Sept, 9 2000
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Adverse Events Reporting - Impotent Statistics?
Serious adverse drug reactions (ADRs), defined as those requiring hospitalisation, resulting in permanent disability, or death have been cited by a JAMA study as reaching numbers of epidemic proportions. The estimates exclude those attributed to errors in drug administration, non-compliance, overdose, drug abuse, therapeutic failures and possible ADRs. These qualified ADRs were found to result in the deaths of approximately 106,000 hospital patients and the serious injury of at least 2.2 million human beings annually as of 1998 in the US alone. Though these findings are alarming in and of themselves, they exclude other confounding factors that drive the numbers up exponentially. These include ADRs that are unrecognised or unreported which only serve to further confound attempts to accurately assess the number of individuals who are dying or being seriously harmed by the use of prescription drugs.
Though the JAMA findings propose to exclude ADRs resulting from medication errors, distinguishing them from actual ADRs resulting from a drug's pharmacological properties can be very difficult. According to the United States Government Accounting Office (GAO), the investigative arm of Congress, the distinctions between medication errors and exclusively drug induced ADEs, (FDA vernacular for ADRs, hereafter referred to as ADEs), associated with the inherent risks of drugs is sometimes ambiguous. This is due to the fact that some drugs are difficult to use safely because toxic doses are only slightly higher than those deemed appropriate for treatment. A second confounding factor is that appropriate prescription levels may vary over time and require frequent adjustment. Bupropion DPMs cite such qualifications in treatment protocol.xyeach dpm These two factors contribute significantly to the opportunity for medication errors that would not have been included in the JAMA findings.
Other findings that could conceivably add to the JAMA findings concern limitations of the FDA's spontaneous reporting MEDWATCH system, designed to gather ADE data. Although it has been asserted that the current system can be effective in uncovering unusual or rare events, it can not reliably detect ADEs that occur long after drug cessation. The number of ADEs resulting from long term administration of drugs for chronic disease also remain elusive. Reports to the FDA Adverse Event Reporting System (AERS) only reflect an estimated 1% to a conservative 10 % of ADEs and are unlikely to be representative of the much larger number of unreported events. This can be attributed in part to the fact that health care providers, pharmacists, patients, and others are not obligated to report suspected ADEs to the FDA. Although a wide range of commonly used drugs cause ADEs which can pose serious health consequences for patients, there is insufficient data available to discern the frequency these ADEs. Bupropion is proven to pose serious health consequences as per each of its DPMs. Even more disturbing, it has been asserted by the GAO that there is little certainty about the frequency of fatal ADEs because the data on fatalities is even sparser than the data on overall ADE incidence.
According to the FDA, in everyday clinical practice, adverse events associated with the use of medical products can lead to hospitalisation, permanent disability, and death. The agency classifies ADE's into two categories. Type "A" are defined as predictable, expected extensions of a drug's known pharmacological properties. Type "B" are characterized as unpredictable events; this would include drug allergies or immunological reactions,(e.g., anaphylaxis), idiosyncratic reactions, and carcinogenic/teratogenic events. Type B reactions are often the most serious, a major cause of drug induced disease, potentially life-threatening, and often deadly. The FDA classification qualifications often overlap in regards bupropion, as a number of the ADEs associated with the drug as per DPMs for each formulation cite instances of possible drug allergy or immunological reactions, (e.g. anaphylaxis.) Due to the fact they are included in the DPMs, they are considered expected (Type A), though can also be designated as "unpredictable", (Type B.) The FDA has stated they focus more on Type B reactions, further complicating the discerning of serious bupropion ADEs.
Anaphylaxis as defined per Taber's Medical Dictionary (TMD) is the induction of "a hypersensitive state of the body to a foreign protein or drug." It goes on to say, "Reactions which constitute anaphylactic shock occur suddenly. They include increased irritability, dyspnea, cyanosis, sometimes convulsions, unconsciousness, and death." It is further defined as including reactions primarily due to contraction of smooth muscle fibers, classified as involuntary, and found principally in the internal organs, especially in the digestive tract, respiratory passages, urinary and genital ducts, urinary bladder and gall bladder, and walls of blood vessels. Death usually results from spasm of muscles of bronchioles. Symptomology is further classified as Mild including slight fever, redness of skin, itching, and urticaria (hives). Severe is classified as including dyspnea (shortness of breath), violent cough, chest constriction, cyanosis, fever, skin eruption, pulse variations, convulsions, and collapse.
The Zyban DPM states, "a patient should stop taking Zyban and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritis, hives, chest pain, edema, and shortness of breath) during treatment." It also states that adverse events sufficiently troublesome enough to cause discontinuation of treatment occurring in 8% of 706 patients in the two trials cited therein included 2.8% who experienced non-specified rashes. This could conceivably be considered a sign of severe anaphylaxis as per TMD definition cited above. Information provided within the DPM in "Table 3: Treatment-Emergent Adverse Event Incidence in Dose-Response Trial"(noted as selected adverse events) reveals a number of anaphylactic-type events. Of the 461 individuals treated with 100 to 300 mg/day, incidences of hives, rash, allergic reaction, and pruritis (severe itching) illustrate a culminative incidence rate of 8%. A rate of 0% to <1% was noted for the 150 individuals placed on placebo. "Table 4: Treatment Emergent Adverse Event Incidence in the Comparative Trial" (also qualified as selected adverse events) cites incidents of chest pain, increased cough, facial edema, dyspnea, rash, pruritis and urticaria at a culminative rate of over 13% of the 243 participating individuals. Placebo rates involving only 159 individuals cites events in these areas at a culminative rate of 5%.
Total culminative results for both trials illustrate a 21% rate of possible anaphylactic/allergic type responses in treated individuals, translated into more than a 1/5-incidence rate. Though the culminative placebo rate for both trials is stated to be a little over 5%, it is of interest to note that in each of these trials the placebo comparisons are extrapolated from a substantially smaller sample group than the percentages involving a far larger number of those treated with bupropion. These observations are supportive of the drug's possible propensity to induce allergic and immunological responses. It also illustrates manufacturer defined anaphylactoid/anaphylactic type reactions, all contentions supportive of the fact that all are an expected consequence of exposure.
In addition to the anaphylactic/allergic type trials' ADEs, it is of interest to note that convulsion is classified as being a severe manifestation of anaphylaxis. Though not cited within the aforementioned trials information, bupropion has a less than favourable history concerning seizures (non-specified.) Seizures are defined in the TMD as "A sudden attack of pain, or a disease, or of certain symptoms", further classified as "s., convulsive. 1. A convulsion, q.v. 2. An attack of epilepsy" and "s., larval", a seizure indicative of abnormal brain waves as per electroencephalogram (EEG) findings but not evidenced by clinical symptoms. First synthesized by Burroughs Research in 1966, bupropion was originally marketed in the United States as the IR formulation and was pulled from the market for three years following a high incidence of seizures reported in one clinical trial. The drug was allowed back on the market, earmarked with a warning of a .4% (4/1000) seizure (non-specified) risk, and slowly gained popularity in the limited antidepressant market. It was not until the introduction of the SR formulation, and it's subsequent renaming and launching as Zyban that bupropion gained wide spread market acceptance. This formulation claimed a lowered seizure risk of .1% (1/1000). As per TMD seizure definition in regards convulsive seizures, it is highly conceivable that the seizure phenomena associated with bupropion is anaphylactoid/allergic in nature.
Though the prognosis in mild cases of anaphylaxis is considered self-limiting, in severe cases, death may occur if emergency treatment is not given. Indicative treatment for severe cases include the use of vasopressor agents, notably epinephrine, and the use of corticosteroids, among other intervention measures. The DPM for Zyban states that an increased seizure risk is associated with systemic steroids, which are "known to lower the seizure threshold," and with use of over-the-counter stimulants. Epinephrine is a potent stimulant. Ergo, in severe cases of anaphylactic type ADEs, life saving treatments themselves can be contraindicated.
Drugs proving to be associated with both types of ADEs are of paramount concern in regards consumers' health and safety. The banned non-steroidal anti-inflammatory drug zomepirac is an excellent example of this classification of drug, very similar in its ADE profile to bupropion. Initial clinical trials conducted in the middle to late 1970's concluded the drug was a "safe and promising" analgesic with few side effects. With over six million arthritics and some 30 million persons with other chronic joint problems in the United States, zomepirac gained wide and immediate acceptance. However, within the first two years on the market, toxicities such as gastric irritation, nephritis and renal failure, were reported as being associated with it's use. Despite the serious nature of these reactions, they were added to the list of type A ADE's in the Physician's Desk Reference (PDR). It wasn't until March of 1983, after unexplained anaphylactic reactions led to several deaths, (type B ADE's), that zomepirac was withdrawn from distribution in the United States and Britain.
*For the purposes of this publication, it is important to note that bupropion hydrochloride (hcl) shares several commonalties with zomepirac. They both first entered clinical trials in the middle to late 1970's, they both initially had favorable side effect profiles and once they became widely accepted, numerous type A ADEs began to be reported. Type A and Type B ADEs are currently mounting in relationship to bupropion, many Type Bs conceivably erroneously designated Type A's as proposed above reported in it's use as Zyban for smoking cessation.
It is of paramount importance to note that due to the fact that bupropion was marketed as an antidepressant prior to it's marketing as Zyban, many of it's psychiatric and other side effects were conceivably attributed to aberrant mental manifestations inherent to the patient's "disease" status. Practicing MDs and psychiatrists are often unaware of psychoactive drug side effects. When coupled with observations from those within the psychiatric community itself that irresponsible inattention to adverse side effects is commonplace among psychiatrists, that they generally continue to ignore the evidence of dangerous side effects, and often neglect to adequately inform their patients of known side effects, it becomes evident that an indeterminate number of bupropion related adverse events have and continue to go unreported. This adds considerable weight to the assertion that bupropion has not received much attention over the years in regards ADEs when used primarily as an antidepressant. Bupropion SR's purported established safety contributed to the facilitation of its acceptance as a smoking cessation aid. Given that it is indeed a psychoactive drug, with numerous serious, though definitively disclaimed side effects associated with it's use as per it's accompanying DPMs, and that many MDs are unaware of these reports, once again an indeterminate amount of ADEs are going unreported.
In addition, a researcher close to the investigators of this report has revealed that hundreds of individuals had been posting via the internet on a website concerning their oftimes serious adverse experiences with both Zyban/Wellbutrin SR and Wellbutrin IR. The site has now disappeared, having been bought out by a larger internet portal. The board now available there for postings concerning Zyban, Wellbutrin SR and IR are exceedingly pro-drug in nature. A thorough search of various other posting boards featured at health information related sites across the world wide web reveals largely pro bupropion forums to date.
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