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:

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

Olmesartan medoxomil

No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with hydrochlorothiazide, digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce or are metabolized by those enzymes are not expected.

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbiturates, Or Narcotics – potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin) – dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive Drugs – additive effect or potentiation.

Cholestyramine and Colestipol Resins – absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH – intensified electrolyte depletion, particularly hypokalemia.

Pressor Amines (e.g. Norepinephrine) – possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Non depolarizing (e.g. Tubocurarine) – possible increased responsiveness to the muscle relaxant.

Lithium – should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparation with olmesartan medoxomil-hydrochlorothiazide.

Non-steroidal Anti-inflammatory Drugs – in some patients the administration of a non-steroidal anti- inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when olmesartan medoxomil-hydrochlorothiazide tablets and non-steroidal anti- inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.

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