UPDATED: 07.28.09 @ 10:50 PM EDT -- This last update, a sidebar-image of an internal FDA e-mail, at right, merits its own post. Click on the image, at right, or click this link, to read more of the story.
▲ . . . .5 mg SD Pivotal BE Study: 20 of 35 healthy subjects had observed cardiac effects on telemetry; 10 subjects experienced bradycardia, 8 tachycardia, 7 sinus pause, 3 junctional escape rhythms, and 1 bradycardia with junctional rhythm. . . .
▲ The medical reviewer changed his conclusions from the original clinical review where he stated the acute schizophrenia study # 41004 was a failed study to a positive study with as asenapine differentiated from the negative control as the positive control did not.
▲ The medical reviewer’s statement is at variance with the regulatory history of the FDA going back many years. The FD&CA indicates that efficacy must be shown by ‘adequate and well controlled studies’. It is common practice in science that experiments and studies need both positive and negative controls in order to be well controlled. This is especially important with treatment for certain psychiatric diseases due to the high and variable placebo response rate, which could differ between two different placebo arms. It’s also unknown why the medical reviewer did not obtain a secondary signature for this review amendment. . . .
GO see the comments, below! Amazing -- and disgusting! [I must be seeing differing pagination than Salmon, and the other anonymous commenters -- but I am trying calibrate where, in my copy, all of the pages referred to (by Salmon and others) appear. I am using the Adobe PDF Reader's master document page number, upper bar of the reader itself, not anything actually marked on these physical pages. Just FYI.]
Keep on diggin' -- one and all!
This river is vast -- deep, wide and very fast-running -- at 19.1Mb -- and 1,000-plus pages of PDF file. Only 48 hours for Salmon to swim all the way upstream, through all of it. Can it be done? I dunno.
But (to switch-up the metaphors, here) there will be golden needles, in this gigantic haystack. Let's start looking -- at page 8 of 1,067:
. . . .The sponsor presented no data pertinent to longer-term efficacy of asenapine for the treatment of schizophrenia. We [the PDAC] will seek such data as a phase 4 commitment, should we decide to issue an approvable letter for this NDA. . . .
▲ [Page 123:] In the combined Phase 2/3 studies, the most commonly reported SAE [or "significant adverse events"] were exacerbations of the psychiatric disorders under treatment. These included: exacerbation of Schizophrenia and other psychotic disorders; completed suicide; suicidal and self-injurious behaviors; mania, Bipolar disorder; depressed mood; and mood disturbances.
Less common SAE included: 1) injury, poisoning, and procedural complications; and 2) infections and infestations. Among the 11 cases of infection, there were 6 cases of pneumonia. Other reported SAE included rhabdomyolysis, syncope, bradycardia, hyponatremia, neuroleptic malignant syndrome (NMS), agitation, and dystonia. The SAE that were probably related to treatment with asenapine include: NMS, dystonia, syncope, and drug toxicity. . . .
▲ 5543-125005: The subject was a 64 y.o. male with Schizophrenia who was treated with asenapine for 31 days. The subject completed suicide by unknown method. No other details were provided for the case. The investigator judged that the death was possibly related to treatment with asenapine, but it is not clear what the rationale was. . . .
▲ A7501007-51241008: A neonatal death occurred for a pregnant subject treated with asenapine. The subject, had 3 previous premature deliveries, and she delivered at 32 weeks gestation. No other details are available. The death was possibly related to treatment with asenapine. . . .
▲ P25520-241041: The subject was a 57 y.o. woman with Schizophrenia who was treated with asenapine for 470 days. She died 4 days after her last dose of asenapine. The subject developed sudden respiratory failure and required treatment on a ventilator. The cause of death was pulmonary embolism. Other adverse events reported during the study were worsening of Schizophrenia and insomnia. The death was probably not related to treatment with asenapine. . . .
▲ P25520-132017: The subject was a 44 y.o. woman with Schizophrenia who was treated with asenapine for approximately 521 days. She was found dead in her home several days after her last study visit. The precise date of death and the cause of death are uncertain. Clinical laboratory findings included a low hemoglobin concentration and hematocrit at Weeks 52 and 64 and a low WBC at Week 64. The lymphocyte count was low at Weeks 40, 52, and 64. The neutrophil counts were normal, as were the platelets, Monocytes, Eosinophils, and basophils. There was no evidence of aplastic anemia or netropenia or agranulocytosis [a potentially lethal side-effect in some patients on clozapine]. Creatinine was mildly elevated at the Week 40 visit. On an unspecified date, the peripheral blood smear revealed hypochromia, anisocytosis, and poikylocytosis. . . .
III. Completed Suicide and Suicidality Analysis
▲ There was not an excess of completed suicides in the asenapine group, compared to the olanzapine group when adjusted for exposure. There were 8 suicides in the asenapine group and 4 in the olanzapine group. There were no suicides in the other treatment groups (placebo, risperidone, and haloperidol). For the involved studies with suicides, only one study had a placebo group (A7501004: a controlled, short-term mania study). All of the other involved studies were long-term, double-blind, active-control studies, without a placebo group.
▲ The total asenapine exposure in the Schizophrenia and Mania programs was 625.5 person-years. There were 8 suicides in the asenapine group. Thus, the rate of suicide adjusted for asenapine exposure was 1.279 suicides per 100 person-years. The total olanzapine exposure in the Schizophrenia and Mania programs was 298.1 person-years. There were 4 suicides in the olanzapine group. Thus, the rate of suicide adjusted for olanzapine exposure was 1.342 suicides per 100 person-years. Thus, the adjusted rate in the olanzapine group was 1.049 times the rate in the asenapine group.
▲ For the combined Schizophrenia program, there were 7 suicides in the asenapine group and 2 suicides in the olanzapine group. The total asenapine exposure in the Schizophrenia program was 573.3 person years. The total olanzapine exposure was 234.1 person-years. Thus, the adjusted rates of suicide were 1.22 suicides per 100 person-years in the asenapine group and 0.854 suicides per 100 person-years in the olanzapine group. The rate in the asenapine group was 1.428 times the rate in the olanzapine group. . . .
[Pages 266 to 270:]
IV. Selected Serious Adverse Events and Other Adverse Events of Interest. . . .
▲ The majority of serious adverse events in all treatment groups in the asenapine program were psychiatric adverse events related to the illnesses under treatment (Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder). . . . In the asenapine groups, 94% of all serious adverse events were psychiatric adverse events. . . .
▲ 25501-1. A 22 y.o. healthy volunteer with a resting HR of 58 bpm received a 30-mg oral dose of asenapine. Approximately 2.5 hours after the dose, the subject sat up in bed and felt dizzy and nauseated. The ECG telemetry strip showed a HR slowing and an 8.7-second pause. This was followed by heart block and nodal bradycardia., which spontaneously converted to sinus rhythm. He had a similar episode 2 hours later. He recovered from the episodes.
Neurally Mediated Reflex Bradycardia
The subject above probably experienced neurally mediated reflex bradycardia (NMRB). NMRB is not unexpected with a drug that has alpha-1-adrenergic antagonist properties. The Cardiorenal consultants discuss this phenomenon. The consultants agree with the sponsor’s interpretation that the cardiovascular adverse event was related to NMRB. There were several similar cases in healthy volunteers who received asenapine in the clinical pharmacology studies. There was one possible case of NMRB in a subject with Schizophrenia who was treated with asenapine. Neurally Mediated Reflex Bradycardia (NMRB) is a benign, self-limiting event, and the most common cause of vasovagal syncope. It involves central hypovolemia, vasodepression, and bradycardia. Bradycardia can be accompanied by periods of asystole that are due to either sinus pause or heart block. NMRB can occur with or without sinus pause and is typically associated with postural challenge. Healthy, young volunteers with a high resting vagal tone display a higher incidence of NMRB than do do psychiatric patients[Ed. Note: How so?]. . . .
▲ 041033-101012: The subject was a 44 y.o. healthy volunteer who was treated with asenapine (one dose) and fluvoxamine (6 doses). The subject developed bradycardia and sinus pauses during sleep while on telemetry. He was wakened and remained asymptomatic. The subject recovered. The event was thought to be related to study drug treatment. This was probably a case of neurally mediated reflex bradycardia related to treatment with asenapine. . . .
▲ A7501001-10020007: The subject was a 51 y.o. male with Schizophrenia who participated in a dedicated QT study. He was treated with one dose of asenapine. About 1.5 hours after the dose, he experienced severe bradycardia, and he was taken to an emergency room. He had ECG changes suggestive of myocardial infarction. He did not have chest pain. He was treated with oxygen, atropine, aspirin, metoprolol, tenectplase, lidocaine, and magnesium, and he was admitted to a cardiac care unit. Coronary angiogram was negative. He developed atrial fibrillation which resolved spontaneously. The event was possibly related to treatment with asenapine. This was possibly a case of neurally mediated reflex bradycardia. . . .
▲ 25525-101029: A healthy subject developed atrial fibrillation during treatment with asenapine and paroxetine as part of a drug-drug interaction study. The event was probably related to treatment with either one or both drugs. The subject had chemical cardioversion and recovered. . . .
▲ 25517-247010: The subject was a 43 y.o. female with Schizophrenia who was treated with one dose of asenapine 5 mg. She experienced nausea, vomiting, dizziness, syncope and angioneurotic edema on the same day. The syncope occurred approximately 40 minutes of the dose. The subject did not have any known drug allergies or significant medical history. The investigator concluded that the events were probably related to treatment with asenapine. . . .
More to come, as I work my way through. The two sidebars are images for the original asenapine FDA IND -- in November of 1996. Do click each, to enlarge -- they are self-explanatory.
Again, let me repeat that: Paging Dr. Salmon -- Dr. Salmon, to the FDA Reading Room -- Stat. Per a comment below, Salmon is now on the case. Cool. Salmon is right -- this will take weeks, not 46 hours -- and counting.