P&T News: December 1993, Vol. 14, No. 6

Adverse Drug Reaction Reporting

Mary B. Ross, R.Ph.
Peer Review Status: Internally Reviewed

Defining an Adverse Drug Reaction
Various definitions of an ADR or drug-induced side effect have been developed. The World Health Organization defines an ADR as "any response to a drug which is noxious, unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function."5 The FDA defines an ADR as "an adverse event occurring in the course of the use of a drug product in professional practice;...occurring from drug overdose, whether accidental or intentional; ... from drug abuse; from drug withdrawal; and any significant failure of expected pharmacologic action."6

Using these definitions, the UIHC Pharmacy and Therapeutics Subcommittee has developed a definition of a s significant ADR that includes any reaction that meets the designation of fatal, severe (serious), or moderate. A fatal adverse effect is one that directly or indirectly contributes to the death of the patient. A severe or serious effect is one that is potentially life-threatening or toxic, causes permanent disability, requires intensive medical care, or requires hospitalization. If an ADR requires treatment with drug therapy, requires a change in drug therapy, increases length of hospitalization, or causes temporary disability, it is classified as moderate. Other types of ADRs considered by the Pharmacy and Therapeutics Subcommittee to be significant include new or unexpected reactions, including drug interactions (i.e., not listed in the current manufacturer's labeling or occurring in greater severity that listed); reactions occurring with increased frequency; or reactions associated with congenital anomalies.

Classifications of ADRs that the Pharmacy and Therapeutics Subcommittee routinely reports to the FDA include: previously unreported or very unusual ADRs; severe ADRs (life-threatening, requiring intensive medical care, requiring medical or surgical intervention to prevent permanent damage, causing or prolonging hospitalization, or causing permanent damage, including congenital anomalies); an ADR possibly, probably, or definitely contributing to a fatal outcome; and ADR reports to a single agent that appear to cluster or demonstrate a developing trend.

Importance of Reporting
There are a number of reasons why ADRs should be identified and reported to the Pharmacy and Therapeutics Subcommittee, the FDA, and the manufacturer, the most important reasons being the need to update prescribing information and to prevent future ADRs. During clinical trials, drugs are generally studied in several hundred to several thousand relatively healthy patients, usually for only a limited duration of time. Patients on multiple drug therapy, pediatric patients, elderly patients, and patients with decreased renal and hepatic function are often excluded. Once the drug is commercially available, these exclusion criteria are no longer applicable, therapy may continue long-term, and previously undetected problems may be identified. Additionally, adverse effects may occur at such a low frequency that they are not being detected in the small numbers of patients included in the clinical trials; widespread use may uncover serious adverse effects.

Examples of changes made as a result of ADRs reported to FDA include: the market withdrawal of temafloxacin due to reports of severe hypoglycemia and death in elderly patients with decreased renal function;7 "black-box" warnings against the use of ACE inhibitors during the second and third trimesters of pregnancy due to reports of fetal and neonatal injury, including hypotension, skull hypoplasia, anuria, renal failure, oligohydramnios, and death;8 and documentation of drug-induced cardiovascular adverse effects (QT prolongation, ventricular arrhythmia, torsades de pointes, cardiac arrest, and death) because of a drug interaction between terfenadine and ketoconazole and between terfenadine and erythromicin.9

An additional reason to document ADRs includes identification of subpotent, superpotent, or contaminated products. Clusters of reports of ADRs or lack of response have been instrumental in initiating product recalls.

Prompt identification of ADRs can decrease morbidity and mortality, length-of-stay, health care costs, and liability. In addition, if identified, some ADRs are preventable and steps can be taken to prevent subsequent reactions. Examples include: pretreatment with phenytoin to prevent seizures associated with high-dose busulfan therapy; and alternate antibiotic therapy or a decrease in theophylline dose to prevent toxic theophylline levels in a patient who would normally receive a quinolone antibiotic or erythromycin.

Finally, institutions must report ADRs to be in compliance with Joint Commission on Accreditation of Healthcare Organization (JCAHO) standards.

Reporting Forms
ADRs have traditionally been reported to the FDA using Adverse Reaction Report (Drugs and Biologics) Form 1639. In June 1993, the FDA introduced the Med Watch Medical Products Reporting Program to facilitate reporting of problems with most medical products, including drugs (Figure 1). Adverse experiences with medications (drugs and biologics), medical devices (including in vitro diagnostics), nutritional products (dietary supplements, medical foods, infant formulas), and other products regulated by the FDA should be reported using the MedWatch form.

To facilitate reporting of ADRs by health care professionals at UIHC, pads of bright-yellow, pocket-sized ADR reporting cards will be placed on patient care areas within the next few weeks. Completed cards should be forwarded to the Drug Information Center for follow-up by the Pharmacy and Therapeutics Subcommittee.

Adverse Drug Reaction Reporting at UIHC
At UIHC, ADR reporting is coordinated by the Pharmacy Department's Drug Information Center. Reports are then reviewed by the Pharmacy and Therapeutics Subcommittee prior to being recommended for forwarding to the FDA and manufacturer. Those ADRs recommended for forwarding are first sent to the patient's attending physician for review and approval and then on to the FDA and manufacturer.

ADR reports are sent to the FDA under the Pharmacy and Therapeutics Subcommittee's name; individual health care professional's names are not included. Patient's name or registration numbers are not included on the form, and hence are kept confidential. If additional follow-up is requested by the FDA, the name of the patient's physician is disclosed only after receiving his/her permission. Additionally, the policy of protecting personal privacy is codified in FDA regulations.

During Fiscal Year 1992-93, 578 ADR reports were identified at UIHC; 317 of these reports were further identified as potentially significant and presented to the Pharmacy and Therapeutics Subcommittee for in-depth review. The reporting sources of these ADRs are depicted in Figure 2. Figure 3 illustrates the causative agents by drug category. Anti-infectives were the most frequently identified drugs. The top 11 causative agents were vancomycin, amphotericin B, gentamicin, contrast dye, morphine, acyclovir, sulfamethoxazole/trimethoprim, diltiazem, etoposide, and intravenous immune globulin.

The Pharmacy and Therapeutics Subcommittee has endorsed several initiatives to enhance the reporting of ADRs within the institution. New, serious, or recurring ADR reports will be featured on a regular basis in the P&T News. Automated technologies such as on-line laboratory values (e.g., positive C. difficile cultures, rapidly increasing serum creatinines) and on-line ADR reporting forms will be used as means for capturing additional ADRs. Pocket-sized ADR reporting cards will be placed on the patient care areas to facilitate reporting by health care professions within UIHC.

In summary, ADR reporting is the responsibility of all health care professionals at UIHC.

References
1. JAMA 1975;234:1236-41.
2. Ann Intern Med 1988;108:145-7.
3. Am J Hosp Pharm 1989;46:929-44.
4. Health Week 1988;2(Aug8):1, 12.
5. Requirements for adverse reaction reporting. Geneva, Switzerland. 1975.
6. Fed Reg 1985;50(30):7500-1.
7. FDA Med Bull 1992;22(Sept):4.
8. FDA Med Bull 1992;22(April):2.
9. FDA Med Bull 1993;23(March):2-3.

Red Man Syndrome: A Preventable Adverse Drug Reaction

Mary B. Ross, R.Ph.
Peer Review Status: Bradley E. Britigan, M.D., Associate Professor, Infectious Diseases Division, Department of Internal Medicine

Red man syndrome (RMS), a common adverse effect of vancomycin, is characterized by a sudden fall in blood pressure, a maculopapular rash, angioedema, pruritus, urticaria, erythema, wheezing and dyspnea. Rarely, RMS may be so extreme as to cause cardiovascular collapse. In addition to discomfort to the patient, RMS can lead to possible interruption of therapy and the risk of inappropriately labeling a patient as allergic to vancomycin.

The reaction is believed to be mediated by immunologic histamine release.1 It is most often seen with a rapid intravenous dose of vancomycin.2 The onset of the reaction can occur any time during the infusion. The symptoms generally resolve within a few hours after the infusion has stopped. Although initially thought to be caused only by too rapid of an infusion, the literature contains reports of the reaction occurring with slow intravenous infusion,3,4 intraperitoneal administration, and oral vancomycin administration.5

It has been proposed that histamine mediates the symptoms commonly classified as RMS.1,6 Polk et al., evaluated 11 healthy subjects in a randomized crossover study.6 Doses of 500 mg of vancomycin in 100 ml of dextrose 5% in water and 1000 mg of vancomycin in 200 ml of dextrose 5% in water were administered over 1 hour as an intravenous infusion. The subjects then received the alternate dose one week later. Six subjects received the 1000 mg dose first. Blood assays for plasma histamine concentration were drawn 60 minutes, 30 minutes and immediately before the infusion and 10, 20, 30, 40, 50, and 60 minutes into the infusion. Vancomycin levels were drawn at the end of the first infusion. Resting blood pressures were obtained after 10 minutes. Subjects were observed for signs of pruritus, erythema, or angioedema. Reactions were categorized as mild, moderate or severe. Nine of the 11 subjects experienced RMS with the 1000 mg dose, no subject experienced symptoms upon receiving the 500 mg dose. There was no change in blood pressure in any subjects at either dose. Histamine concentrations were plotted for both groups. There was a slight, but significant difference (p<0.05) between the baselines area under the curve (AUC) and the drug infusion curve in the 500 mg group. The differences seen in the 1000 mg group were much larger. A significant correlation (Spearman's rank correlation coefficient = 0.75, p<0.02) existed between the area under the plasma histamine concentration versus time curve for the period during the infusion and the severity of the reaction. The data suggest that the amount of histamine released into the plasma correlates with the severity of the reaction.

Another study7 used similar methods to evaluate the use of pretreatment antihistamines in healthy subjects receiving vancomycin 1000 mg in 200 ml dextrose 5% in water infused over 1 hour. Subjects received either oral hydroxyzine 50 mg, oral ranitidine 300 mg, oral hydroxyzine and ranitidine, or a placebo two hours prior to the infusion. There was a seven day washout interval between each regimen. The incidence of RMS in unprotected subjects was 92%. Only one in 12 subjects experienced pruritus or erythema after pretreatment with hydroxyzine (an H1 antagonist). Addition of an H2 antagonist demonstrated no real advantage.

Extending the infusion time for doses ³ 1000 mg may also be a relatively effective preventative approach. In a double-blind, two-way, cross-over study that included ten healthy volunteers, eight of the subjects had evidence of RMS during one-hour infusions as compared with only three of the subjects experiencing mild symptoms with a two-hour infusion.8 These investigators also concluded that differences in one-hour postinfusion and 12-hour postinfusion drug concentrations were not appreciable between the one-hour and two-hour infusions.

There are limitations that must be recognized in these studies. Each included very small sample sizes. Also the subjects were healthy volunteers. As discussed by Polk et al, 6 bacterial antigens have been reported to release histamines from basophils in vitro. If this reaction also occurs in vivo, a blunted histamine response might be expected in patients with infections who are receiving vancomycin. End organ sensitivity may vary between infected patients and healthy subjects. Therefore, the incidence and severity of RMS may have been greatly exaggerated in healthy volunteers.

Despite their shortening, these studies6-8 suggest that reduction in the incidence or severity of RMS may be approached in several ways: using a dosing regiment of vancomycin 500 mg every six hours whenever possible (instead of 1000 mg doses every 12 hours),9 administration of an antihistamine as a pretreatment, or increasing infusion duration to as much as two hours.8

However, these recommendations cannot be carried out in all patients. A 500 mg dose of vancomycin every six hours may not be feasible in some patient groups. Therapeutic peak and acceptable trough serum drug levels are not always attainable with this dosing regimen, especially in renally compromised patients.

Possible changes in the pharmacokinetic profile of vancomycin due to prolonged infusion times must be assessed. Although one study8 suggested minimal variation in the serum vancomycin levels between one-hour and two-hour infusion times, the multicompartment distribution of the drug must be taken into account. Different infusion times must be recognized when comparing drug levels. The added difficulty of a two-hour infusion in the severely ill patient with many other intravenous medications must also be addressed.

The proposed use of antihistamine pretreatment raises the question of what patient groups are candidates for pretreatment. The actual incidence of RMS in treated patients is difficult to assess as it is generally believed that many patients who experience mild symptoms are never recognized as suffering an adverse reaction.6 Since there are no harbingers of patients likely to experience this adverse reaction, and no way to predict severity, across-the-board use of antihistamines would have to be adopted. This approach may be extreme, but certainly patients experiencing an adverse reaction in the past could routinely be premedicated with antihistamines.

The present recommendation at UIHC for vancomycin infusions consists of a 60-minute infusion time for vancomycin doses of 1000 mg or less. A 1000 mg dose is routinely placed in a 250 ml bag of dextrose 5% for peripheral vein infusions. A dose larger than 1000 mg should be infused over 90 minutes. Stricter adherence to these guidelines may decrease the incidence of RMS at UIHC. Patients who have had a past adverse response to vancomycin might benefit from antihistamine pretreatment or the lengthening of the infusion time to two hours.

References
1. Anesthesiology 1987;67:122-5.
2. Ann Intern Med 1979;91:581.
3. Ann Intern Med 1986;104:285-6.
4. N Engl J Med 1985;313:756-7.
5. Ann Intern Med 1991;115:401-11.
6. J Infect Dis 1988;157:502-7.
7. J Infect Dis 1989;160:876-80.
8. Antimicrob Agents Chemother 1990;34:550-4.
9. Antimicrob Agents Chemother 1987;31:393-7.
10. Pediatrics 1990;86:572-80.
11. J Infect Dis 1993;168:773-6.
12. J Infect Dis 1991;164:1180-5.

The Drug Use Evaluation Program is coordinated by the Drug Use Evaluation Subcommittee. Each Clinical Service is represented on the Subcommittee, as are representatives from Nursing, Pharmacy, and the Quality Assessment Support Service.

The drug use evaluation process includes the review of high-risk, high-use drugs, in addition to drugs whose cost-benefit is unclear. Drugs are selected for review by the DUE Subcommittee. Criteria development involves participation by each Clinical Service with subsequent approval by the Pharmacy and Therapeutics Subcommittee. Once criteria are approved, data are gathered and analyzed by clinical pharmacists in conjunction with the Medical Staff. Summary results are communicated to each Clinical Service through their respective DUE physician representative.

The DUE Program encourages input from the clinical faculty, housestaff, and other healthcare practitioners on drug selection and methods for improving patient care through systematic review of drug therapy.

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