Prospective postmarketing surveillance of Selara eplerenone , a selective mineralocorticoid receptor antagonist, was performed to confirm its safety and efficacy for hypertension treatment in Japan. The change in blood pressure after initiation of eplerenone treatment was also examined. For examination of changes in blood pressure, patients were excluded if eplerenone was contraindicated or used off-label. No treatments including antihypertensive drugs were restricted during the surveillance period. Across Japan, 3, patients were included for safety analysis.
|Published (Last):||13 May 2004|
|PDF File Size:||1.60 Mb|
|ePub File Size:||20.3 Mb|
|Price:||Free* [*Free Regsitration Required]|
Prospective postmarketing surveillance of Selara eplerenone , a selective mineralocorticoid receptor antagonist, was performed to confirm its safety and efficacy for hypertension treatment in Japan. The change in blood pressure after initiation of eplerenone treatment was also examined. For examination of changes in blood pressure, patients were excluded if eplerenone was contraindicated or used off-label.
No treatments including antihypertensive drugs were restricted during the surveillance period. Across Japan, 3, patients were included for safety analysis. The incidence of adverse drug reactions was 2.
The major adverse drug reactions observed were hyperkalemia 0. There were no significant new findings regarding the type or incidence of adverse reactions, and eplerenone had a clinically significant antihypertensive effect, leading to favorable blood pressure control. Hypertension is a major public health issue in many countries.
The risk for cardiovascular events has been shown to be high among patients with hypertensive conditions, particularly among those who have comorbidities such as diabetes, chronic kidney disease CKD , metabolic syndrome, cerebrovascular disorders, or organ dysfunction including heart disease.
Therefore, it is important to provide guidance for lifestyle modifications and to administer strict treatment with antihypertensive drugs according to the target blood pressure BP levels, depending on the comorbidities [ 2 ].
In addition, combination therapy consisting of drugs with different mechanisms of action has been recommended to further lower BP without causing adverse drug reactions ADRs [ 2 ]. Mineralocorticoid receptor antagonists MRAs have been shown to exert antihypertensive effects by binding to mineralocorticoid receptors MRs and blocking MR-dependent signal transduction.
However, it has been approved for the treatment of hypertension in only 11 countries including Japan, the United States, Canada, and Singapore. This postmarketing surveillance PMS was conducted to identify unknown ADRs that are not stated in the package insert of Selara tablets [ 7 ], estimate the incidence of ADRs including hyperkalemia in general practice, and elucidate the factors that affect the safety of the drug when it is used in Japanese hypertensive patients.
Additionally, the antihypertensive effects of eplerenone were evaluated. Between May and April , we conducted a PMS that targeted hypertensive patients in Japan who had not previously been treated with eplerenone.
A written agreement was obtained from participating institutions. GPSP is the authorized standard for PMS studies of approved drugs in clinical practice, and no formal ethics committee approval or informed consent was necessary to conduct surveillance under this ordinance. Because a PMS does not restrict the administration of the study drug or concomitant treatments, the outcomes observed in the PMS reflect the overall consequences of administration of the study drug and concomitant treatments in real-world settings.
We aimed to collect 3, cases using a centralized registration method to be able to detect unknown ADRs at a frequency of 0. There were no exclusion criteria for patient registration. The physicians in charge were encouraged to consult the Guidelines for the Management of Hypertension to determine the severity of hypertension in a comprehensive manner. For hepatic function abnormality and renal impairment, categories determined by the physician in charge were adopted. Although precise definitions of severity were not provided, the physicians in charge were asked to judge the severity in a comprehensive manner, considering the disease duration, complications, concomitant medications, and other relevant factors.
Administration of any concomitant treatment including other antihypertensive drugs was not restricted. The observation period was 12 weeks and began upon initiation of treatment. Adverse events AEs were assessed as a safety endpoint.
All unfavorable or unintended signs, symptoms, and diseases that occurred in patients who received eplerenone, regardless of whether there was a clear causal relationship with eplerenone, were considered AEs. Of the patients that were surveyed, it was confirmed that those included in the safety analysis had taken eplerenone at least once during the observation period. However, patients that did not meet the requirements for determining safety according to the selection criteria i.
The effectiveness of blood pressure reduction was assessed weeks after initiation of eplerenone treatment.
Creatinine clearance was calculated using the Cockcroft-Gault formula. In the analysis of the binary data, the frequencies and incidence of AEs were calculated. In the current PMS, 3, patients were registered from of contracted institutions. Filled case report forms for 3, of these patients were collected from institutions.
The participating institutions mainly included private practices and clinics The other institutions included national, public, and private university hospitals. Of the 3, cases in which the PMS had been completed, were excluded because of a breach of contract or imperfect contract , lack of information regarding AEs no revisit, , violation of registration , or a lack of information regarding eplerenone treatment. In total, 3, patients were therefore included in the safety analysis.
The effect of eplerenone on BP was analyzed in 1, patients who met the criteria stated in the method section. Among the 3, patients included in the safety analysis, Elderly individuals 65 years of age or older accounted for The severity of hypertension was mild in Concomitant diabetes was observed in Concomitant renal impairment was observed in The mean duration of eplerenone treatment was days, and the median was At the time eplerenone treatment was initiated, CCB Among the patients included in the safety analysis, eplerenone treatment was discontinued in The reasons for discontinuation were AEs All the deaths were judged as not attributable to eplerenone.
Among the patients included in the safety analysis, ADRs were observed in 75, and the incidence was 2. The most common ADRs were hyperkalemia 0. ADRs that were unpredictable from the package insert of Selara tablets were observed in 11 patients and included renal impairment , shingles , acute myeloid leukemia , lymphadenitis , loss of appetite , spasm , ear fullness , gastric ulcer , fecal incontinence , and photosensitivity reaction.
No clinically significant change in the mean pulse rate was observed. Among the patients included in the safety analysis, serious ADRs were observed in 0. These included hyperkalemia 0. There have been concerns regarding a possible increase in serum potassium levels caused by the pharmacological actions of eplerenone.
Hyperkalemia or increased serum potassium was observed in 20 and 6 patients, respectively Table 2. Among these patients, The ADRs were judged serious in 11 of 26 patients Table 3.
Of these patients, 3 had moderate or mild hepatic function disorder, 8 had moderate or mild renal impairment, and 3 had functional class II heart failure according to the New York Heart Association NYHA classification system.
Among the patients whose outcomes were known, 9 halted or withdrew from eplerenone treatment, and 1 did not change the dose. The incidence of adverse events was 4. Very little change in the serum potassium level was observed in patients with serum potassium levels of over 4.
In contrast, the percentage of patients with serum potassium values over 5. The major ADRs of these patients were hyperkalemia 3. Among the 2, patients who were prescribed antihypertensive medications other than eplerenone at the time of initiation of eplerenone treatment, 2 cases developed hypotension. Both were prescribed more than 2 antihypertensive drugs in addition to eplerenone. The incidence of adverse drug reactions classified according to the concomitant antihypertensive medication is presented in the Supplementary Material Table S2 to S9.
Serious adverse events were seen in 15 among 2, patients who were taking concomitant antihypertensive medications at the time of initiation of eplerenone. The most frequent serious adverse events were hyperkalemia 8 cases followed by renal impairment 3 cases.
The BP changes from baseline were larger in the groups with higher baseline BP, and there was little change in the group with the lowest BP level at baseline. MRAs are not the first-line drugs recommended by the JSH or JSH guidelines [ 8 ], but they are recommended for treatment of resistant hypertension. This PMS showed that CCBs and ARBs, which are recommended as first-line drugs by the guidelines, were the most frequent drugs to be prescribed concomitantly with eplerenone.
The ADRs most frequently observed in the clinical trials cited in the new-drug application of eplerenone in Japan included headache 6. The difference in the frequency of ADRs between the PMS and the clinical trials is attributable to differences in study design, as a PMS is an observational study and the clinical trials were interventional studies. According to a survey by the Japanese Society of Nephrology [ 9 ], the frequency of CKD increases with age among Japanese men and women.
In this PMS, patients who were reported to have hyperkalemia or increased serum potassium accounted for Retention of serum potassium is known to occur more frequently in patients with renal impairment. In this PMS, the occurrence of adverse events was more frequent in patients with renal impairment, and many of the events were hyperkalemia. Therefore, the results of this surveillance also suggest that patients with renal impairment are more prone to hyperkalemia and that serum potassium levels should be properly monitored according to the package insert.
Regarding the change in serum potassium levels during the treatment period, it is possible that the physicians adjusted the eplerenone dosage or withdrew other potassium-retaining drugs that had been administered concomitantly in patients with high baseline serum potassium levels.
In this PMS, some patients were prescribed eplerenone even though they met the contraindication criteria for Selara tablets. Patients with a serum potassium value over 5. There were In addition, patients with severe hepatic function comprised 0. Clinicians should pay careful attention to the contraindications listed on the package insert when prescribing drugs and conducting regular monitoring of serum potassium levels.
The incidence of hypotension among patients prescribed antihypertensive drugs in addition to eplerenone was considered as not high and the symptoms were improved. Although the incidence of hyperkalemia tended to be higher among patients prescribed ACE inhibitors or ARBs concomitantly with eplerenone, it was considered within the scope of the package insert of Selara tablets.
There was no tendency for the incidence of hyperkalemia to increase when eplerenone was used with either thiazide diuretics or loop diuretics. Therefore, we concluded that it is not necessary to call for special attention or implement new measures to ensure safety for concomitant use of eplerenone and other antihypertensive drugs. In an analysis of the antihypertensive effects of eplerenone based on the BP at baseline, the degree of BP reduction appeared to vary depending on the BP value at the time of initiation of eplerenone.
Because we aimed to investigate the effects of the drugs in real-world settings and because the dosage of all of the antihypertensive drugs including eplerenone could have been modified, the results do not necessarily reflect the effects of eplerenone treatment alone.
However, considering that, on average, clinically significant effectiveness against hypertension was observed during the observation period, the effectiveness of eplerenone as an antihypertensive drug was shown under the conditions in which it is currently used.
Because a relatively large antihypertensive effect was observed immediately after initiation of eplerenone treatment followed by a gradual decrease in BP, a decrease of several mmHg after week 12 was expected. The finding that eplerenone gradually reduced BP over months is consistent with a previous report [ 9 ]. The reason for the gradual decrease in BP and the antihypertensive effects of eplerenone may involve the complex mechanism of action of the drug.
Database Analysis of Eplerenone Use in Japanese Hypertensive Patients in Clinical Practice
Medically reviewed by Drugs. Last updated on Aug 1, Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular CV events, primarily strokes and MI. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Many patients will require more than one drug to achieve blood pressure goals. Control of high blood pressure should be part of comprehensive CV risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.
Eplerenone, a mineralocorticoid receptor antagonist MRA , is available in Japan, but details of its use in clinical settings have not been thoroughly investigated. Data of , hypertensive patients who used the same drugs for six months or more were collected from an insurance database from January 1, , to December 31, Compared to patients on eplerenone or spironolactone, patients on neither drug had fewer comorbidities. Eplerenone was administered in combination with calcium channel blockers and angiotensin II receptor blockers in