P&T News: December 1997
Barbara A. Mutnick, R.Ph., M.H.P.
Peer Review Status: Internally Peer Reviewed
During fiscal year 1996-97, 422 adverse drug reaction (ADR) reports were generated by UIHC personnel and reviewed by the Pharmacy and Therapeutics Subcommittee. Of these reports, 100 were recommended for forwarding to the Food and Drug Administration (FDA) via the Medwatch Program because they were identified as severe, unusual, or occurring with a newly marketed drug.
FDA's Medwatch Program and Newly Released Drugs
Clinical trials effectively assess efficacy and risk-benefit
ratios, but they are generally not large enough or of long enough
duration to provide all the information on a new drug's safety.
Vigilant post-marketing surveillance must be performed by all health
care professionals in order to continue the necessary monitoring of
newly marketed agents. New data are used to update the prescribing
information of recently approved agents. Table 1 lists some of the
recent labeling changes prompted by submission of adverse drug
reaction reports to the MedWatch Program.
Adverse Drug Events
The World Health Organization defines an ADR as an effect that is
"noxious and unintended, and which occurs at doses used in man for
prophylaxis, diagnosis or therapy." A more comprehensive term is
adverse drug event (ADE) which is defined as "an injury resulting
from medical intervention related to a drug."1 An ADE would include
injuries resulting from drugs used inappropriately or at incorrect
doses. For example, the oversedation and aspiration pneumonia
resulting from a 10-fold overdose of a drug, would be excluded from
ADR reporting, but would be considered an ADE.1
Table 1. Labeling Changes Due to Post-Marketing Surveillance
|
Fenfluramine (Pondimin[R]) |
FDA requested manufacturer to add information about the increased risk of primary pulmonary hypertension to product labeling. |
|
Lamotrigine (Lamictal [R]) |
A "block box" warning added to product labeling warning that this product is not indicated for use in patients under the age of 16 because an increased incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis were noted. |
|
Zafirlukast (Accolate [R]) |
Warning of elevation of liver enzymes added to product labeling. A warning about the potentially fatal Churg-Strauss Syndrome has been added to the product labeling. |
|
Protease Inhibitors |
These agents have been reported to increase blood sugar levels and cause diabetes in HIV patients. Blood glucose levels need to be monitored in patients receiving these agents. |
|
Aminodarone (Cordarone [R]) |
FDA requested labeling to include information about optic neuritis and optic neuropathy occurring in patients receiving this agent. |
|
Loratadine/pseudoephedrine (Claritin-D [R] 24
Hour) |
This agent is contraindicated in patients having difficulty in swallowing, upper gastrointestinal tract narrowing, or decreased esophageal peristalsis. Claritin-D [R] 24 Hour noted to cause gastrointestinal obstruction in some patients. |
|
Terfenadine (Seldane [R]) |
Product labeling to include contraindication with mibefradil (Posicor[R]), new drug interactions with protease inhibitors, and recommendation for reduced dosing in renal impairment. |
|
Dexfenfluramine (Redux [R]) |
Reports of development of heart valve disorder; products removed from the market. |
|
Troglitazone (Rezulin [R]) |
Cases of idiosyncratic hepatocellular injury, including death, have been reported; recommendations for periodic screening of serum transaminase were made. |
|
Mibefradil (Posicor [R]) |
Reports of a drug interaction with simvastatin; three cases of rhabdomyolysis, including one fatality; the package insert is being revised. |
|
Troglitazone (Rezulin [R]) |
New recommendations include measuring liver enzymes and bilirubin levels at the start of therapy, monthly for the first six months of therapy, every two months for the remainder of the first year of therapy, and periodically thereafter. |
Recent literature includes studies of causes and effects of ADEs. It is estimated that ADEs account for as many as 140,000 deaths annually in the United States. The most recent estimation of the cost of treating drug-related morbidity and mortality in this country is $136 billion dollars a year.2 In one study published in early 1997, 6.5 per 100 admissions were deemed to be caused by ADEs; 28% of these ADEs were judged to be preventable. The most commonly identified preventable ADEs were cardiac (most frequently hypotension, which was severe enough to require therapy), central nervous system (confusion or delirium), and respiratory complications. Preventable ADEs were more serious in nature and on average doubled the additional length of stay from 2.2 to 4.6 days over non-preventable ADES. Likewise, preventable ADEs were generally almost twice as expensive to treat; the estimated postevent costs were $2,595 per non-preventable ADE case versus $4,685 per preventable ADE case.3
Warfarin Adverse Drug Reaction Reports
In some instances, ADEs have been included in our adverse drug
reaction data. Reports due to drug-drug interactions, the lack of
appropriate patient education, and poor compliance are examples of
the type of ADEs that are components of our ADR Reporting Program.
The inclusion of ADE information in UIHC's ADR program was instrumental in initiating a recently completed warfarin drug use evaluation review.
As a result of this drug use evaluation, the Drug Use Evaluation and Pharmacy and Therapeutics Subcommittees made the following recommendations to prevent future warfarin-associated adverse effects: 1) Increase pharmacist involvement in patient teaching when patients are started on therapy while hospitalized. Patients will receive verbal counseling and receive preprinted educational materials on dosing, importance of having INR/prothrombin time checked, food and drug interactions, and signs of bleeding; 2) Document patient teaching about warfarin therapy in the medical record; and, 3) Develop educational materials for prescribers and pharmacists on dosing, drug and food interactions, and monitoring anticoagulation therapy.
Summary
All health care professionals are reminded to report ARDs. Of
utmost importance in the process is the documentation of the ADR in
the patient's medical record. This documentation will aid in the
establishment of a clear cause and effect relationship that becomes
part of the patient's medical history and will become readily
available for use by all healthcare professionals involved in the
care of the patient.
The continued reporting of ADRs will provide sufficient data to recognize developing trends of preventable adverse reactions and aid in the initiation of proactive programs to minimize the subsequent occurrence of these ADRs. To expedite the reporting process for the Nursing and Medical Staff, bright yellow Adverse Drug Reaction Reporting Cards are available on all patient care units and clinic areas.
References
Within the first year after marketing approval, the FDA received 83 reports of seizures in patients using tramadol. This led to labeling changes and issuance of a "Dear Doctor" letter. During tramadol's second year on the market, the FDA received more than 200 reports of seizures.
Using the FDA's database of adverse drug events, all domestic U.S. reports for tramadol-related seizures that the FDA had received by July 31, 1996, were reviewed. There were 124 seizures cases from the U. S. Of those 121 reports that had descriptions of events, 52 (43.0%) were described as generalized tonic-clonic or grand mal, 47 (38.8%) as "seizure," and 22 (18.2%) as miscellaneous.
Among the available data, seizures occurred within one day following the initial dose in 38 cases, and within 12 hours following the last tramadol dose in 30 cases. Thirty (24.2%) of 124 reports suggested the possibility of overdose by either excess milligrams per dose or by insufficient time intervals between dosages. Seventy-five (60.5%) of 124 patients consumed an average of 400 mg or less of tramadol per day. Concomitant medications with potential to increase seizure risk were taken in 72 cases, and included tricyclic antidepressants in 28 cases and selective serotonin reuptake inhibitors in 20 cases. Twelve patients (9.7%) had a history of seizures.
The large number of spontaneous reports received by the FDA suggests that tramadol may cause seizures. Many reports noted seizures occurring within 1 day of starting treatment with tramadol. Most patients were healthy and between the ages of 20 and 39 years, and most had no previous seizure history. This adverse drug effect can occur at recommended dosages, although an overdose may increase the risk of tramadol-related seizures. Concomitant treatment with antidepressant medications also appears to increase the risk of tramadol-related seizures.
Abstracted from: JAMA. 1997; 278:166 1.