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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
(loe SAR tan)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypertension (HTN); treatment of diabetic nephropathy in patients with type 2 diabetes mellitus (noninsulin dependent, NIDDM) and a history of hypertension; stroke risk reduction in patients with HTN and left ventricular hypertrophy (LVH)
Use: Unlabeled
To slow the rate of progression of aortic-root dilation in pediatric patients with Marfan's syndrome
Pregnancy Risk Factor
C (1st trimester); D (2nd and 3rd trimesters)
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
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known if losartan is found in breast milk; the manufacturer recommends discontinuing the drug or discontinuing nursing based on the importance of the drug to the mother.
Contraindications
Hypersensitivity to losartan or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose), angioedema may occur rarely. It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE-inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early management is critical. Intramuscular (I.M.) administration of epinephrine may be necessary.
• 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.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be needed.
• Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first.
• Renal artery stenosis: Use 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 with 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:
• African-American patients: When used to reduce the risk of stroke in patients with HTN and LVH, may not be effective in the African-American population.
• 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
Note: The incidence of some adverse reactions varied based on the underlying disease state. Notations are made, where applicable, for data derived from trials conducted in diabetic nephropathy and hypertensive patients, respectively.
>10%:
Cardiovascular: Chest pain (12% diabetic nephropathy)
Central nervous system: Fatigue (14% diabetic nephropathy)
Endocrine: Hypoglycemia (14% diabetic nephropathy)
Gastrointestinal: Diarrhea (2% hypertension to 15% diabetic nephropathy)
Genitourinary: Urinary tract infection (13% diabetic nephropathy)
Hematologic: Anemia (14% diabetic nephropathy)
Neuromuscular & skeletal: Weakness (14% diabetic nephropathy), back pain (2% hypertension to 12% diabetic nephropathy)
Respiratory: Cough (≤3% to 11%; similar to placebo; incidence higher in patients with previous cough related to ACE inhibitor therapy)
1% to 10%:
Cardiovascular: Hypotension (7% diabetic nephropathy), orthostatic hypotension (4% hypertension to 4% diabetic nephropathy), first-dose hypotension (dose related: <1% with 50 mg, 2% with 100 mg)
Central nervous system: Dizziness (4%), hypoesthesia (5% diabetic nephropathy), fever (4% diabetic nephropathy), insomnia (1%)
Dermatology: Cellulitis (7% diabetic nephropathy)
Endocrine: Hyperkalemia (<1% hypertension to 7% diabetic nephropathy)
Gastrointestinal: Gastritis (5% diabetic nephropathy), weight gain (4% diabetic nephropathy), dyspepsia (1% to 4%), abdominal pain (2%), nausea (2%)
Neuromuscular & skeletal: Muscular weakness (7% diabetic nephropathy), knee pain (5% diabetic nephropathy), leg pain (1% to 5%), muscle cramps (1%), myalgia (1%)
Respiratory: Bronchitis (10% diabetic nephropathy), upper respiratory infection (8%), nasal congestion (2%), sinusitis (1% hypertension to 6% diabetic nephropathy)
Miscellaneous: Infection (5% diabetic nephropathy), flu-like syndrome (10% diabetic nephropathy)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acute psychosis with paranoid delusions, ageusia, allergic reaction, alopecia, anaphylactic reactions, anemia, angina, angioedema, anorexia, anxiety, arrhythmia, arthralgia, arthritis, ataxia, AV block (second degree), bilirubin increased, blurred vision, bradycardia, bronchitis, BUN increased, confusion, conjunctivitis, constipation, CVA, depression, dermatitis, dysgeusia, dyspnea, ecchymosis, epistaxis, erythroderma, erythema, facial edema, fever, flatulence, flushing, gastritis, gout, hematocrit decreased, hemoglobin decreased, Henoch-Schönlein purpura, hepatitis, hyponatremia, hypotension, impotence, joint swelling, maculopapular rash, malaise, memory impairment, MI, migraine, muscle weakness, myositis, neoplasm, nervousness, orthostatic effects, pancreatitis, paresthesia, peripheral neuropathy, pharyngitis, photosensitivity, pruritus, rash, rhabdomyolysis, rhinitis, serum creatinine increased, sleep disorder, somnolence, syncope, tachycardia, taste perversion, thrombocytopenia, tinnitus, transaminases increased, tremor, urinary frequency, urticaria, vasculitis, ventricular arrhythmia, vertigo, visual acuity decreased, vomiting, xerostomia
Metabolism/Transport Effects
Substrate of CYP2C9 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C19 (weak), CYP2C8 (moderate), CYP2C9 (moderate), CYP3A4 (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
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Losartan. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy
CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Risk D: Consider therapy modification
CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. 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
Fluconazole: May decrease the metabolism of Losartan. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. 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
Milk Thistle: May increase the serum concentration of Losartan. 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
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates. 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
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
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
Rifamycin Derivatives: May increase the metabolism of Angiotensin II Receptor Blockers. 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
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
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: St John's wort may decrease levels of losartan. Some herbal medications may worsen hypertension (eg, licorice); others may increase the antihypertensive effect of losartan (eg, shepherd's purse). Some herbal medications may increase the hypoglycemic effects of losartan (eg, alfalfa). Management: Avoid St John's wort. Avoid bayberry, blue cohosh, ginseng (American), kola, licorice, and yohimbe. Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, and shepherd's purse. Avoid alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, and stinging nettle.
Storage
Store at 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
As a selective and competitive, nonpeptide angiotensin II receptor antagonist, losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II; losartan interacts reversibly at the AT1 and AT2 receptors of many tissues and has slow dissociation kinetics; its affinity for the AT1 receptor is 1000 times greater than the AT2 receptor. Angiotensin II receptor antagonists may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, they do not affect the response to bradykinin, and are less likely to be associated with nonrenin-angiotensin effects (eg, cough and angioedema). Losartan increases urinary flow rate and in addition to being natriuretic and kaliuretic, increases excretion of chloride, magnesium, uric acid, calcium, and phosphate.
Pharmacodynamics/Kinetics
Onset of action: 6 hours
Distribution: Vd: Losartan: 34 L; E-3174: 12 L; does not cross blood-brain barrier
Protein binding, plasma: High
Metabolism: Hepatic (14%) via CYP2C9 and 3A4 to active metabolite, E-3174 (40 times more potent than losartan); extensive first-pass effect
Bioavailability: 25% to 33%; AUC of E-3174 is four times greater than that of losartan
Half-life elimination: Losartan: 1.5-2 hours; E-3174: 6-9 hours
Time to peak, serum: Losartan: 1 hour; E-3174: 3-4 hours
Excretion: Urine (4% as unchanged drug, 6% as active metabolite)
Clearance: Plasma: Losartan: 600 mL/minute; Active metabolite: 50 mL/minute
Dosage
Oral:
Hypertension:
Children 6-16 years:
U.S. labeling: 0.7 mg/kg once daily (maximum: 50 mg/day); doses >1.4 mg/kg (maximum: 100 mg) have not been studied
Canadian labeling:
≥20 kg to <50 kg: 25 mg once daily (maximum: 50 mg once daily)
≥50 kg: 50 mg once daily (maximum: 100 mg once daily)
Adults: Usual starting dose: 50 mg once daily; can be administered once or twice daily with total daily doses ranging from 25-100 mg
Patients receiving diuretics or with intravascular volume depletion: Usual initial dose: 25 mg once daily
Aortic-root dilation with Marfan's syndrome (unlabeled use): Children 14 months to 16 years: Initial: 0.6 mg/kg/day; can be increased to a maximum of 1.4 mg/kg/day (not to exceed adult maximum of 100 mg/day)
Nephropathy in patients with type 2 diabetes and hypertension: Adults: Initial: 50 mg once daily; can be increased to 100 mg once daily based on blood pressure response
Stroke reduction (HTN with LVH): Adults: 50 mg once daily (maximum daily dose: 100 mg); may be used in combination with a thiazide diuretic
Dosing adjustment in renal impairment:
Children: Use is not recommended if GFR <30 mL/minute/1.73 m2
Adults: No adjustment necessary.
Dosing adjustment in hepatic impairment:
Children 6-16 years:
U.S. labeling: No specific dosing recommendations are provided in the approved labeling, however it may be advisable to initiate therapy at a reduced dosage.
Canadian labeling: Use is not recommended.
Adults: Reduce the initial dose to 25 mg/day
Administration: Oral
May be administered without regard to meals.
Monitoring Parameters
Supine blood pressure, electrolytes, serum creatinine, BUN, urinalysis, symptomatic hypotension and tachycardia, CBC
Dietary Considerations
May be taken without regard to meals. Some products may contain potassium.
Patient Education
Preferable to take at same time each day without regard to meals. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. Do not use potassium supplement or salt substitutes without consulting prescriber. If you have diabetes, you may be cautioned to monitor glucose levels closely; may alter glucose control. May cause dizziness, fainting, lightheadedness, postural hypotension, or diarrhea. Report immediately swelling of face, lips, or mouth; difficulty swallowing; chest pain or palpitations; unrelenting headache; or CNS changes (delusions or depression).
Geriatric Considerations
Serum concentrations of losartan and its metabolites are not significantly different and no initial dose adjustment is necessary even in low creatinine clearance states (<30 mL/minute). Many elderly may be volume depleted due to diuretic use and/or blunted thirst reflex resulting in inadequate fluid intake.
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).
Cardiovascular Considerations
Heart Failure: Currently, the use of angiotensin II receptor blockers (ARBs) should not supersede angiotensin converting enzyme inhibitors (ACEIs) in the treatment of heart failure. One may be considered, however, when an ACEI cannot be tolerated. Because they are angiotensin II blockers rather than inhibitors of ACE, ARBs do not cause increases in bradykinin levels. ELITE II (Pitt, 2000) compared losartan (50 mg/day) with captopril (150 mg/day) in a heart failure population (mean EF 31%). There were 280 deaths in the losartan group and 250 in the captopril group. Mortality was insignificantly higher for losartan (17.7% vs 16% for captopril). The secondary endpoint (sudden cardiac death or resuscitated cardiac arrest) favored captopril, but the improvement did not achieve statistical significance. The discontinuation rate for adverse events was significantly lower for losartan. In the doses used, losartan appears to be less effective or as effective as captopril.
CHARM-Alternative is a prospective, randomized trial (Granger, 2003) in ACE inhibitor intolerant patients with HF. Patients were randomized to candesartan (target dose: 32 mg/day; mean dose at 6 months: 23 mg/day) or placebo. Baseline characteristics included NYHA Class II or III (97% of patients), and mean LVEF 30%. Therapy included beta-blocker (55%), diuretic (86%), spironolactone (24%), and digitalis (46%). During a 33-month follow up, the combined primary endpoint (CV death or heart failure hospitalizations) was significantly reduced in the candesartan group mainly because of reduced hospitalization. Death due to cardiovascular disease was not significantly different. There were significantly more MIs (75) in the candesartan group than in the placebo group (48). Candesartan was discontinued because of hypotension, renal dysfunction, and hyperkalemia.
Heart Failure: Concomitant ACE-I Therapy: The Val-HeFT study (Cohn, 2001) randomized HF patients maintained on standard therapy to valsartan (320 mg/day; mean dose 254 mg/day) or placebo. The primary outcome was mortality and a combined endpoint of morbidity and mortality (cardiac arrest, hospitalization for HF, need for intravenous inotrope or vasodilator). Patients (5010 in number) with predominately NYHA class II or III heart failure (85% on diuretic; 67% on digoxin; 35% on beta-blocker; ~93% on ACEI; 5% on spironolactone) were randomized to valsartan or placebo. The mean duration of follow-up was 23 months. Overall mortality was similar in both groups. The incidence of combined endpoints was lower with valsartan than placebo (p=.009) primarily because of decreased heart failure hospitalizations in the valsartan group. In a post hoc analysis of the endpoints in subgroups defined by baseline treatments (ACEI or beta-blockers), valsartan had a positive effect on patients receiving neither or one of these drugs. A higher incidence of mortality was seen in patients receiving valsartan in combination with an ACEI and a beta-blocker.
The CHARM-Added trial is a prospective, randomized trial (McMurray, 2003) evaluating the addition of candesartan therapy (target dose: 32 mg/day; mean dose at 6 months: 24 mg/day) to HF patients maintained on an ACEI. Baseline characteristics: NYHA class II (24%), class III (73%), and mean LVEF 28%. Baseline therapy was similar to CHARM-Alternative except all patients were maintained on an ACEI and ~55% were on a beta-blocker. The median duration of follow-up was 41 months. The combined primary endpoint (CV death or heart failure hospitalizations) was significantly reduced in the candesartan group.
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 (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.
Marfan's Syndrome: Marfan's syndrome is a genetic disorder due to a mutation in the gene encoding for fibrillin-1 (FBN-1) and is associated with progressive aortic root dilation and may subsequently result in aortic dissection. The deficiency of FBN-1 leads to an increase in the activity of transforming growth factor β (TGF-β) which is thought to contribute to aortic root dilation and other Marfan's syndrome characteristics. Angiotensin II receptor blockers have been shown to inhibit TGF-β signaling.
Recently, a retrospective study evaluated the use of angiotensin II receptor blockers specifically losartan (1 patient received irbesartan) in a cohort of 18 pediatric patients (age range 14 months to 16 years) with Marfan's syndrome. All patients had evidence of severe aortic root enlargement. Patients who received losartan were initiated with 0.6 mg/kg/day and increased to a maximum dose of 1.4 mg/kg/day. The patient who received irbesartan was initiated with 1.4 mg/kg/day and increased to a maximum dose of 2 mg/kg/day. Patients were followed for a median of 26 months. The mean rate of change in aortic-root diameter prior to initiation of ARB therapy was 3.54 ± 2.87 mm per year. After initiation of ARB therapy, the rate of change decreased to 0.46 ± 0.62 mm per year (p<0.001). A similar decline in rate of change was seen in the patient treated with irbesartan. This small cohort study demonstrates that ARB therapy in patients with aortic-root dilation due to Marfan's syndrome may be of benefit. Future randomized controlled clinical trials will be needed to confirm these findings (Brooke, 2008).
Myocardial Infarction: The 2004 ACC/AHA STEMI guidelines suggest an angiotensin receptor blocker should be administered to STEMI patients who are intolerant of ACE inhibitors and who have either clinical or radiological signs of heart failure or LVEF <0.4. The OPTIMAAL trial evaluated whether losartan (50 mg/day) would be superior or noninferior to captopril (150 mg/day) in post-MI patients. They were randomized to one of two treatments and followed up for 2.7 years. There was no difference between the two treatment groups (499 deaths in losartan group; 447 deaths in the captopril-treated group). The VALIANT trial compared the effects of valsartan, captopril, and the combination in patients who had suffered a recent MI (0.5 to 10 days prior) complicated by left ventricular systolic dysfunction (Pfeffer, 2003). The primary endpoint was mortality from any cause. Mortality in the valsartan group and the valsartan-captopril group was similar to the captopril group alone. Valsartan was found to be noninferior to captopril in this patient population. Combining valsartan with captopril increased the rate of adverse events without improving survival. Hypotension and renal dysfunction were more common in the valsartan group. Cough, rash, and taste disturbances were more common in the captopril group.
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
Key adverse event(s) related to dental treatment: Orthostatic hypotension.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness or insomnia; may rarely cause anxiety, confusion, depression, and sleep disorders
Mental Health: Effects on Psychiatric Treatment
Barbiturates may decrease the effects of losartan
Nursing: Physical Assessment/Monitoring
Use caution in presence of impaired renal function, significant aortic/mitral stenosis, or history of angioedema and airway surgery. Monitor for hypotension on a regular basis during therapy. Caution patients with diabetes to monitor glucose levels closely; may alter glucose control.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as potassium: 25 mg, 50 mg, 100 mg
Cozaar®: 25 mg [contains potassium 2.12 mg (0.054 mEq)]
Cozaar®: 50 mg [contains potassium 4.24 mg (0.108 mEq)]
Cozaar®: 100 mg [contains potassium 8.48 mg (0.216 mEq)]
Pricing: U.S. (www.drugstore.com)
Tablets (Cozaar)
25 mg (30): $64.28
50 mg (30): $88.13
Tablets (Losartan Potassium)
25 mg (90): $125.99
50 mg (90): $176.99
100 mg (90): $259.97
Extemporaneously Prepared
A 2.5 mg/mL losartan oral suspension may be made with tablets and a 1:1 mixture of Ora-Plus® and Ora-Sweet® SF. Combine 10 mL of purified water and ten losartan 50 mg tablets in an 8-ounce amber polyethylene terephthalate bottle. Shake well for at least 2 minutes. Allow concentrate to stand for 1 hour, then shake for 1 minute. Separately, prepare 190 mL of a 1:1 mixture of Ora-Plus® and Ora-Sweet® SF; add to tablet and water mixture in the bottle and shake for 1 minute. Label "shake well" and "refrigerate". Return promptly to refrigerator after each use. Stable for 4 weeks when stored in amber polyethylene terephthalate prescription bottles and refrigerated (Cozaar® prescribing information, 2008).
Cozaar® prescribing information, Merck & Co, Inc, Whitehouse Station, NJ, 2008.
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.
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Last full review/revision March 2012
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