Olmesartan Medoxomil and Hydrochlorothiazide

The recommended starting dose of Olmesartan Medoxomil and Hydrochlorothiazide tablets 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 Olmesartan Medoxomil and Hydrochlorothiazide tablets is 20/12.5 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 40/25 mg if necessary.

Patients titrated to the individual components olmesartan and hydrochlorothiazide may instead receive the corresponding dose of Olmesartan Medoxomil and Hydrochlorothiazide tablets.

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 tablets 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)].

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 tablets. 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 tablets 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 Olmesartan Medoxomil and Hydrochlorothiazide tablets. 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 tablets [see Drug Interactions (7)].

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.

Electrolyte and Metabolic Imbalances

Olmesartan Medoxomil and Hydrochlorothiazide tablets contain 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 tablets also contain 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.

Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

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 tablets in cases where no other etiology is identified.

The following adverse reactions with Olmesartan Medoxomil and Hydrochlorothiazide tablets 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)]

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 Olmesartan Medoxomil and Hydrochlorothiazide tablets.

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 tablets and 0% and 0% respectively, given placebo in controlled clinical trials.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Olmesartan Medoxomil and Hydrochlorothiazide tablets. 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 nonfatal 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.

Agents Increasing Serum Potassium

Co-administration of Olmesartan Medoxomil and Hydrochlorothiazide tablets 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.

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 Olmesartan Medoxomil and Hydrochlorothiazide tablets and other agents that affect the RAS.

Do not co-administer aliskiren with Olmesartan Medoxomil and Hydrochlorothiazide tablets in patients with diabetes [see Contraindications (4)]. Avoid use of aliskiren with Olmesartan Medoxomil and Hydrochlorothiazide tablets in patients with renal impairment (GFR < 60 ml/min).

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)].

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.

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Olmesartan Medoxomil and Hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see Use in Specific Populations (8.1)].

Symptomatic Hypotension and Syncope: Advise patients that lightheadedness can occur, especially during the first days of therapy, and to report this symptom to a healthcare provider. Inform patients that dehydration from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to an excessive fall in blood pressure. If syncope occurs advise patients, to contact their healthcare provider.

Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.

Acute Myopia and Secondary Angle-Closure Glaucoma: Advise patients to discontinue Olmesartan Medoxomil and Hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms of acute myopia or secondary angle-closure glaucoma [see Warnings and Precautions (5.6)].

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 7/2017
OLMNH:R4

NDC 0378-1422-93

Olmesartan
Medoxomil and
Hydrochlorothiazide
Tablets
40 mg/12.5 mg

Rx only 30 Tablets

Each film-coated tablet contains:
Olmesartan medoxomil, USP 40 mg
Hydrochlorothiazide, USP 12.5 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM1422H1