The FDA has approved Schering Plough’s new antipsychotic, asenapine (Saphris), for the treatment of schizophrenia and mania associated with bipolar disorder in adults.
Dr. Thomas Laughren, FDA’s director of psychiatry products, indicated that FDA will not be making separate presentations, "since we are in essential agreement with the data to be presented by the sponsor."
The drug’s approval is highly controversial: the primary biopharmaceutics (OCP) reviewer raised numerous safety concerns but was not afforded an opportunity to present his analysis to the committee.
Asenapine’s approval for the treatment of schizophrenia is based on four short-term (6-week) randomized clinical trials, of which only two studies (Studies 41004 and 41023) were presented as showing "statistically significant," though clinically insignificant, efficacy findings.
However, contrary to Dr. Laughren’s assertion,
"As summarized in Dr. Chen’s review, there were 2 positive (41004 and 41023) trials and one negative (41021) trial supporting adequate efficacy to recommend approval of asenapine for adults in the acute treatment of schizophrenia"
those efficacy claims were disputed by Dr. Yeh-Fong Chen, FDA’s statistical reviewer, who raised concerns about the high dropout rate in study 41004, (60% overall, 66% among placebo group): suggesting the possibility of bias.
She also raises "a reasonable concern…whether a study with >50% dropout rate can still be accepted as a pivotal study."
Furthermore, "Regarding Study 41023, the fact that asenapine 10 mg BID performed numerically worse than asenapine 5 mg BID also adds difficulty to the interpretation of the asenapine’s efficacy finding."
FDA’s review of the application for bipolar disorder focused on 2 short-term (3-week), double-blind, randomized, flexible dose, placebo- and olanzapine-controlled, parallel group studies of asenapine in adult patients with manic or mixed episodes of bipolar 1 disorder. See, FDA Background package :
The drug was approved in the form of sublingual tablets: it is stated that this is due to its "very poor oral bioavailability."
Are there safety issues for concern regarding the drug’s potential toxicity?
Concerns about serious, potentially life-threatening risks are linked to this drug:
FDA’s primary biopharmaceutics (OCP) reviewer, Dr. Ron Kavanaugh, who analyzed the all phase II and III trials’ adverse events data submitted for review, raised concerns about cardiotoxicity in young healthy volunteers, hepatoxicity (blood toxicity), and suicide/ suicide attempts.
See: Table 185, p.772 FDA Background package
Serious safety issues emerged in early trials conducted in young, healthy volunteers, resulting in the termination of several studies due to severe cardiac events:
"Study 25506 was a pharmacokinetic study of intravenous administration of asenapine at four different doses, with each dose to be administered to two healthy male volunteers which was then to be followed by a pilot bioavailability study of 30 mg orally in the two volunteers who received the highest tolerated intravenous dose.
The study was stopped after the first two subjects due to asystole requiring external cardiac massage and atropine. Although attributed by the sponsor to a vasovagal effect, an external cardiologist deemed it a serious AE of asenapine affecting the conducting system of the heart." p.785 FDA Background package
Study 25501 was a multiple rising dose study to examine the pharmacokinetics in 12 young, healthy, male volunteers using [asenapine] both after a single oral dose (30 mg) and at steady state (5 days, 15 mg twice daily orally).
Study 25509, the sponsor’s summary of the initial sublingual (SL) Single Rising Dose Study states:
"From a safety point of view, the administration [of asenapine at] doses greater than 4 mg / day is precluded for two reasons (1) risk of hepotoxicity (2) due to the fact that low oral bioavailability predisposes to highly variable plasma levels, patients may be put at increased risk of cardiovascular adverse experiences." p. 792 FDA Background package
Dr. Kavanaugh’s Table 192 "Summary of Selected Cardiac AEs" as described in the sponsor’s summaries of early trials. p.798 FDA Background Package
Dr. Thomas Laughren, FDA director of psychiatry products, dismissed out of hand the safety concerns raised by FDA primary pharmacology reviewer and the efficacy concerns raised by FDA’s statistician.
There were 27 deaths in the asenapine program overall, including 22 deaths in patients taking asenapine.
Of the 22 asenapine deaths, 8 were suicides and 9 of the asenapine deaths were from serious medical events: e.g., pulmonary embolism (2), pneumonia, CVA, complications of seizure, metastatic lung cancer, fetal death in premature delivery, heart failure, MI.
However, most (about 94%) of the serious adverse events were exacerbations of psychiatric illness. This raises additional doubts about the drug’s efficacy for schizophrenia or bipolar disorder, two major psychiatric conditions.
Dr. Laughren strongly endorsed approval of asenapine. he formal presentations at the advisory hearing were limited to the following study reviews by Schering Plough, the sponsor:
Study 041004 compared asenapine 5 mg bid, risperidone 3 mg bid, and placebo.
There were roughly 60 patients per group. Dropouts were substantial (more than 60%), with completion rates for the 3 groups, as follows: asenapine-46%; risperidone-42%; placebo-34%.
Study 041021 compared asenapine 5 mg bid, asenapine 10 mg bid, olanzapine 15 mg qd, and placebo.
Neither asenapine group was statistically superior to placebo, however, the olanzapine group was superior to placebo (p=0.017). Thus, this was a completely negative study for asenapine.
Study 041022 compared a flexible dose of asenapine (5-10 mg bid) with olanzapine and placebo. Neither active drug group was statistically superior to placebo. Thus, this was a failed study.
FDA’s statistician, Dr. Yeh-Fong Chen, noted in her written review: "Not only did the study drug and the active control fail to show any efficacy findings, but patients in the placebo group even performed numerically better than those in the study drug group."
Study 041023 compared asenapine 5 mg bid, asenapine 10 mg bid, haloperidol 4 mg bid, and placebo. There were roughly 110 patients per group. Completion rates for the 4 groups were as follows: asenapine 5 mg bid-63%; asenapine 10 mg bid-67%; haloperidol-59%; placebo-57%.
Dr. Chen notes in her written review: "Based on the protocol specified primary analysis, data only showed statistically significant findings for asenapine 5 mg BID. This reviewer plotted the visit-wise LOCF and OC analysis results and noted that… the observed effect size for 10 mg was smaller than that for the 5 mg regardless of analysis methods."
FDA’s review of the application for Efficacy in Bipolar Disorder focused on 2 short-term (3-week), double-blind, randomized, flexible dose, placebo- and olanzapine-controlled, parallel group studies of asenapine in adult patients with manic or mixed episodes of bipolar 1 disorder. Dosing was 5-10 mg bid for asenapine and 5-20 mg qd for olanzapine.
Study A7501004 was a multinational trial (61 centers, including both US and nonUS sites). There were roughly 200 patients per each active group and 100 for placebo. Completion rates were as follows: asenapine-67%; olanzapine-79%; placebo-58%. Both active drug groups were statistically superior to placebo on both the primary and key secondary endpoints.
Study A7501005 was a multinational trial (55 centers, including both US and non US sites). There were roughly 200 patients per each active group and 100 for placebo. Completion rates were as follows: asenapine-63%; olanzapine-80%; placebo-62%.
FDA acknowledged: The sponsor presented no data pertinent to longer-term efficacy of asenapine for the treatment of either schizophrenia or mania/mixed episodes.
It is astonishing that FDA would approve Asenapine for the treatment of bipolar disorder disorder-–
inasmuch as its efficacy remains in doubt, and 94% of the drug’s serious adverse events were exacerbation of psychiatric illness.
FDA’s failure to consider the compelling evidence of hazards posed by the so-called ‘atypical’ antipsychotics– from two major government-sponsored, long-term NIMH studies when assessing the safety / efficacy of asenapine–is irresponsible.
1. The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) in schizophrenia study overturned industry-promoted assumptions about the safety and efficacy of antipsychotics of asenapine’s class. The CATIE study demonstrated the lack of improved efficacy by the so-called ‘atypical’ antipsychotic drugs from older neuroleptics, while documenting these drugs’ severe, debilitating, life-shortening adverse effects and poor patient outcomes.
The data from the sponsor’s asenapine trials raise even greater concerns about this drug’s safety–as analyzed by FDA’s primary biopharmaceutics (OCP) reviewer.
2. The STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) found that the use of second generation antipsychotic (Risperdal) was LEAST effective (4.6%) compared to an anti-convulsant (Lamitcal, 23.8%) or even a sugar pill (Inositol, 17.4%).
Furthermore, evidence from STEP-D shows that "Suicidal ideation was significantly more prevalent among patients who were taking a second-generation antipsychotic than those who were not (26 percent and 17 percent) and those who were taking an antidepressant and those who were not (25 percent and 14 percent)."
See, Suicidal Ideation and Pharmacotherapy Among STEP-BD Patients, Psychiatric Services, 2007.
There were 12 suicides in the asenapine program overall, including 8 on asenapine and 4 on olanzapine.
FDA acknowledges: "The distribution of time of treatment to occurrence of suicide was somewhat unusual for asenapine, i.e., 8, 12, 18, 31, 33, 96, 152, and 257 days. The comparable numbers for olanzapine were as follows: 13, 37, 191, and 376 days."
Asenapine’s poor performance is underscored by an even higher drop out rate in head to head trials against olanzapine (Zyprexa), whose drop out rate in pre-marketing trials was a matter of concern that has been justified by the drug’ link to debilitating, chronic, life-shortening disease.
Dr. Laughren’ background memorandum to the advisory committee acknowledges:
"A major deficiency in the application from a biopharmaceutics standpoint is a failure to adequately determine what moieties are circulating in plasma. OCP maintains that the sponsor has identified only about 3% of circulating material in plasma. Also from the standpoint of mass balance, OCP maintains that only about 30% of the dose has been characterized regarding elimination pathways. They feel that the application cannot be approved before these deficiencies are addressed. The sponsor disputes these findings, and claims that they have identified up to 30% of circulating metabolites and 70% of the dose. At this point, however, this issue is unresolved." See, FDA Background Package
With numerous serious "unresolved" concerns about safety and efficacy, how can FDA claim Asenapine is "Safe and Effective"?
According to the American Society of Health System Pharmacists (below), Asenapine label warnings will include:
"Instances of tardive dyskinesia, a serious movement disorder, were reported during clinical trials of asenapine. The labeling states that if this condition occurs, consideration should be given to discontinuing therapy when "clinically appropriate."
"Cessation of therapy is also recommended if neuroleptic malignant syndrome (NMS), a life-threatening neurologic condition associated with the use of antipsychotic drugs, occurs during treatment with asenapine. Symptoms of NMS include "high fever, sweating, unstable blood pressure, stupor, muscular rigidity, and autonomic dysfunction," according to the National Institute of Neurological Disorders and Stroke.
"Other serious conditions that may occur during treatment with asenapine or other atypical antipsychotic drugs include hyperglycemia, diabetes mellitus, and orthostatic hypotension."
How can a drug that failed to even meet the low efficacy level of existing antipsychotics– Risperdal, Zyprexa–
whose documented debilitating and life-threatening risks emerged within the very short duration of the trials, be declared "Safe and Effective" for long-term chronic use?
One cannot but wonder what standards FDA officials are following before issuing the government seal of approval to drugs that offer no improved clinical benefit–and whose serious risks have not been fully evaluated.
Posted by Vera Hassner Sharav
American Society of Health System Pharmacists
Asenapine Approved for Treatment of Schizophrenia, Bipolar Disorder
BETHESDA, MD 14 August 2009—FDA and Schering-Plough Corporation today announced the approval of asenapine sublingual tablets for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults.
Schering-Plough expects the atypical antipsychotic drug to be available during the final quarter of this year under the brand name Saphris.
As with other drugs in the class, the labeling (PDF) for asenapine includes a boxed warning stating that the drug is "not approved" for use in elderly patients with dementia-related psychosis. Patients with this condition who are treated with antipsychotic drugs are at increased risk of death, the labeling warns.
The labeling also warns that cerebrovascular accidents and transient ischemic attacks have occurred in elderly patients with dementia-related psychosis when treated with antipsychotic drugs.
Efficacy data on asenapine were collected during three six-week clinical trials in patients with schizophrenia and two three-week trials in patients with bipolar disorder. According to FDA, the drug outperformed placebo in both bipolar-disorder trials and two of the schizophrenia studies.
The most frequent adverse events reported by clinical trial participants with schizophrenia were restlessness, decreased oral sensitivity, and drowsiness. Among patients with bipolar disorder, the most frequent adverse events were drowsiness, dizziness, movement disorders, and weight gain.
Instances of tardive dyskinesia, a serious movement disorder, were reported during clinical trials of asenapine. The labeling states that if this condition occurs, consideration should be given to discontinuing therapy when "clinically appropriate."
Cessation of therapy is also recommended if neuroleptic malignant syndrome (NMS), a life-threatening neurologic condition associated with the use of antipsychotic drugs, occurs during treatment with asenapine. Symptoms of NMS include "high fever, sweating, unstable blood pressure, stupor, muscular rigidity, and autonomic dysfunction," according to the National Institute of Neurological Disorders and Stroke.
Other serious conditions that may occur during treatment with asenapine or other atypical antipsychotic drugs include hyperglycemia, diabetes mellitus, and orthostatic hypotension.
The recommended starting dosage of asenapine in adults with schizophrenia is 5 mg taken twice daily. For patients with bipolar disorder, the recommended starting dosage is 10 mg taken twice daily. If this dosage is not tolerated, the labeling recommends reducing the dosage to 5 mg taken twice daily.
Asenapine 5- and 10-mg tablets will be sold in 10-tablet blister packs in boxes of 60 or 100. Each tablet should remain in the blister pack until needed and then removed with dry hands. The tablet should be placed under the tongue and allowed to dissolve completely, and the patient should not eat or drink for 10 minutes after taking the tablet.
The labeling warns against crushing, chewing, or swallowing the sublingual tablets.
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