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Tribenzor (Olmesartan Medoxomil / Amlodipine Besylate / Hydrochlorothiazide) - Warnings and Precautions

 
 



WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue Tribenzor as soon as possible. (5.1)
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)
 

WARNINGS AND PRECAUTIONS

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 Tribenzor as soon as possible [see Use in Specific Populations ].

Hypotension in Volume- or Salt-Depleted Patients

Olmesartan medoxomil. Symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Initiate treatment with Tribenzor under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Increased Angina and/or Myocardial Infarction

Amlodipine. Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction upon starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Impaired Renal Function

Tribenzor. Tribenzor has not been studied in patients with impaired renal function. Avoid use in patients with severe renal impairment (creatinine clearance ≤30 ml/min) [see Dosage and Administration (2)].

An adverse event of 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.

If progressive renal impairment becomes evident consider withholding or discontinuing either diuretic or angiotensin receptor blocker therapies.

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 and Clinical Pharmacology].

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.

Hepatic Impairment

Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function [see Dosage and Administration (2)].

Hydrochlorothiazide. Minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Electrolyte and Metabolic Imbalances

Hydrochlorothiazide. Perform periodic determinations of serum electrolytes to detect possible electrolyte imbalance. Observe patients receiving thiazide therapy for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are important when the patient is vomiting excessively or receiving parental fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially during brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Metabolic acidosis may occur. Although a chloride deficit in a particular patient is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus, latent diabetes mellitus may become manifest during thiazide therapy.

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

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hyperparathyroidism. Tribenzor should be discontinued before carrying out tests for parathyroid function.

Hypersensitivity Reaction

Hydrochlorothiazide. 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.

Systemic Lupus Erythematosus

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

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.

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 Tribenzor in cases where no other etiology is identified.

Vasodilation

Amlodipine. Although vasodilation attributable to amlodipine is generally gradual in onset, acute hypotension has rarely been reported after oral administration. Patients with severe aortic stenosis may be at particular risk.

Heart Failure

Tribenzor. Tribenzor has not been studied in patients with heart failure.

Amlodipine. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with New York Heart Association (NYHA) Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction.

Laboratory Tests

Olmesartan medoxomil. In post-marketing experience, increased blood creatinine levels and hyperkalemia have been reported.

Amlodipine. In post-marketing experience, hepatic enzyme elevations have been reported [see Adverse Reactions ].

Hydrochlorothiazide. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy

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 Tribenzor as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Tribenzor, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Tribenzor for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations ].

Nursing Mothers

It is not known whether amlodipine or olmesartan are excreted in human milk, but thiazides appear in human milk and olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to Tribenzor:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The safety and effectiveness of Tribenzor in pediatric patients have not been established.

Geriatric Use

Tribenzor. In a controlled clinical trial, 123 hypertensive patients treated with Tribenzor were ≥65 years of age and 18 patients were ≥75 years of age. No overall differences in the efficacy or safety of Tribenzor were observed in these patient populations; however, greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

There are no studies of Tribenzor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. Initiate amlodipine at 2.5 mg in patients with severe hepatic impairment.

Olmesartan medoxomil. Increases in AUC0-∞ and peak plasma concentration (Cmax) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%.

Hydrochlorothiazide. In patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Renal Impairment

There are no studies of Tribenzor in patients with renal impairment. Avoid use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Olmesartan medoxomil. Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.

Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

Hydrochlorothiazide. Thiazide should be used with caution in patients with severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Black Patients

Of the total number of patients who received Tribenzor in a randomized trial, 29% (184/627) were black. Tribenzor was effective in lowering both systolic and diastolic blood pressure in black patients (usually a low-renin population) to the same extent as in non-black patients.

Page last updated: 2014-09-25

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