|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
Special Alerts
Angiotensin II Receptor Blockers (ARBs) and Cancer Risk
June 2011
The U.S. Food and Drug Administration (FDA) has notified healthcare providers of the results from an ongoing review of ARB use and cancer risk. In June 2010, a published meta-analysis of 5 clinical trials reported a statistically significant increased risk of developing cancer in patients who received treatment with ARBs compared to those who did not. The FDA has completed a meta-analysis of 31 trials to further investigate the association between ARB use and cancer risk. The results of the FDA meta-analysis, along with other available data, have found no evidence for an increased risk of cancer with ARB use.
For additional information, see http://www.fda.gov/Drugs/DrugSafety/ucm257516.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(ep roe SAR tan)
Generic Available (U.S.)
Yes
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypertension; may be used alone or in combination with other antihypertensives
Pregnancy Risk Factor
D
Pregnancy Considerations
[U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. The use of drugs which act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Use is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed in utero should be monitored for hyperkalemia, hypotension, and oliguria.
Lactation
Not recommended
Contraindications
Hypersensitivity to eprosartan or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.
• Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first.
• Renal artery stenosis: Use eprosartan with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in pre-existing renal insufficiency and severe renal impairment.
Concurrent drug therapy issues:
• Angiotensin-converting enzyme (ACE) inhibitors: Concurrent use of ACE inhibitors may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia).
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
Adverse Reactions
1% to 10%:
Central nervous system: Fatigue (2%), depression (1%)
Endocrine & metabolic: Hypertriglyceridemia (1%)
Gastrointestinal: Abdominal pain (2%)
Genitourinary: Urinary tract infection (1%)
Respiratory: Upper respiratory tract infection (8%), rhinitis (4%), pharyngitis (4%), cough (4%)
Miscellaneous: Viral infection (2%), injury (2%)
<1% (Limited to important or life-threatening): Abnormal ECG, abnormal vision, aggravated arthritis, albuminuria, anemia, angina pectoris, anorexia, anxiety, arthritis, arthrosis, asthma, ataxia, atrial fibrillation, back pain, bradycardia, BUN increased, conjunctivitis, constipation, creatine phosphokinase increased, creatinine increased, cystitis, diabetes mellitus, diaphoresis increased, dry mouth, eczema, epistaxis, esophagitis, ethanol intolerance, extrasystoles, facial edema, fatigue, fever, flatulence, furunculosis, gastritis, gastroenteritis, gingivitis, glycosuria, gout, hematuria, herpes simplex, hot flushes, hypercholesterolemia, hyperglycemia, hyper-/hypokalemia, hyponatremia, hypotension, influenza-like symptoms, insomnia, leg cramps, leukopenia, maculopapular rash, malaise, micturition frequency, migraine, nausea, nervousness, neuritis, neutropenia, orthostasis, otitis externa, otitis media, pain, palpitation, paresthesia, periodontitis, peripheral edema, peripheral ischemia, polyuria, pruritus, purpura, rash, renal calculus, rigors, skeletal pain, somnolence, substernal chest pain, tachycardia, tendonitis, thrombocytopenia, tinnitus, toothache, transaminases increased, tremor, urinary incontinence, vertigo, vomiting, weakness, xerophthalmia
Rhabdomyolysis has been reported (rarely) with angiotensin-receptor antagonists.
Metabolism/Transport Effects
Inhibits CYP2C9 (weak)
Drug Interactions
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Dong quai has estrogenic activity. Some herbal medications may worsen hypertension (eg, ephedra); garlic may have additional antihypertensive effects. Management: Avoid dong quai if using for hypertension. Avoid ephedra, yohimbe, ginseng, and garlic.
Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because eprosartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Eprosartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacodynamics/Kinetics
Protein binding: 98%
Metabolism: Minimally hepatic
Bioavailability: 300 mg dose: 13%
Half-life elimination: Terminal: 5-9 hours
Time to peak, serum: Fasting: 1-2 hours
Excretion: Feces (90%); urine (7%, mostly as unchanged drug)
Clearance: 7.9 L/hour
Dosage
Adults: Oral: Dosage must be individualized; can administer once or twice daily with total daily doses of 400-800 mg. Usual starting dose is 600 mg once daily as monotherapy in patients who are euvolemic. Limited clinical experience with doses >800 mg.
Dosage adjustment in renal impairment: Moderate-to-severe impairment: No initial starting dosage adjustment is necessary; however, carefully monitor the patient. Maximum dose: 600 mg daily.
Hemodialysis: Poorly removed (ClHD <1 L/hour)
Dosage adjustment in hepatic impairment: No starting dosage adjustment is necessary; however, carefully monitor the patient
Elderly: No starting dosage adjustment is necessary; however, carefully monitor the patient
Monitoring Parameters
Electrolytes, serum creatinine, BUN, urinalysis
Patient Education
This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, lightheadedness, or postural hypotension. Report chest pain or palpitations; respiratory infection or cold symptoms; unusual cough; swelling of face, tongue, lips, or extremities; changes in urinary pattern; or extreme fatigue.
Geriatric Considerations
No specific dose adjustments are necessary in the elderly due to the drug's major route of elimination. However, since many elderly may be volume depleted due to their “blunted thirst reflex” and use of diuretics, care and monitoring of blood pressure and volume status are necessary upon initiation.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent. Episodes of intraoperative hypotension may be managed by fluid administration and/or modest doses of alpha-adrenergic agents. If discontinued preoperatively, reinstitute when patient is hemodynamically stable. Patients who have undergone coronary artery bypass graft (CABG) surgery should have therapy reinstituted once the patient is stable or initiated in those who were not receiving ACE inhibition prior to CABG surgery; continue indefinitely (Hillis, 2011).
Evidence-Based Information: The angiotensin II receptor antagonists appear to have similar indications as the ACE inhibitors. In heart failure, the angiotensin II antagonists are especially useful in providing an alternative therapy in those patients who have intractable cough in response to ACE inhibitor therapy. Candesartan has been studied as an alternative therapy in chronic heart failure patients who cannot tolerate an ACE-I (CHARM-Alternative) and as an added therapy in heart failure patients who are maintained on an ACE-I (CHARM-Added). In both studies, the combined endpoint of cardiovascular death or heart failure hospitalizations was significantly improved over the placebo-treated group.
Cardiovascular Considerations
Hypertension: According to the 2003 JNC 7 guidelines for the treatment of hypertension, most patients with hypertension will require treatment with at least 2 antihypertensives. First-line therapy for hypertension is a diuretic (eg, hydrochlorothiazide or chlorthalidone). When a diuretic cannot be used or when a compelling indication exists for another drug, other types of antihypertensives may be used (eg, ACEIs, ARBs, beta-blockers, CCBs). Angiotensin II receptor blockers are among the multiple choices of agents that have shown benefit in a number of different patient subtypes. Compelling indications for an ARB include patients with heart failure, diabetes, or chronic kidney disease. The LIFE trial (Dahlof, 2002) confirmed that ARB (losartan 50-100 mg daily) was better tolerated than a beta-blocker blocker (atenolol), and resulted in significant reduction in mortality, angina, or HF hospitalization (primary endpoint). Stroke and new-onset diabetes were significantly reduced in the losartan treatment group.
Treatment should be targeted to a goal blood pressure of <140/90 mm Hg. If diabetes or renal disease coexists, the blood pressure goal should be <130/80 mm Hg.
Cautions: ARB therapy may elicit an increase in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. Severe hypotension may occur in patients who are sodium- and/or volume-depleted; initiate lower doses and monitor closely when starting therapy in these patients. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the lack of effect on the response to bradykinin, angiotensin receptor blockers are less likely to be associated with nonrenin-angiotensin effects such as cough and angioedema. The angiotensin II antagonists do not cause increases in levels of bradykinin as the ACEIs do.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause fatigue or depression
Mental Health: Effects on Psychiatric Treatment
Risk of lithium toxicity may be increased by eprosartan; monitor lithium levels
Nursing: Physical Assessment/Monitoring
Use caution in presence of renal impairment. Assess potential for interactions with other pharmacological agents or herbal products that may impact blood pressure. Monitor for hypotension on a regular basis during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 600 mg
Teveten®: 400 mg, 600 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Teveten)
400 mg (30): $90.99
600 mg (30): $109.99
References
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2012,” Diabetes Care, 2012, 35(Suppl ):11-63.
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine,” J Am Coll Cardiol, 2007, 50(7):e1-e157.
Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.
Chobanian AV, Bakris GL, Black HR, et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,” JAMA, 2003, 289(19):2560-71.
Cohn JN and Tognoni G, “Valsartan Heart Failure Trial Investigators. A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure,” N Engl J Med, 2001, 345(23):1667-75.
Conlin P, Moore T, Swartz S, et al, “Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients,” Hypertension, 2000, 36(3):461-5.
Dahlof B, Devereux RB, Kjeldsen SE, et al, “Cardiovascular Morbidity and Mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): A Randomised Trial Against Atenolol,” Lancet, 2002, 359(9311):995-1003.
Dickstein K, Kjekshus J, et al, "Effects of Losartan and Captopril on Mortality and Morbidity in High-Risk Patients After Acute Myocardial Infarction: The OPTIMAAL Randomised Trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan," Lancet , 2002, 360(9335):752-60.
Epstein BJ and Gums JG, "Angiotensin Receptor Blockers Versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations," Ann Pharmacother, 2005, 39(3):470-80.
Hillis LD, Smith PK, Anderson JL, et al, “2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 124(23):2610-42.
Granger CB, McMurray JJ, Yusuf S, et al, "Effects of Candesartan in Patients With Chronic Heart Failure and Reduced Left-Ventricular Systolic Function Intolerant to Angiotensin-Converting-Enzyme Inhibitors: The CHARM-Alternative Trial," Lancet, 2003, 362(9386):772-6.
“K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative,” Am J Kidney Dis, 2002, 39(2 Suppl 2):1-246. Available at http://www.kidney.org/professionals/KDOQI/guidelines_ckd/toc.htm
McMurray JJ, Ostergren J, Swedberg K, et al, "Effects of Candesartan in Patients With Chronic Heart Failure and Reduced Left-Ventricular Systolic Function Taking Angiotensin-Converting-Enzyme Inhibitors: The CHARM-Added Trial," Lancet, 2003, 362(9386):767-71.
Pfeffer MA, McMurray JJ, Velazquez EJ, et al, "Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both," N Engl J Med, 2004, 350(2):203.
Pitt B, Poole-Wilson PA, Segal R, et al, "Effect of Losartan Compared With Captopril on Mortality in Patients With Symptomatic Heart Failure: Randomised Trial - The Losartan Heart Failure Survival Study ELITE II," Lancet, 2000, 355(9215):1582-7.
Sipahi I, Debanne SM, Rowland DY, et al, “Angiotensin-Receptor Blockade and Risk of Cancer: Meta-Analysis of Randomised Controlled Trials,” Lancet Oncol, 2010, 11(7):627-36.
Smith SC Jr, Benjamin EJ, Bonow RO, et al, “AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update: A Guideline From the American Heart Association and American College of Cardiology Foundation,” Circulation, 2011, 124(22):2458-73.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
|
