Drug Criteria & Outcomes: Formulary evaluation: Olmesartan medoxomil (Benicar)

By Kevin Lewis, PharmD candidate
Harrison School of Pharmacy
Auburn (AL) University

Background

The management of hypertension remains a primary focus of health care. Hypertension is a cardiovascular risk factor that is directly associated with other disease states, including congestive heart failure (CHF), myocardial infarction, cerebrovascular accidents, and peripheral arterial insufficiency. Heart disease and stroke are two major causes of death and are correlated with more than $259 billion in costs. There is great concern regarding hypertension because it usually progresses undetectably, with no distinguishing signs or symptoms of the condition. The only accurate diagnosis of hypertension is an elevated blood pressure.

Numerous classes of anti-hypertensive agents are used to reduce blood pressure, each with a different mechanism of action. A variety of combinations are commonly implemented to produce an added therapeutic benefit. The angiotensin II receptor antagonists (AIIRBs) are a relatively new class of anti-hypertensive agents that have recently emerged and established a role in the therapy of hypertension. The drugs in this class include the following: irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan), candesartan cilexetil (Atacand), eprosartan (Teveten), and olmesartan medoxomil (Benicar). Olmesartan is the most recent AIIRB approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension, and the information below is an evaluation to determine whether olmesartan should be added to the hospital formulary.

Mechanism of action

Olmesartan is an angiotensin II receptor blocker that is selective for the AT1 subtype. The AT1 receptor is primarily found in vascular smooth muscle and is directly associated with cardiovascular homeostasis. By blocking this receptor, the pressor effects of angiotensin II (e.g., vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation, renal reabsorption of sodium, and stimulation of the sympathetic system) will be prevented. This produces a pharmacological effect of lowering blood pressure. The mechanism of action of olmesartan is basically the same for all AIIRBs.

Indication

Olmesartan currently has an indication similar to that for the other agents of this class, which is the treatment of hypertension. Olmesartan can be used as monotherapy or in combination with other anti-hypertensive agents. Unlike olmesartan, other agents of this class have been studied for therapeutic indications such as CHF. Long-term data for the treatment of CHF is still pending, but several AIIRBs have shown beneficial effects. For example, valsartan has recently received Food and Drug Administration (FDA) approval for therapy for CHF.

Dosing

Olmesartan is available in dosages of 5 mg, 20 mg, and 40 mg. The full prescribing information does not specify when the 5 mg dosage should be used. According to the manufacturer, the choice of a lower dose is at the discretion of the health care provider in treating patients who are volume-depleted or who have significant renal and/or hepatic impairment. These are precautionary measures, and the 5 mg dose allows the practitioner to decrease the dose as deemed necessary. The initial dose of monotherapy with olmesartan is 20 mg once daily in those individuals who are not volume-depleted. It is recommended to increase the dose to 40 mg once daily after two weeks of therapy if an additional lowering in blood pressure is necessary. No greater therapeutic benefit was demonstrated with doses over 40 mg daily, and there is also no advantage to taking the equivalent daily dose twice daily compared to once daily. Dose adjustment based on gender or age is not required because of similar clinical responses. There is no dose adjustment necessary in hepatic dysfunction, but caution in hepatobiliary disease is advised because olmesartan is significantly metabolized by the biliary system. Dose adjustment for renal dysfunction has not been adequately addressed in clinical trials.

Pharmacokinetics

The table illustrates the differences and similarities of the various pharmacokinetic parameters. As the table illustrates, olmesartan is similar to other drugs in its class in terms of maximal onset, protein binding, and dosing frequency. Olmesartan is formulated as a prodrug similar to candesartan and losartan. It is not metabolized by the CYP-450 enzyme system, so potential drug interactions are less likely compared to losartan and irbesartan, which are metabolized by this system. Food does not affect the absorption of olmesartan, irbesartan, and candesartan, but it does decrease the absorption of other AIIRBs, with valsartan being the most affected.

Irbesartan represents the most bioavailable agent, and telmisartan displays the longest half-life. There are no specific recommendations for AIIRB dosage adjustment in renal dysfunction, but caution should be taken in dosing valsartan in severe dysfunction. When dosing losartan, valsartan, and telmisartan, severe hepatic dysfunction should be considered, as dose adjustment is necessary. Overall, olmesartan does not exhibit any important, unique pharmacokinetic features compared to the other drugs in its class.

Contraindications

No significant contraindications exist except for those who are allergic to any of the components within the drug product.

Warnings and precautions

As with the other AIIRBs, olmesartan should not be administered during the second or third trimester in pregnant women. There have been reports that agents that act directly on the renin-angiotensin system can lead to injury or death to the fetus. It is recommended to discontinue olmesartan therapy as soon as pregnancy is detected, even though fetal adverse effects have not been correlated with the first trimester. The AIIRBs are classified as pregnancy category C in the first trimester and D for the second and third trimesters. There are also precautionary measures to be taken in those individuals who are volume-depleted and/or salt-depleted based upon symptomatic hypotension incidence. Also, those individuals who rely on the renin-angiotensin system for renal function need to be carefully monitored upon initiation of olmesartan or any of the AIIRBs.

Adverse reactions

Along with the other AIIRBs, olmesartan is generally a well-tolerated drug, with temporary side effects that are not associated with the dose. Placebo-controlled studies revealed the following adverse events in greater than 1% of patients (note: incidence was about equal to or greater than incidence for those receiving placebo): headache, hematuria, hyperglycemia, back pain, bronchitis, increase in creatine phosphokinase, flu-like symptoms, inflicted injury, hypertriglyceridemia, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. Another adverse event that occurred was dizziness. Unlike the other effects listed above, there was a higher incidence of dizziness in the treatment group compared to the placebo group; this was a similar effect with the other AIIRBs. Overall, these adverse reactions are similar for the entire class.

Drug interactions

Because olmesartan is not metabolized by the CYP-450 system, there are no significant drug interactions involving this system. This is also true for candesartan, valsartan, and eprosartan. Those that are metabolized by the CYP-450 system may have altered pharmacokinetics, but in general these interactions are not considered to be clinically significant. The bioavailability of olmesartan is not significantly affected when taken with antacids. There have been no notable drug interactions with warfarin or digoxin reported.

Cost

As illustrated by the cost/comparison table, all AIIRBs are similar in price. Currently, all strengths of olmesartan are the same price.

Evidence of efficacy and safety based on clinical trials

Several abstracts are available to demonstrate the efficacy of olmesartan. All of the study designs included a randomized, double-blind, intent-to-treat, placebo-controlled clinical trial. All of the abstracts evaluated had a sample size of at least 325 patients. Multiple studies concluded that olmesartan is a proven anti-hypertensive agent based on ambulatory blood pressure assessment after six or eight weeks of therapy compared to placebo. The safety profile of the drug was also demonstrated in these studies.

General conclusions were that most side effects occurred at about the same incidence rate in both the treatment group and the placebo group. In one study, after 12 weeks of therapy with 10 mg of olmesartan or 50 mg of atenolol, it was shown that there was no significant difference between the two in lowering diastolic blood pressure. However, there was a statistically significant difference in favor of olmesartan therapy in reduction of systolic blood pressure. The trial’s overall reliability is hard to determine because only the abstract of the trial is currently available, and systolic blood pressure was not a primary endpoint outcome measure in the conclusion section of the study. In addition, there were not any statistical analysis tests described within the abstract. The efficacy of the other AIIRBs has proven to be equivalent in reducing blood pressure compared to other antihypertensive drug classes (i.e., ACE inhibitors, calcium channel blockers, beta-blockers, and hydrochlorthiazide).

Another study evaluated olmesartan QD regimen of 5 mg, 20 mg, or 80 mg compared to a BID regimen of 2.5 mg, 10 mg, or 40 mg and illustrated that there was no significant advantage with the twice-daily regimen because olmesartan maintained its peak effect 24 hours after administration. Diastolic blood pressure was reduced by 8-11 mm Hg, and systolic pressure was reduced by 10-17 mm Hg. Olmesartan was also compared to amlodipine, a calcium channel blocker, and both lowered blood pressure with similar results, showing no statistically significant difference. Olmesartan lowered systolic pressure by an average of 13 mm Hg while amlodipine reduced it by 12.9 mm Hg.

A similar comparative study was conducted with olmesartan and felodipine. Once again, there was no statistically significant difference regarding reduction of blood pressure. It was stated in the abstract that 5.9% of patients experienced adverse drug reactions (ADRs) with olmesartan, while those in the felodipine group had a 12.4% incidence of ADRs. This can be misleading, because the abstract also noted that the distribution of ADRs between the two groups was approximately equal. There were no further comments on ADR issues; therefore, one should question the reliability of the ADR incidence statement until further details are available.

One clinical trial compared olmesartan 20 mg daily to three other AIIRBs, including losartan 50 mg, valsartan 80 mg, and irbesartan 150 mg daily; these doses are considered to be approximately equivalent. The clinical trial consisted of a randomized, double-blind, parallel group, starting dose study including 588 patients diagnosed with hypertension. Ambulatory blood pressure measurements were taken every 24 hours for an eight-week period. The results portrayed a statistically significant reduction in diastolic and systolic blood pressure in the olmesartan group compared to the other three groups. Olmesartan produced an average decrease in diastolic pressure of 11.5 mm Hg, losartan 8.2 mm Hg, valsartan 7.9 mm Hg, and irbesartan 9.9 mm Hg. The average systolic pressure reductions were as follows: olmesartan 13 mm Hg, losartan 8.9 mm Hg, valsartan 9.2 mm Hg, and irbesartan 10.8 mm Hg. All differences were seen within the first two weeks of therapy. However, at the end of four weeks, the changes in systolic pressure were not statistically different among the four drugs but remained statistically different in regards to diastolic pressure. Olmesartan also proved to produce significantly more lowering of the average 24-hour diastolic and systolic blood pressure (8.5/12.5 mm Hg) vs. losartan (6.2/9.0 mm Hg) and valsartan (5.6/8.1 mm Hg). However, there was no significant difference between olmesartan and irbesartan (7.4/11.3 mm Hg). The limitations of this study included a small sample size, exclusion of the total number of individuals assigned to each treatment group, and all results being based on a mean reduction of blood pressure. In addition, the study was terminated after an eight-week period. There are no long-term data available to validate these conclusions.

All of the studies listed above are limited by various factors. For example, the number of patients included in the studies was too small to make reliable conclusions in relationship to the general population. Also, another factor seen in all of the studies is the absence of long-term data. There is not enough information currently to make a definite conclusion on relative efficacy of olmesartan compared to the other AIIRBs. More studies need to be conducted to validate the preliminary data given in these early studies.

Conclusions and recommendations

Based on the above information pertaining to olmesartan, there are no distinguishing differences between it and the other AIIRBs. They are all indicated for the treatment of hypertension, all have basically the same mechanism of action, and all are generally well-tolerated in terms of adverse events. Olmesartan is also limited relative to the others regarding indications. For example, several other AIIRBs have broader indications, some that are not FDA-approved but that have demonstrated efficacy (such as CHF). The FDA has recently approved valsartan for the treatment of CHF.

Olmesartan is effective for hypertension, but there is not enough reliable information to demonstrate important advantages compared to the other AIIRBs. With this in mind, the cost of the product needs to be addressed. As noted above, there are other AIIRBs that are less expensive, but this cost difference is most likely minor. Although it is true that olmesartan has shown statistically significant differences among some of the AIIRBs with blood pressure reduction, more studies need to be done to establish any clinically significant differences in the treatment of hypertension. Studies are not strong enough to conclude that olmesartan has a distinct advantage over the other agents for treatment of hypertension. There is no substantial reason to add olmesartan to the hospital formulary at this time. Olmesartan orders should be converted to the formulary drug irbesartan in approximate equivalent dosage regimens (i.e., olmesartan 20 mg converted to irbesartan 150 mg or proportionately) unless "no substitution" is written with the drug order.

Resources

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• Avapro® package insert. Bristol-Myers Squibb Co. Princeton, NJ; 1998.

• Cozaar® package insert. Solvay Pharmaceuticals. Buffalo Grove, IL; 1999.

• Diovan® package insert. Novartis Pharmaceuticals Corp. East Hanover, NJ; 1998.

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• A multi-center, double-blind, efficacy, tolerability and safety study of the oral angiotensin II-antagonist olmesartan medoxomil versus atenolol in patients with mild to moderate essential hypertension. Study 866/18; data on file. Sankyo Pharma. New York; 2002.

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• Angiotensin II receptor antagonists formulary proposal. Presented to Pharmacy and Therapeutics Committee, Huntsville (AL) Hospital, May 2000.