Tribenzor (Page 2 of 9)

5.4 Impaired Renal Function

Tribenzor.

Impaired renal function was reported in 2.1% of subjects receiving Tribenzor compared to 0.2% to 1.3% of subjects receiving dual combination therapy of olmesartan medoxomil and amlodipine, olmesartan medoxomil and hydrochlorothiazide or amlodipine and hydrochlorothiazide.

If progressive renal impairment becomes evident consider withholding or discontinuing Tribenzor.

Olmesartan medoxomil. Changes in renal function occur in some individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Tribenzor due to the olmesartan medoxomil component [ see Drug Interactions ( 7.2) and Clinical Pharmacology ( 12.3) ].

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with Tribenzor because of the olmesartan medoxomil component.

Hydrochlorothiazide. Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.

5.5 Patients with Hepatic Impairment

Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Electrolyte and Metabolic Imbalances

Tribenzor contains hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Tribenzor also contains olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia.

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.

5.7 Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

5. 8 Systemic Lupus Erythematosus

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

5. 9 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. 10 Sprue-like Enteropathy

Olmesartan medoxomil. 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 Tribenzor in cases where no other etiology is identified.

6 ADVERSE REACTIONS

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.

Tribenzor

In the controlled trial of Tribenzor, patients were randomized to Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg), olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg. Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574 patients with hypertension who received Tribenzor for 8 weeks.

The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes, and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with Tribenzor 40/10/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10/25 mg. The most common reason for discontinuation with Tribenzor was dizziness (1%).

Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to Tribenzor.

The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:

Table 1
Adverse Reaction OM40/ AML10/ HCTZ25 mg (N = 574) n (%) OM40/ AML10 mg (N = 596) n (%) OM40/ HCTZ25mg (N = 580) n (%) AML10/ HCTZ25 mg (N = 552) n (%)
Edema peripheral 44 (7.7) 42 (7.0) 6 (1.0) 46 (8.3)
Headache 37 (6.4) 42 (7.0) 38 (6.6) 33 (6.0)
Fatigue 24 (4.2) 34 (5.7) 31 (5.3) 36 (6.5)
Nasopharyngitis 20 (3.5) 11 (1.8) 20 (3.4) 16 (2.9)
Muscle spasms 18 (3.1) 12 (2.0) 14 (2.4) 13 (2.4)
Nausea 17 (3.0) 12 (2.0) 22 (3.8) 12 (2.2)
Upper respiratory tract infection 16 (2.8) 26 (4.4) 18 (3.1) 14 (2.5)
Diarrhea 15 (2.6) 14 (2.3) 12 (2.1) 9 (1.6)
Urinary tract infection 14 (2.4) 8 (1.3) 6 (1.0) 7 (1.3)
Joint swelling 12 (2.1) 17 (2.9) 2 (0.3) 16 (2.9)

Syncope was reported by 1% of Tribenzor subjects compared to 0.5% or less for the other treatment groups.

Olmesartan medoxomil

Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.

Amlodipine

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.

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