hydrochlorothiazide 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 olmesartan medoxomil and hydrochlorothiazide. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on olmesartan medoxomil and hydrochlorothiazide [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

Olmesartan medoxomil and hydrochlorothiazide contains hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Olmesartan medoxomil and hydrochlorothiazide 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 olmesartan medoxomil and hydrochlorothiazide in cases where no other etiology is identified.

6 ADVERSE REACTIONS

The following adverse reactions with olmesartan medoxomil and hydrochlorothiazide are described elsewhere:

• Hypotension in Volume- or Salt-Depleted Patients [see Warnings and Precautions (5.2)]
• Impaired Renal Function [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
• Electrolyte and Metabolic Imbalances [see Warnings and Precautions (5.5)]
• Acute Myopia and Secondary Angle-Closure Glaucoma [see Warnings and Precautions (5.6)]
• Systemic Lupus Erythematosus [see Warnings and Precautions (5.7)]
• Sprue-Like Enteropathy [see Warnings and Precautions (5.8)]

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.

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/Hydrochlorothiazide (N=247) (%)	Olmesartan (N=125) (%)	Hydrochlorothiazide (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 olmesartan medoxomil and hydrochlorothiazide.

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/blood urea nitrogen (BUN): Minor elevations in creatinine and BUN occurred in 1.7% and 2.5% respectively, of patients taking olmesartan medoxomil and hydrochlorothiazide and 0% and 0% respectively, given placebo in controlled clinical trials.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of olmesartan medoxomil and hydrochlorothiazide. 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 [CI], 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 ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.