Monitoring and -M anaging Adverse Drug Reactions by Jack E. Fincham, PhD
Introduction Adverse drug reactions (ADRs) are any noxious and unintended responses to medication that occur at doses used in humans for prophylaxis, diagnosis, or therapy.1 These reactions place a tremendous therapeutic and economic burden on the U.S. health care system. Studies of ambulatory patients indicate that approximately 20% of the population have ADRs. 2 Many of these reactions result in hospitaliza-
CE Credit
CE Credit: To obtain two (2) hours of continuing education credit for completing "Monitoring and Managing Adverse Drug Reactions," complete the assessment exercise and CE registration form and return it to APhA A certificate will be awarded upon achieving a passing grade of 70% or better. Pharmacists successfully completing this article within two years of date of issue can receive credit.
Iffi l PC
The American Phanna-
ceutical Association is approved by the American Council on Phannaceutical Education as a proVider of continuing pharmaceutical education. ~
APhA provider number:
\gI 680-202-92-002
The author of this article is Jack E. Fincham, PhD, professor and associate dean, Creighton University School of Pharmacy and Allied Health, Omaha, Nebr.
AMERICAN PHARMACY
"Monitoring and Managing Adverse Drug Reactions," is a self-study continuing education program appearing in American Pharmacy for pharmacists, developed by the American Pharmaceutical Association. Objectives: After reading this continuing education article, the pharmacist should be able to: 1. Explain the pharmacist's role in monitoring and managing adverse drug reactions (ADRs). 2. List four ADRs that require patient referral to a physician. 3. Delineate the roles of the Food and Drug Administration and the JOint Commission on the Accreditation of Healthcare Organizations in monitoring and reporting ADRs. 4. Describe how to manage three common ADRs. 5. Understand the importance of ADR reporting after a drug has been released on the market.
tion, although the exact number is uncertain. Several widely quoted studies indicate that 3% to 5% of hospital admissions result froin ADRs and that these admissions cost $3 billion per year. 3,4 Studies of institutionalized patients have indicated that up to 28% of patients have an ADR while hospitalized. s This article reviews the monitoring and management of ADRs by pharmacists. Because of their unique position in the health care system, pharmacists often see the first indication that a patient has had an ADR. Upon recognizing the possibility of an ADR, the pharmacist must first help resolve the reaction and then determine how to best use this information. Verifying that an ADR has occurred may be complicated by multiple drug regimens, improper drug administration, or lack of conclusive evidence that a drug or drugs are the cause of the reaction.
Monitoring Adverse Drug Reactions All health care professionals should monitor for ADRs on an ongoing basis. In the ambulatory setting, pharmacists monitor for ADRs as they monitor their patients' drug therapy. Through counseling and continual patient assessment, pharmacists can observe changes in a patient's response to drug therapy that may indicate the occurrence of an ADR. In the hospital, pharmacists have less direct patient contact and may need to rely on nurses and physicians to aid in ADR monitoring. Stat. orders for certain drugs may indicate that an ADR may have occurred in an institutionalized patient (Table 1). Through monitoring and follow-up of patients who received these medications, pharmacists can meet the requirements of the Joint Commission on the Accreditation of Healthcare Organizations 0CAHO) for ADR monitoring. 4 This monitoring can be initiated through computer-generated reports, manual screening, or an alerting process when the drugs are ordered from the hospital pharFebruary 1992/166 Vol. NS32, No.2
macy. Also, several unusual events occurring during the drug administration process can indicate an AD R (listed in Table 2). In the hospital setting, an ADR should be suspected when drugs are abruptly discontinued or when maintenance drugs recently ordered are not being administered. The Food and Drug Administration (FDA) is the primary organization involved in. monitoring and reporting ADRs. A system sponsored by FDA for voluntary reporting of ADRs by U.S. health professionals has been in place for approximately two decades. The principle objective of the monitoring system provides the FDA regulatory division with information about adverse effects of drugs after they have been released on the market. 6 This information can provide an early warning of unsuspected ADRs and can yield important clues for use in controlled studies. Product labeling can then be altered to reflect ADRs caused by the drug. Table 1
Drugs Ordered ·Stat.' That May Indicate the Occurrence of an ADR Atropine Benztropine Corticosteroids Dextrose Diphenhydramine Epinephrine Naloxone Phenytoin Phytonadione Protamine Sodium polystyrene sulfonate
Table 2
Indicators of Potential ADRs in Institutional Practice Abrupt discontinuance of a maintenance medication Discontinuance of an antibiotic after one or two administered doses Return of medicatioh carts with unadministered drugl) not pre,. scribed for use lias needed" Return of intravenous piggybacks Or larg'e volume parenterals '
Vol. NS32, No.2 February 1992/167
Reporting Adverse Drug Reactions Role of the Food and Drug Administration Suspected ADRs are reported to the FDA on Form FDA 1639 (Figure 1) for drugs and biologics (e.g., insulin or erythropoietin). (Vaccines are not considered a drug or biologic product, and adverse reactions occurring with these agents should be reported on Form FDA VAERS-l.) Form FDA 1639 has 26 items, which allow the reporter of the ADR to provide as much information as possible about the reaction. Manufacturers notified of ADRs are required to file a report using the form. Item 26 is included on the manufacturer's form to ensure that duplication of reported information does not occur. Recently, it has been suggested that both FDA and manufacturers be notified of ADRsJ This is the prerogative of the reporting individual. Whether the reaction has been reported to the manufacturer should be noted on the forms (item 26c). Pharmaceutical manufacturers must report reactions within 15 days of notification of company personnel by a health professional. FDA must hold the identity of the reporter of the ADR and patient involved in strictest confidence. In addition, the reporter can remain anonymous if he or she feels hesitant about completing the initial reporter section. Form FDA 1639 can be obtained from the Division of Epidemiology and Surveillance of the FDA at the following telephone number: (301) 443-4580. The form is also reprinted in the Physicians ' Desk Reference and in The FDA Medical Bulletin, which is mailed to various health professionals. Blank forms may also be photocopied and used in lieu of a form obtained from other sources. In various practice settings, the pharmacist may need to consult with a physician if not all the information required for Form FDA 1639 is available. Pharmacists practicing in hospitals or nursing homes will have access to laboratory values or findings that may be useful to include on the form under item 13. Although not all information will always be available to fill out the form, an incomplete filing is better than none at all. Because assigning a particular ADR to a specific drug is often difficult, pharmacists should not get stymied when trying to ascertain whether a drug caused an ADR. FDA determines whether a drug caused an ADR by using epidemiologic methods to examine the actual drug usage (denominator data) and by looking at all reactions for a particular drug in the aggregate (numerator data). If a drug is discontinued after a reaction occurs and if the reaction recurs when therapy is resumed, then the probability of the drug having caused the reaction increases. The system for voluntary reporting of ADRs in the United States may be inadequate, and the reactions reported to AMERICAN PHARMACY
Figure 1.
Form FDA 1639 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRA TlON (HFN · 730) ROCKVILLE . MD 20857
Form Approved OMB No. 09 '0 ·0230. FDA CON TRO L NO
ADVERSE REACTION REPORT
A CC ESS ION NO
(Drugs and Biologics)
)
REACTION INFORMA TlON
I. 2 AGE YRS
1 PATIENT ID/INITIALS (In Confidence)
3 SEX
4 ·6
11 J J j 1 I I I I I
REACTION ONSET
I
MO
0'
8 . · 12
1
1
CHECK ALL APPROPRIA TE :
"
0 0 0
7. DESCRIBE REACTION (S)
13 RELEVANT TESTS /LABORA TORY DATA
PATIENT DIED REACTION TREATED W ITH Rx DRUG RESULTED IN, OR PROLONGED, INPATIENT HOSPITALIZA TION
0
RESULTED IN PERMANENT DISABILITY
0
NONE OF THE ABOVE
SUSPECT DRUG(S) INFORMA TlON
II .
20 DID REACTION ABATE AFTER STOPPING DRUG ?
14. SUSPECT DR UG(S) (Give manufacturer and lot no. for vaccines/biologics)
D
1 16 RO U TE OF ADM INISTRAT ION
15 . DAILY DOSE
21 17 . INDICA TlON (S) FOR USE
18 . DATES O F ADM INIST RAT IO N (FromlTo)
J
19 DURAT ION OF ADMINISTRAT ION
D
YES
0
NO
0
NA
DID REACTION REAP PEAR AFTER REINTRODUCTIONJ
YES
0
NO
0
NA
CONCOMITANT DRUGS AND HISTORY III. 22. CONCOMITAN T D RU GS AND DA TES OF ADM INISTRA TION (Exclude those used to treat reaction)
23 . OTHER RELE VANT HISTORY (e .g. diagnoses. allergies. pregnancy with LMP. etc)
IV.
ONLY FOR REPORTS SUBMITTED BY MANUFACTURER
INITIAL REPORTER (In con fide nce)
V.
24 . NAME AND ADDRESS OF MANUFACTURER (Include Zip Code)
26 · 26a NAME AND ADDRESS OF REPORTER (Include Zip Code)
24a . IND/ NDA . NO FOR SUSPECT DRUG
26b TELEP HONE NO (Include area code)
24c. DATE RECE IVED BY MANUFACTURER
25 D
15 DAY REPORT' YES
o
j2 4b MFR CONTROL NO
24d REPORT SO U RCE (Check all that apply)
o
D
FORE IGN
ST U Dy O
LITERATU RE
O
HEALTH PROFESS IO NA _ OCONS U MER 25a REPOR T TY PE
NO
o
INIT IA L
0
26c HAV E YOU ALSO REPORTED THIS REACT ION TO THE MANUFACTUR ER ?
0
YES
O
NO
26d ARE YOU A HEAL TH PROFESS IONAL' FOLO W l; P
0
YES
o
NO
NOTE : Required of manufacturers by 21 CFR 314 .80 FORM FDA 1639 (7186)
Submission of a report does no t necessa r i ) y const itute an adm issi o n that the drug caused t he adverse react ion
PRE VIOU S EDIT ION MA Y 3E USED l1U.S. GOVERNMENT PR INTING OFFIC E
AMERICAN PHARMACY
199 1
1302/29026
February 1992/ 168 Vol. NS32, No. 2
FDA may be only a small fraction of actual reactions occurring with marketed drugs.
Figure 2
FDA Reporting Guidelines for Adverse Drug Reactions
Reporting in the Institutional Setting The ]CAHO accredits institutions based on their adherence to established standards and criteria. One criterion for drug therapy involves monitoring ADRs within the institution on a concurrent basis to benefit the patient with the ADR, as well as future patients at risk for the ADR. The ]CAHO guidelines mandate concurrent review of ADRs in institutions but do not require external reporting to FDA.8 The ] CAHO does not define what an ADR is, but leaves that determination up to the individual facility. Pharmacists practicing in hospitals and nursing homes can help to ensure proper drug use by monitoring and reporting ADRs. Guidelines for reporting ADRs can be found in Figure 2. Institutional monitoring and reporting of ADRs can help provide more information about the side-effect profile of marketed drugs. 9 However, each hospital system for monitoring ADRs allows little opportunity for sharing information with other facilities. Reported information must be shared outside the institution. Although the reporting system is in place, health professionals in the hospital setting seldom use it. In some cases, health professionals are unaware of the reporting system, and in others, it may not be clear who should report ADRs. In the institutional setting, the person ultimately responsible for reporting an ADR-physicians, nurses, pharmacists, or committees such as the Pharmacy and Therapeutics (P&D Committee- should be established. A well-defined process for reporting ADRs should be in place regardless of practice site. Reporting ADRs to FDA can help prevent occurrences in patients in other facilities. Assessment of cases from many reports can reveal patterns of subpopulations at risk for ADRs when taking certain drugs, and product labeling can be changed. Also, the identification of sub populations at risk allows for prospective avoidance of ADRs in patients with similar demographic or clinical profiles. Traditionally, ADRs occurring in hospitals and nursing home patients have been rarely reported by the institutionsJO,ll The need for monitoring and reporting ADRs in nursing homes is especially important because the elderly are susceptible to ADRs. For example, drug interactions may occur more often because multiple medications are administered. 12 Researchers in one study showed that more than 750/0 of ADRs in three nursing home populations were due to digitalis glycosides, antipsychotics, sedatives, hypnotics, diuretics, and anti-inflammatory agents. 13 The risk for ADRs rises as the number of medications consumed increases. George and Twomey14 reported that ADRs occurred at a rate of 60/ 0 when one to three drugs were administered concurrently and at a rate of 520/0 when VoL NS32, No.2 February 1992/169
The reaction is unexpected basep on the package insert infor~ mation and your clinical experience. The reaction is serious, e.g., requires hdspitalization, ~mer gency room oare, or other special treatment; or the re~actlon results in a patient f~tality. Serious reactions should be reported aven 'if they are expeoted, such reports are useful to identify patient characteristics that may pose inoreased risks. Particular vigilance should be maintained for newly marketed drugs and specific groups of patients, such as children, pregnant women, and th~ elderly. Submission of a report to FDA does not necessarily constitute proof or admission the drug caused the ADR; it is a suspicion only.
more than eight drugs were. Also, elderly patients who previously had ADRs are more likely to have recurrent reactions. 1S Although the reasons for this phenomenon remain unclear,16 the ramifications are not, because drug-induced illness is an important cause of hospitalization among the elderly, and a resultant effect is the need to admit residents of long-term-care facilities to hospitals. 17 The importance of pharmacist involvement in ADR monitoring cannot be overemphasized. 18 In a study of the impact of chart reviews, pharmacist drug-regimen reviews pinpointing ADRs were shown to decrease hospitalization in 68 of 517 patients in long-term-care facilities~ 19
Deciding What Reactions to Report Simple or well-known minor ADRs (e.g., nausea with nonsteroidal anti-inflammatory drug therapy, drowsiness with sedating antihistamines) need not be reported to FDA. However, unique reactions with drugs that have been on the market a long time should be reported (e.g., heparin-induced thrombocytopenia). Serious reactions to any drugs should be reported, regardless of the length of time the drug has been on the market. Reactions occurring with a newly released drug should be reported, especially if the reaction does not appear in the package insert (official labeling). Because of the AMERICAN PHARMACY
number of ADR reports they receive, hospital pharmacists must recognize the need to report ADRs externally.11 Nursing-home consultant or provider pharmacists can help monitor and report ADRs in their facilities. Simple reliance on other health professionals to report ADRs will not optimally benefit the patients in nursing homes, or those patients receiving similar regin1ens elsewhere.
Management of Adverse Drug Reactions Adverse drug reactions not only have to be monitored and reported; but they also have to be treated. Those cases that the pharmacist cannot handle require physician referral. Self-limiting ADRs include hives, itching, rashes, dizziness, headaches, swelling, mild shortness of breath, and similar allergic responses. Other reactions, such as anaphylaxis or respiratory depression, are medical emergencies and require immediate attention.
Ambulatory Pharmacy Practice Because pharmacists in community or chain pharmacy practice generally have more contact with patients than institutional pharmacists, they are more involved in managing ADRs in patients. The following list of types of reactions and subsequent actions by the pharmacist show how reactions can be managed in the outpatient or ambulatory setting. These ADRs are simply examples; actual reactions often happen in an atypical or idiosyncratic manner. Reaction is drug dependent. If the reaction occurs soon after dosing and is a minor reaction (e.g., nausea occurring after taking ibuprofen), a minor modification in drug administration may alleviate the situation without a need for further action (e.g., taking the drug with food). On the other hand, if severe nausea or vomiting occurs along with black tarry stools, the patient should be referred to his or her physician imn1ediately. Reaction appears to be dosing-interval dependent. If the reaction is a normal response to the drug but happens at inopportune times, the dosing time(s) could be changed with the prescriber's approval to diminish the reaction. For example, if nocturnal diuresis occurs after taking furosemide in the evening, the furosemide could be taken earlier in the afternoon. Reaction is severe and unexpected. If the reaction is severe (e.g., anaphylaxis after administration of penicillin, bullous dermatitis after administration of piroxicam), the drug should be discontinued immediately and the patient should be referred for emergency medical treatment without delay. Reaction is an exaggeration of the drug's expected AMERICANPHARMACY
response. If the reaction is an extension of the dru g's expected pharmacologic action (e.g., daytime sedation after taking flurazepam the previous evening), the patient may respond more appropriately with a smaller dose, or an alternative drug may be more suitable (e.g., in this case, use of triazolam because of its shorter half-life). Reaction may be due to one of many drugs a patient is taking. If the patient sees several physicians, and one drug is suspected of causing the reaction from all the drugs taken (e.g., severe and systemic response to cycloplegic ophthalmic drops), all of the prescribing physicians should be notified. The patient should stop taking the suspected drug until the prescriber(s) agree on an alternative. Reaction occurs after rechallenge with the drug. If the same reaction occurs after discontinuation and resumption of the drug therapy, the reaction can usually be attributed to that particular drug. Permanent discontinuation of the drug is called for after consultation with the prescribing physician, and a suitable alternate therapy should be found. Reaction occurs with a different but chemically related drug from the same therapeutic class. If the patient has had an adverse effect with a different drug from the saIne class of drugs from which a newly prescribed drug is derived (peptic ulcer disease after previous therapy with a nonsteroidal anti-inflammatory drug) , it would be inappropriate to initiate therapy with a different but similar drug (e.g., another nonsteroidal anti-inflammatory agent). Reaction occurs but does not require drug discontinuation. For example, hypotension, pedal edeIna, flushing, or dizziness often occur after administration of numerous antihypertensive medications such as nifedipine. 2o None of these effects would necessarily require discontinuation of the drug. In fact, the side effects may decrease after time without an attendant decrease in the drug's desired effect. In this case, the patient should be told to rise slowly fron1 a chair or from bed and always look for something sturdy to hold on to when rising. Also, the patient may need to wear larger shoes or less restrictive hose or socks until the pedal eden1a decreases. The patient should be told that flushing and dizziness are recognized effects of the drug that mayor may not diminish over time. ADRs may be associated with specific organ systen1s (Table 3); no organ system is immune from the effects of ADRs . The pharmacists ' actions suggested in Table 3 depend on the severity, intensity, and physiologic location of the reaction in question. Pharmacists should counsel patients to help them differentiate those reactions that are minor annoyances from those that require further care. Patients should be questioned to detennine if they have sought care from other sources, and their physician should be notified if the ADR is severe. Many reactions can be managed by the pharmacist working with the patient without being referred to a physician. February 1992/ 17 0 VoL NS32, No. 2
For example, patients with contact dermatitis caused by transdermal drug delivery systems may need to simply rotate the application site for the patch placement, or perhaps after consultation with the prescribing physician, replace the patch sooner than the recommend ed interval (every 5 days as opposed to 7 days). Drugs with s ignific an t anticholinergic activity (antihistamines, a n x io l ytics, hypertensive agents, and tricyclic antidepressants) often ca use dry n10uth, wh ich may be perceived as an ADR. These agents probably do not have to be discontinued, but the effects of the dry mouth need to be handled. Alcohol-containing 1110uthwashes that enhance th e dryness should be avoided, and cigarette smoking shou ld be reduced. Sucking on sugar-free lozenges or chewing sugarfree gUln n1ay help to alleviate the dryness. Also, the patient can take frequent sips of water to help the condition. Focusing on only Inental status changes as an exan1ple of ADRs, Berlinger and Spector have noted that offending drugs include psychoactive drugs, anticholinergics, benzo di azepines, levodopa, methyldopa, reserpine, digitalis glycosides, cilnetidine, diuretics, and insulin.1 7 Other researchers have noted the daytilne cany-over effects of b enzodiazepines,21 anticholinergic toxicity, 22 and central nervous system toxicity due to antihypertensive therapy.23 Potential ADRs may be avoided or their intensity diminished by lowVol. NS32, No .2 February 1992/171
Table 3.
Guidelines for Pharmacist Management of Organ System ADRs Actions Needed
Effects
Central Nervous System Requiring reassurance of patient
Anxiety and depression (unless severe)
Requiring dosing time change
Drowsiness or fatigue (possibly begin to administer the drug at bedtime), insomnia (administer drug earlier in the day)
Requiring discontinqation and referral to physician
Extrapyramidal effects, hallucinations or nightmares, headache, hyperactivity, pa in, tinnitus, and vertigo
Cardiovascular Requiring physician referral
Angina, arrhythmia, hypertension, hypotension, irregular pulse, palpitations, and syncope
Dermatologic Requiring reassurance of patient, treatment with nonprescription agents
Rash, itch, hives (if reaction progresses to involve respiration emergency treatment is urgent), and perspiration
Requiring referral to physician
Alopecia, bruising, flushing, and ecchymoses
Gastrointestinal Requiring reassurance of patient, treatment with nonprescription agents (antacids, antidiarrheals, laxatives- dependent on symptoms)
Constipation, diarrhea, dry mouth (treat with lozenges, ice chips), flatulence, indigestion, nausea, and vomiting
Requiring discontinuation and physician referral
Black tarry stools; hematemesis
Genitf?urinary Requiring discontinuation and physician referral
Anuria, difficulty voiding, and hematuria
Musculoskeletal Requiring reassurance of patient, treatment with nonprescription analgesics
Arthralgia and myalgia
Respiratory Requiring reassurance of patient and treatment with nonprescription agents
Nasal congestion and rhinitis
Requiring discontinuation and physician referral
Bronchospasm, labored breathing, and respiratory depression
Sensory Requiring reassurance of patient
Altered taste
Requiring discontinuation and physician referral
Auditory or visual disturbances
Other Requiring discontinuation and physician referral
Fever and superinfection
AMERICAN PHARMACY
ering doses of certain drugs (psychotropics, diuretics, and antihistamines). If doses can be altered without loss of therapeutic efficacy, this should be recommended to the physician as a method of reducing the severity of the ADR. Finally, patients need to be informed of the intended action of all drugs disp ensed to them. Counseling the patient on potential drug action and effect can lessen the impact of an ADR. Not all reactions can be avoided, but th~ informed patient will be better prepared to give the phannacist feedback when unanticipated effects occur. Not every side-effect profile of every drug must be sh are d with patients. However, because more and more lay sources of information are available to patients, the phannacist should be prepared to counsel patients on drug effects.
Institutional Practice The treatn1ent of ADRs in institutions is handled through nursing, pharmacy, and medical intervention. Pharmacists may be consulted about suggested treatments for patients with ADRs. Also, protocols may be in place to deal w ith emergency requirements in the institutional setting. Phannacists can document the occurrence of ADRs and alert the medical, nursing, and administrative staffs through the P&T comlnittee in hospitals and the pharmaceutical services committee in nursing hon1es of significant ADRs in the institution , to avert similar ADRs that are preventable on a prospective basis. Certainly, not every ADR can be prevented, but some can be avoided through appropriate documentation and cautious use of certain drugs. Probably the most crucial concern for hospital pharmacists is the establishment of a systematic review process for ADR surveillance. Several models of programs are described in the literature. 24 Successful programs are multidisciplinary in nature and thus involve pharmacy, nursing, and medical staffs as well as the hospital administration through quality assurance or quality review components. The focal point for dissemination of reports is the pham1acy and therapeutic (P&T) committee. Because of their prominent role in P&T committee functioning, pharmacists can see that the infonnation presented to the P&T committee is dispersed throughout the hospital, and thus help to ensure appropriate and knowledgeable use of drugs within the facility. This is one of the objectives of ]CAHO's "full circle" concept, i.e. , infonnation obtained through prospective monitoring should be brought back to the appropriate medical, nursing, or phannacy staff for review. Educational interventions should be instituted, and through this process, steps taken to prevent future ADRs. Long-term-care phannacists need to recognize the need to document and report the occurrence of ADRs to assist in establishing a more complete side-effect profile for each medication. Because the elderly are often excluded from clinical trials,9 ADRs in this group should be reported exterAMERICAN PHARMACY
nally to allow the elderly in other facilities, as well as the alnbulatory elderly, to benefit from the information gained.
Conclusion Pharn1acists should not be overly concerned about assessing the cause of ADRs, but should do what is necessary to help the patient manage the sequelae of the reaction. Calm and understanding treatment of the patient by the phannacist can help the patient understand how to deal with the ADR. Referral to a physician or an emergency care center is ilnportant when the reaction requires immediate attention. Phannacists, regardless of practice setting, have a significant and necessary role to play in managing and monitoring ADRs. Enhanced efforts by pharmacists will help patients and thus society cope with unexpected ADRs. Through an enhanced level of activity in ADR n1anagement and monitoring, all involved in the use of drugs w ill benefit through more appropriate drug use.
References' 1. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacal Ther. 1977;21 :247-54. 2. Wood AJ, Oates JA. Adverse reactions to drugs. In: Petersdorf R, Adams R, Braunwald E, et ai, eds. Harrison's Principles of Internal Medicine, 10th ed. New York: McGraw-Hili; 1987:402-9. 3. Lakshmann MC, Hershe CO, Breslau D. Hospital admissions caused by iatrogenic disease. Arch Intern Med. 1986;146:1931 - 4. 4. Melmon KL. Preventable drug reactions-causes and cures. N Engl J Med. 1971;284:1361 - 8. 5. Miller RR. Drug surveillance utilizing epidemiologic methods. Am J Hasp Pharm. 1973;30:584- 92. 6. Pearson KC, Kennedy DL. Adverse drug reactions and the Food and Drug Administration. J Pharm Prac. 1989:2(4):209- 13. 7. Sullivan JW. A pharmaceutical manufacturer's perspective on reporting adverse drug experiences. Am J Hasp Pharm. 1990;47:1342-5. 8. AMH/91 Accreditation Manual for Hospitals, vol 1. Standards Joint Commission on Accreditation of Healthcare Organizations Accreditation Manual. Chicago: JCAHO. 1991, H-91 . 9. Slone D, Shapiro S, Miettinen 0, et al. Drug education after marketing. Ann Intern Med. 1979;90:257- 61. 10. Fincham JE, Garner DD, Brown TR. Occurrence and reporting of adverse drug reactions in Mississippi nursing homes. Consult Pharm. 1988;3:267-70. 11. Fincham JE. Hospital and nursing home pharmacists' attitudes toward adverse drug reaction reporting. J Soc Admin Pharm. 1990:7(3):117-22. 12. Ramsey LE, Tucker GT. Clinical pharmacology: drugs and the elderly. Br Med J. 1981;1:125--7. 13. Sbon JA. Assessment of an adverse drug reactions monitoring program in nursing homes. Can J Hasp Pharm. 1985;38:120-5. 14. George J, Twomey JA. Causes of polyneuropathy in the elderly. Age Ageing. 1986;15:241-6. 15. Jue SG. Adverse drug reactions in the elderly. In: Vestal RE, ed. Drug treatment in the elderly. Boston: Adis Health Science Press;1984:29-42. 16. Budden F. Adverse drug reactions in long-term care facility residents. J Am Geriatr Soc. 1985;33:449- 50. 17. Berlinger WG, Spector R. Adverse drug reactions in the elderly. Geriatrics. 1984;39(5):45--58. 18. Burkholder DF. Adverse drug effects and their impact on patient care. Drug Inte" Clin Pharm. 1979;13:421-4.
February 1992/172 Vol. NS32, No.2
19. Kidder SW. The cost benefit of drug review s in long-term care facilities. Am Pharm. 1982;NS22:399- 401.
7.
Which of the fo llowing is true? a. ] CAHO has criteria in place dealing with the monitoring of ADRs in hospitals. b. ] CAHO requires hospitals to submit ADR repons to FDA. c. ] CAHO has no criteria relating to ADRs in the hospital setting. d. All of the above are true. e. None of the above are true.
8.
One tangible be nefit of FDA's voluntary ADR reporting program is that da ta collected can be used to update product labeling. a. True b. False
9.
Adverse drug reactions that occur in nursing ho mes should be reponed because of which of the following? a. The e lderly are susceptible to ADRs for several reasons. b. Drug inte ractions may occur due to multiple drug regimens used to treat illness in the elderly. c. Elderly patients who previously had ADRs are more likely to have reactions again. d. All of the above. e. None of the above.
20. Piepho RW. Culbertson VL. Rhodes RS. Drug interactions with the calcium entry blockers. Circulation. 1987;75:V-181-V-194. 21 . Carskadon MAo Seidel WF. Greenblatt DJ. et al. Daytime carryover of triazolam and temazepam in elderly insomniacs. Sleep. 1982;5(4)361 - 71 . 22. Blazer DG. Federspiel CF. Ray WA. et al. The risk of anticholinergic toxicity in the elderly: a study of prescribing practices in two populations. J Gerontal. 1983;38( 1):31 - 5. 23. Hale WE. Stewart RB. Marks RG . Central nervous system symptoms of elderly subjects using antihypertensive drugs. JAm Geriatr Soc. 1984;32(1 ): 5-10. 24. Prosser TR. Kamysz PL. Multidisciplinary adverse drug reaction surveillance program. Am J Hasp Pharm. 1990;47:1334-9.
AssesslTlent Questions
1.
Pharmaceutical manufacturers must re port ADRs to FDA within 30 days of notification of company personnel by a health professional. a. True b. False
2.
Which of the fo llowing statements regarding FDA vo luntaIY ADR reporting program is true? a. Because ADR repo rting by health professio nals is so thorough, FDA receives repo ns of vinually all ADRs in the United States. b. Every item o n Form FDA 1639 must be completed. c. Because ADR reponing is inadequate, pharmacists need to become more involved. d. All of the above are true. e. None of the above are true.
3.
4.
5.
6.
In which of the following types of reactio ns is FDA most interested? a. Serious reactions occurring with newly marketed drugs. b. Minor reactio ns occurring with drugs that have been on the market for a long period of time. c. Reactions that occur with a drug that has been o n the market for a long period of time and that are documented in the package labeling, e.g., nausea and vomiting. d. All of the above are true. e . None of the above are true. Which of the following stat. orders for a drug in a hospital setting may indicate an ADR with the orde red drug being used to reverse o r slow the reaction? a. Docusate b. Epinephrine c. Terfenadine d. Milk of magnesia e . All of the above Which of the following does not indicate a potential ADR in institutional practice? a. Return of medication cans with prn drugs unadministered b. Discontinuation of an antibiotic after one or two administered doses c. Abrupt discontinuation of a maintenance medication d. Return of intravenous piggybacks or large-volume parenterals e. Laboratory values indicative of he matologic d isturbances Which of the following statements is correct? a. FDA maintains a compulsory ADR reponing program for health profeSSionals. b. Pharmaceutical manufacturers are not required to submit reponed ADRs after their notification. c. ADRs occurring in hospitals must be reponed to FDA. d. All of the above are correct. e. None of the above is correct.
Vol. NS32, No. 2 February 1992/ 173
10. Researchers have determined in one study that more than 75% of ADRs in three nursing home populations were due to digitalis glycosides, anti psychotics, sedatives, hypnotics, diuretics, and anti-inflammatory agents. a. True b. False 11. Research indicates that ADR occurrence decreases as the number of med ications consumed increases. a. True b. False 12. LaboratOIY values indicating elevated levels of which of the following ma y indicate the pote ntial for occurrence of an ADR? a. Digoxin b. Theophylline c. PhenytOin d. Aminoglycosides e . All of the above 13. Adverse drug reactions that are usually self-limiting include all of the following except: a. Hives b. Itching c. Rashes d. Respiratory depression e. Dizziness 14. In genera l, pharmacists in community o r chain pharmacy p ractice have more contact w ith patients tha n institutional phannacists, and as such have broader levels of concerns to deal with when patients have ADRs. a. True b. False 15. Concerning pharmaCist involvement in the management of ADRs in the ambulatory setting, which of the following is true? a. Pharmacists should counsel patients to allow them to differentiate those reactions that are minor annoyances from those that require funher care. b. Many reactions can be dealt with by the pharmacist working with the patient, and some patients need not be referred to physicians. c. The physician should be notified when patients have severe ADRs. d. All of the above. e. Both a and b are correct.
AMERICAN PHARMACY
16. Patients prescribed drugs with significant anticholinergic activity leading to dry mouth should be counseled to do which of the following? a. Use alcohol-containing mouthwashes in place of nonalcoholic-based mouthwashes. b . Suck on sugar-free lozenges. c. Chew sugar-free gum. d. All of the above. e. Both band c. 17. Which of the following reactions would not necessitate discontinuation of a drug? a. Anaphylaxis after administration of penicillin b. Bullous dermatitis after administration of a nonsteroidal anti-inflammatolY drug. c. Reaction occurs upon rechallenge with the drug in question d. Reaction does not recur upon rechallenge with the drug in question e. All of the above 18. Pharmacists should be concerned about assessing the absolute cause of ADRs before submitting reports to FDA. a. True b. False 19. The logical department for distributing the findings of ADRs in the hospital setting is: a. The nursing staff b . The pharmacy staff c. The medical staff d. The administration e. None of the above. 20. Which of the following cardiovascular ADRs requires referral to the prescribing physician or other suitable sources of treatment? a. Angina b. Arrhythmias c. Palpitations d. Syncope e . All of the above
Instructions Monitoring and Managing Adverse Drug Reactions
To receive two (2) hours of continuing education credit, or 0.2 CEUs, for the successful completion of this program , you must: 1. Type or print your name, address, and Social Security number in the space provided in the boxed area below. 2. Mail your completed answer sheet for scoring to :
Processing Desk/ Edu cation An1erican Pharmaceutical Association 22 15 Constitution Ave., NW Washington, DC 20037 3. Enclose handling fee ($5.00 for APhA members; $15.00 for
no nmembers; 12-month CE program enrollees are exempt from this fee) for grading the assessme nt instrument and for issuing the certificate . Certificates w ill be iss ued upon successful completion of the assessment exercise (70% or better). If you do not achieve 70% or better, no credit will be recorded , and you will be notified . Please allow f our weeks f or processing. Each exercise must be submitted within two years after the date of issue. Answer Sheet
5.
0 0 0 0 0
6.
0
7.
0 0 0 0
1. 2. 3. 4.
8. 9. 10.
R In an emergency your Medic Alert --- X emblem triggers access to your
computerized medical record 24 hours a day,
wherever you are i:~~
I
fHdU~: _AL,ER.t,
l~lgOo~
~d4~f MedicAlert® AMERICAN PHARMACY
® ® ® ® ® ® ® ® ® ®
© © © © © © © © © ©
@ @ @ @ @ @ @ @ @ @
® ® ® ® ® ® ® ® ® ®
11 .
0
12.
0
13.
0
14.
0 0
15.
19.
0 0 0 0
20.
0
16. 17. 18.
® ® ® ® ® ® ® ® ® ®
© © © © © © © © © ©
@
@
® ® ® ® ® ® ®
@
®
@
® ®
@ @ @ @ @
@
Monitoring and Managing Adverse Drug Reactions APhA provider number for this program is: 680-202-92-002
o o o
Make paY111ents to APhA: $5 fee enclosed (member rate) $15 fee enclosed (nonmember rate) $45 annual continuing education program fee already paid
Name __________________________________________ Address _________________________________________ City _____________________ State Social Security
ZIP __________
# _____________________________
Program Evaluation Please rate this program for: Overall Quality Excellent Fair Poor Good Content Excellent Good Fair Poor How well did this program achieve its educational obj ectives? _ VelY Well Well Somewhat ot at all Suggestions for other programs: _____________________________
February 19921174 Vol. NS32, No.2
Introduction Adverse drug reactions (ADRs) are any noxious and unintended responses to medication that occur at doses used in humans for prophylaxis, diagnosis, or therapy.1 These reactions place a tremendous therapeutic and economic burden on the U.S. health care system. Studies of ambulatory patients indicate that approximately 20% of the population have ADRs. 2 Many of these reactions result in hospitaliza-
CE Credit
CE Credit: To obtain two (2) hours of continuing education credit for completing "Monitoring and Managing Adverse Drug Reactions," complete the assessment exercise and CE registration form and return it to APhA A certificate will be awarded upon achieving a passing grade of 70% or better. Pharmacists successfully completing this article within two years of date of issue can receive credit.
Iffi l PC
The American Phanna-
ceutical Association is approved by the American Council on Phannaceutical Education as a proVider of continuing pharmaceutical education. ~
APhA provider number:
\gI 680-202-92-002
The author of this article is Jack E. Fincham, PhD, professor and associate dean, Creighton University School of Pharmacy and Allied Health, Omaha, Nebr.
AMERICAN PHARMACY
"Monitoring and Managing Adverse Drug Reactions," is a self-study continuing education program appearing in American Pharmacy for pharmacists, developed by the American Pharmaceutical Association. Objectives: After reading this continuing education article, the pharmacist should be able to: 1. Explain the pharmacist's role in monitoring and managing adverse drug reactions (ADRs). 2. List four ADRs that require patient referral to a physician. 3. Delineate the roles of the Food and Drug Administration and the JOint Commission on the Accreditation of Healthcare Organizations in monitoring and reporting ADRs. 4. Describe how to manage three common ADRs. 5. Understand the importance of ADR reporting after a drug has been released on the market.
tion, although the exact number is uncertain. Several widely quoted studies indicate that 3% to 5% of hospital admissions result froin ADRs and that these admissions cost $3 billion per year. 3,4 Studies of institutionalized patients have indicated that up to 28% of patients have an ADR while hospitalized. s This article reviews the monitoring and management of ADRs by pharmacists. Because of their unique position in the health care system, pharmacists often see the first indication that a patient has had an ADR. Upon recognizing the possibility of an ADR, the pharmacist must first help resolve the reaction and then determine how to best use this information. Verifying that an ADR has occurred may be complicated by multiple drug regimens, improper drug administration, or lack of conclusive evidence that a drug or drugs are the cause of the reaction.
Monitoring Adverse Drug Reactions All health care professionals should monitor for ADRs on an ongoing basis. In the ambulatory setting, pharmacists monitor for ADRs as they monitor their patients' drug therapy. Through counseling and continual patient assessment, pharmacists can observe changes in a patient's response to drug therapy that may indicate the occurrence of an ADR. In the hospital, pharmacists have less direct patient contact and may need to rely on nurses and physicians to aid in ADR monitoring. Stat. orders for certain drugs may indicate that an ADR may have occurred in an institutionalized patient (Table 1). Through monitoring and follow-up of patients who received these medications, pharmacists can meet the requirements of the Joint Commission on the Accreditation of Healthcare Organizations 0CAHO) for ADR monitoring. 4 This monitoring can be initiated through computer-generated reports, manual screening, or an alerting process when the drugs are ordered from the hospital pharFebruary 1992/166 Vol. NS32, No.2
macy. Also, several unusual events occurring during the drug administration process can indicate an AD R (listed in Table 2). In the hospital setting, an ADR should be suspected when drugs are abruptly discontinued or when maintenance drugs recently ordered are not being administered. The Food and Drug Administration (FDA) is the primary organization involved in. monitoring and reporting ADRs. A system sponsored by FDA for voluntary reporting of ADRs by U.S. health professionals has been in place for approximately two decades. The principle objective of the monitoring system provides the FDA regulatory division with information about adverse effects of drugs after they have been released on the market. 6 This information can provide an early warning of unsuspected ADRs and can yield important clues for use in controlled studies. Product labeling can then be altered to reflect ADRs caused by the drug. Table 1
Drugs Ordered ·Stat.' That May Indicate the Occurrence of an ADR Atropine Benztropine Corticosteroids Dextrose Diphenhydramine Epinephrine Naloxone Phenytoin Phytonadione Protamine Sodium polystyrene sulfonate
Table 2
Indicators of Potential ADRs in Institutional Practice Abrupt discontinuance of a maintenance medication Discontinuance of an antibiotic after one or two administered doses Return of medicatioh carts with unadministered drugl) not pre,. scribed for use lias needed" Return of intravenous piggybacks Or larg'e volume parenterals '
Vol. NS32, No.2 February 1992/167
Reporting Adverse Drug Reactions Role of the Food and Drug Administration Suspected ADRs are reported to the FDA on Form FDA 1639 (Figure 1) for drugs and biologics (e.g., insulin or erythropoietin). (Vaccines are not considered a drug or biologic product, and adverse reactions occurring with these agents should be reported on Form FDA VAERS-l.) Form FDA 1639 has 26 items, which allow the reporter of the ADR to provide as much information as possible about the reaction. Manufacturers notified of ADRs are required to file a report using the form. Item 26 is included on the manufacturer's form to ensure that duplication of reported information does not occur. Recently, it has been suggested that both FDA and manufacturers be notified of ADRsJ This is the prerogative of the reporting individual. Whether the reaction has been reported to the manufacturer should be noted on the forms (item 26c). Pharmaceutical manufacturers must report reactions within 15 days of notification of company personnel by a health professional. FDA must hold the identity of the reporter of the ADR and patient involved in strictest confidence. In addition, the reporter can remain anonymous if he or she feels hesitant about completing the initial reporter section. Form FDA 1639 can be obtained from the Division of Epidemiology and Surveillance of the FDA at the following telephone number: (301) 443-4580. The form is also reprinted in the Physicians ' Desk Reference and in The FDA Medical Bulletin, which is mailed to various health professionals. Blank forms may also be photocopied and used in lieu of a form obtained from other sources. In various practice settings, the pharmacist may need to consult with a physician if not all the information required for Form FDA 1639 is available. Pharmacists practicing in hospitals or nursing homes will have access to laboratory values or findings that may be useful to include on the form under item 13. Although not all information will always be available to fill out the form, an incomplete filing is better than none at all. Because assigning a particular ADR to a specific drug is often difficult, pharmacists should not get stymied when trying to ascertain whether a drug caused an ADR. FDA determines whether a drug caused an ADR by using epidemiologic methods to examine the actual drug usage (denominator data) and by looking at all reactions for a particular drug in the aggregate (numerator data). If a drug is discontinued after a reaction occurs and if the reaction recurs when therapy is resumed, then the probability of the drug having caused the reaction increases. The system for voluntary reporting of ADRs in the United States may be inadequate, and the reactions reported to AMERICAN PHARMACY
Figure 1.
Form FDA 1639 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRA TlON (HFN · 730) ROCKVILLE . MD 20857
Form Approved OMB No. 09 '0 ·0230. FDA CON TRO L NO
ADVERSE REACTION REPORT
A CC ESS ION NO
(Drugs and Biologics)
)
REACTION INFORMA TlON
I. 2 AGE YRS
1 PATIENT ID/INITIALS (In Confidence)
3 SEX
4 ·6
11 J J j 1 I I I I I
REACTION ONSET
I
MO
0'
8 . · 12
1
1
CHECK ALL APPROPRIA TE :
"
0 0 0
7. DESCRIBE REACTION (S)
13 RELEVANT TESTS /LABORA TORY DATA
PATIENT DIED REACTION TREATED W ITH Rx DRUG RESULTED IN, OR PROLONGED, INPATIENT HOSPITALIZA TION
0
RESULTED IN PERMANENT DISABILITY
0
NONE OF THE ABOVE
SUSPECT DRUG(S) INFORMA TlON
II .
20 DID REACTION ABATE AFTER STOPPING DRUG ?
14. SUSPECT DR UG(S) (Give manufacturer and lot no. for vaccines/biologics)
D
1 16 RO U TE OF ADM INISTRAT ION
15 . DAILY DOSE
21 17 . INDICA TlON (S) FOR USE
18 . DATES O F ADM INIST RAT IO N (FromlTo)
J
19 DURAT ION OF ADMINISTRAT ION
D
YES
0
NO
0
NA
DID REACTION REAP PEAR AFTER REINTRODUCTIONJ
YES
0
NO
0
NA
CONCOMITANT DRUGS AND HISTORY III. 22. CONCOMITAN T D RU GS AND DA TES OF ADM INISTRA TION (Exclude those used to treat reaction)
23 . OTHER RELE VANT HISTORY (e .g. diagnoses. allergies. pregnancy with LMP. etc)
IV.
ONLY FOR REPORTS SUBMITTED BY MANUFACTURER
INITIAL REPORTER (In con fide nce)
V.
24 . NAME AND ADDRESS OF MANUFACTURER (Include Zip Code)
26 · 26a NAME AND ADDRESS OF REPORTER (Include Zip Code)
24a . IND/ NDA . NO FOR SUSPECT DRUG
26b TELEP HONE NO (Include area code)
24c. DATE RECE IVED BY MANUFACTURER
25 D
15 DAY REPORT' YES
o
j2 4b MFR CONTROL NO
24d REPORT SO U RCE (Check all that apply)
o
D
FORE IGN
ST U Dy O
LITERATU RE
O
HEALTH PROFESS IO NA _ OCONS U MER 25a REPOR T TY PE
NO
o
INIT IA L
0
26c HAV E YOU ALSO REPORTED THIS REACT ION TO THE MANUFACTUR ER ?
0
YES
O
NO
26d ARE YOU A HEAL TH PROFESS IONAL' FOLO W l; P
0
YES
o
NO
NOTE : Required of manufacturers by 21 CFR 314 .80 FORM FDA 1639 (7186)
Submission of a report does no t necessa r i ) y const itute an adm issi o n that the drug caused t he adverse react ion
PRE VIOU S EDIT ION MA Y 3E USED l1U.S. GOVERNMENT PR INTING OFFIC E
AMERICAN PHARMACY
199 1
1302/29026
February 1992/ 168 Vol. NS32, No. 2
FDA may be only a small fraction of actual reactions occurring with marketed drugs.
Figure 2
FDA Reporting Guidelines for Adverse Drug Reactions
Reporting in the Institutional Setting The ]CAHO accredits institutions based on their adherence to established standards and criteria. One criterion for drug therapy involves monitoring ADRs within the institution on a concurrent basis to benefit the patient with the ADR, as well as future patients at risk for the ADR. The ]CAHO guidelines mandate concurrent review of ADRs in institutions but do not require external reporting to FDA.8 The ] CAHO does not define what an ADR is, but leaves that determination up to the individual facility. Pharmacists practicing in hospitals and nursing homes can help to ensure proper drug use by monitoring and reporting ADRs. Guidelines for reporting ADRs can be found in Figure 2. Institutional monitoring and reporting of ADRs can help provide more information about the side-effect profile of marketed drugs. 9 However, each hospital system for monitoring ADRs allows little opportunity for sharing information with other facilities. Reported information must be shared outside the institution. Although the reporting system is in place, health professionals in the hospital setting seldom use it. In some cases, health professionals are unaware of the reporting system, and in others, it may not be clear who should report ADRs. In the institutional setting, the person ultimately responsible for reporting an ADR-physicians, nurses, pharmacists, or committees such as the Pharmacy and Therapeutics (P&D Committee- should be established. A well-defined process for reporting ADRs should be in place regardless of practice site. Reporting ADRs to FDA can help prevent occurrences in patients in other facilities. Assessment of cases from many reports can reveal patterns of subpopulations at risk for ADRs when taking certain drugs, and product labeling can be changed. Also, the identification of sub populations at risk allows for prospective avoidance of ADRs in patients with similar demographic or clinical profiles. Traditionally, ADRs occurring in hospitals and nursing home patients have been rarely reported by the institutionsJO,ll The need for monitoring and reporting ADRs in nursing homes is especially important because the elderly are susceptible to ADRs. For example, drug interactions may occur more often because multiple medications are administered. 12 Researchers in one study showed that more than 750/0 of ADRs in three nursing home populations were due to digitalis glycosides, antipsychotics, sedatives, hypnotics, diuretics, and anti-inflammatory agents. 13 The risk for ADRs rises as the number of medications consumed increases. George and Twomey14 reported that ADRs occurred at a rate of 60/ 0 when one to three drugs were administered concurrently and at a rate of 520/0 when VoL NS32, No.2 February 1992/169
The reaction is unexpected basep on the package insert infor~ mation and your clinical experience. The reaction is serious, e.g., requires hdspitalization, ~mer gency room oare, or other special treatment; or the re~actlon results in a patient f~tality. Serious reactions should be reported aven 'if they are expeoted, such reports are useful to identify patient characteristics that may pose inoreased risks. Particular vigilance should be maintained for newly marketed drugs and specific groups of patients, such as children, pregnant women, and th~ elderly. Submission of a report to FDA does not necessarily constitute proof or admission the drug caused the ADR; it is a suspicion only.
more than eight drugs were. Also, elderly patients who previously had ADRs are more likely to have recurrent reactions. 1S Although the reasons for this phenomenon remain unclear,16 the ramifications are not, because drug-induced illness is an important cause of hospitalization among the elderly, and a resultant effect is the need to admit residents of long-term-care facilities to hospitals. 17 The importance of pharmacist involvement in ADR monitoring cannot be overemphasized. 18 In a study of the impact of chart reviews, pharmacist drug-regimen reviews pinpointing ADRs were shown to decrease hospitalization in 68 of 517 patients in long-term-care facilities~ 19
Deciding What Reactions to Report Simple or well-known minor ADRs (e.g., nausea with nonsteroidal anti-inflammatory drug therapy, drowsiness with sedating antihistamines) need not be reported to FDA. However, unique reactions with drugs that have been on the market a long time should be reported (e.g., heparin-induced thrombocytopenia). Serious reactions to any drugs should be reported, regardless of the length of time the drug has been on the market. Reactions occurring with a newly released drug should be reported, especially if the reaction does not appear in the package insert (official labeling). Because of the AMERICAN PHARMACY
number of ADR reports they receive, hospital pharmacists must recognize the need to report ADRs externally.11 Nursing-home consultant or provider pharmacists can help monitor and report ADRs in their facilities. Simple reliance on other health professionals to report ADRs will not optimally benefit the patients in nursing homes, or those patients receiving similar regin1ens elsewhere.
Management of Adverse Drug Reactions Adverse drug reactions not only have to be monitored and reported; but they also have to be treated. Those cases that the pharmacist cannot handle require physician referral. Self-limiting ADRs include hives, itching, rashes, dizziness, headaches, swelling, mild shortness of breath, and similar allergic responses. Other reactions, such as anaphylaxis or respiratory depression, are medical emergencies and require immediate attention.
Ambulatory Pharmacy Practice Because pharmacists in community or chain pharmacy practice generally have more contact with patients than institutional pharmacists, they are more involved in managing ADRs in patients. The following list of types of reactions and subsequent actions by the pharmacist show how reactions can be managed in the outpatient or ambulatory setting. These ADRs are simply examples; actual reactions often happen in an atypical or idiosyncratic manner. Reaction is drug dependent. If the reaction occurs soon after dosing and is a minor reaction (e.g., nausea occurring after taking ibuprofen), a minor modification in drug administration may alleviate the situation without a need for further action (e.g., taking the drug with food). On the other hand, if severe nausea or vomiting occurs along with black tarry stools, the patient should be referred to his or her physician imn1ediately. Reaction appears to be dosing-interval dependent. If the reaction is a normal response to the drug but happens at inopportune times, the dosing time(s) could be changed with the prescriber's approval to diminish the reaction. For example, if nocturnal diuresis occurs after taking furosemide in the evening, the furosemide could be taken earlier in the afternoon. Reaction is severe and unexpected. If the reaction is severe (e.g., anaphylaxis after administration of penicillin, bullous dermatitis after administration of piroxicam), the drug should be discontinued immediately and the patient should be referred for emergency medical treatment without delay. Reaction is an exaggeration of the drug's expected AMERICANPHARMACY
response. If the reaction is an extension of the dru g's expected pharmacologic action (e.g., daytime sedation after taking flurazepam the previous evening), the patient may respond more appropriately with a smaller dose, or an alternative drug may be more suitable (e.g., in this case, use of triazolam because of its shorter half-life). Reaction may be due to one of many drugs a patient is taking. If the patient sees several physicians, and one drug is suspected of causing the reaction from all the drugs taken (e.g., severe and systemic response to cycloplegic ophthalmic drops), all of the prescribing physicians should be notified. The patient should stop taking the suspected drug until the prescriber(s) agree on an alternative. Reaction occurs after rechallenge with the drug. If the same reaction occurs after discontinuation and resumption of the drug therapy, the reaction can usually be attributed to that particular drug. Permanent discontinuation of the drug is called for after consultation with the prescribing physician, and a suitable alternate therapy should be found. Reaction occurs with a different but chemically related drug from the same therapeutic class. If the patient has had an adverse effect with a different drug from the saIne class of drugs from which a newly prescribed drug is derived (peptic ulcer disease after previous therapy with a nonsteroidal anti-inflammatory drug) , it would be inappropriate to initiate therapy with a different but similar drug (e.g., another nonsteroidal anti-inflammatory agent). Reaction occurs but does not require drug discontinuation. For example, hypotension, pedal edeIna, flushing, or dizziness often occur after administration of numerous antihypertensive medications such as nifedipine. 2o None of these effects would necessarily require discontinuation of the drug. In fact, the side effects may decrease after time without an attendant decrease in the drug's desired effect. In this case, the patient should be told to rise slowly fron1 a chair or from bed and always look for something sturdy to hold on to when rising. Also, the patient may need to wear larger shoes or less restrictive hose or socks until the pedal eden1a decreases. The patient should be told that flushing and dizziness are recognized effects of the drug that mayor may not diminish over time. ADRs may be associated with specific organ systen1s (Table 3); no organ system is immune from the effects of ADRs . The pharmacists ' actions suggested in Table 3 depend on the severity, intensity, and physiologic location of the reaction in question. Pharmacists should counsel patients to help them differentiate those reactions that are minor annoyances from those that require further care. Patients should be questioned to detennine if they have sought care from other sources, and their physician should be notified if the ADR is severe. Many reactions can be managed by the pharmacist working with the patient without being referred to a physician. February 1992/ 17 0 VoL NS32, No. 2
For example, patients with contact dermatitis caused by transdermal drug delivery systems may need to simply rotate the application site for the patch placement, or perhaps after consultation with the prescribing physician, replace the patch sooner than the recommend ed interval (every 5 days as opposed to 7 days). Drugs with s ignific an t anticholinergic activity (antihistamines, a n x io l ytics, hypertensive agents, and tricyclic antidepressants) often ca use dry n10uth, wh ich may be perceived as an ADR. These agents probably do not have to be discontinued, but the effects of the dry mouth need to be handled. Alcohol-containing 1110uthwashes that enhance th e dryness should be avoided, and cigarette smoking shou ld be reduced. Sucking on sugar-free lozenges or chewing sugarfree gUln n1ay help to alleviate the dryness. Also, the patient can take frequent sips of water to help the condition. Focusing on only Inental status changes as an exan1ple of ADRs, Berlinger and Spector have noted that offending drugs include psychoactive drugs, anticholinergics, benzo di azepines, levodopa, methyldopa, reserpine, digitalis glycosides, cilnetidine, diuretics, and insulin.1 7 Other researchers have noted the daytilne cany-over effects of b enzodiazepines,21 anticholinergic toxicity, 22 and central nervous system toxicity due to antihypertensive therapy.23 Potential ADRs may be avoided or their intensity diminished by lowVol. NS32, No .2 February 1992/171
Table 3.
Guidelines for Pharmacist Management of Organ System ADRs Actions Needed
Effects
Central Nervous System Requiring reassurance of patient
Anxiety and depression (unless severe)
Requiring dosing time change
Drowsiness or fatigue (possibly begin to administer the drug at bedtime), insomnia (administer drug earlier in the day)
Requiring discontinqation and referral to physician
Extrapyramidal effects, hallucinations or nightmares, headache, hyperactivity, pa in, tinnitus, and vertigo
Cardiovascular Requiring physician referral
Angina, arrhythmia, hypertension, hypotension, irregular pulse, palpitations, and syncope
Dermatologic Requiring reassurance of patient, treatment with nonprescription agents
Rash, itch, hives (if reaction progresses to involve respiration emergency treatment is urgent), and perspiration
Requiring referral to physician
Alopecia, bruising, flushing, and ecchymoses
Gastrointestinal Requiring reassurance of patient, treatment with nonprescription agents (antacids, antidiarrheals, laxatives- dependent on symptoms)
Constipation, diarrhea, dry mouth (treat with lozenges, ice chips), flatulence, indigestion, nausea, and vomiting
Requiring discontinuation and physician referral
Black tarry stools; hematemesis
Genitf?urinary Requiring discontinuation and physician referral
Anuria, difficulty voiding, and hematuria
Musculoskeletal Requiring reassurance of patient, treatment with nonprescription analgesics
Arthralgia and myalgia
Respiratory Requiring reassurance of patient and treatment with nonprescription agents
Nasal congestion and rhinitis
Requiring discontinuation and physician referral
Bronchospasm, labored breathing, and respiratory depression
Sensory Requiring reassurance of patient
Altered taste
Requiring discontinuation and physician referral
Auditory or visual disturbances
Other Requiring discontinuation and physician referral
Fever and superinfection
AMERICAN PHARMACY
ering doses of certain drugs (psychotropics, diuretics, and antihistamines). If doses can be altered without loss of therapeutic efficacy, this should be recommended to the physician as a method of reducing the severity of the ADR. Finally, patients need to be informed of the intended action of all drugs disp ensed to them. Counseling the patient on potential drug action and effect can lessen the impact of an ADR. Not all reactions can be avoided, but th~ informed patient will be better prepared to give the phannacist feedback when unanticipated effects occur. Not every side-effect profile of every drug must be sh are d with patients. However, because more and more lay sources of information are available to patients, the phannacist should be prepared to counsel patients on drug effects.
Institutional Practice The treatn1ent of ADRs in institutions is handled through nursing, pharmacy, and medical intervention. Pharmacists may be consulted about suggested treatments for patients with ADRs. Also, protocols may be in place to deal w ith emergency requirements in the institutional setting. Phannacists can document the occurrence of ADRs and alert the medical, nursing, and administrative staffs through the P&T comlnittee in hospitals and the pharmaceutical services committee in nursing hon1es of significant ADRs in the institution , to avert similar ADRs that are preventable on a prospective basis. Certainly, not every ADR can be prevented, but some can be avoided through appropriate documentation and cautious use of certain drugs. Probably the most crucial concern for hospital pharmacists is the establishment of a systematic review process for ADR surveillance. Several models of programs are described in the literature. 24 Successful programs are multidisciplinary in nature and thus involve pharmacy, nursing, and medical staffs as well as the hospital administration through quality assurance or quality review components. The focal point for dissemination of reports is the pham1acy and therapeutic (P&T) committee. Because of their prominent role in P&T committee functioning, pharmacists can see that the infonnation presented to the P&T committee is dispersed throughout the hospital, and thus help to ensure appropriate and knowledgeable use of drugs within the facility. This is one of the objectives of ]CAHO's "full circle" concept, i.e. , infonnation obtained through prospective monitoring should be brought back to the appropriate medical, nursing, or phannacy staff for review. Educational interventions should be instituted, and through this process, steps taken to prevent future ADRs. Long-term-care phannacists need to recognize the need to document and report the occurrence of ADRs to assist in establishing a more complete side-effect profile for each medication. Because the elderly are often excluded from clinical trials,9 ADRs in this group should be reported exterAMERICAN PHARMACY
nally to allow the elderly in other facilities, as well as the alnbulatory elderly, to benefit from the information gained.
Conclusion Pharn1acists should not be overly concerned about assessing the cause of ADRs, but should do what is necessary to help the patient manage the sequelae of the reaction. Calm and understanding treatment of the patient by the phannacist can help the patient understand how to deal with the ADR. Referral to a physician or an emergency care center is ilnportant when the reaction requires immediate attention. Phannacists, regardless of practice setting, have a significant and necessary role to play in managing and monitoring ADRs. Enhanced efforts by pharmacists will help patients and thus society cope with unexpected ADRs. Through an enhanced level of activity in ADR n1anagement and monitoring, all involved in the use of drugs w ill benefit through more appropriate drug use.
References' 1. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacal Ther. 1977;21 :247-54. 2. Wood AJ, Oates JA. Adverse reactions to drugs. In: Petersdorf R, Adams R, Braunwald E, et ai, eds. Harrison's Principles of Internal Medicine, 10th ed. New York: McGraw-Hili; 1987:402-9. 3. Lakshmann MC, Hershe CO, Breslau D. Hospital admissions caused by iatrogenic disease. Arch Intern Med. 1986;146:1931 - 4. 4. Melmon KL. Preventable drug reactions-causes and cures. N Engl J Med. 1971;284:1361 - 8. 5. Miller RR. Drug surveillance utilizing epidemiologic methods. Am J Hasp Pharm. 1973;30:584- 92. 6. Pearson KC, Kennedy DL. Adverse drug reactions and the Food and Drug Administration. J Pharm Prac. 1989:2(4):209- 13. 7. Sullivan JW. A pharmaceutical manufacturer's perspective on reporting adverse drug experiences. Am J Hasp Pharm. 1990;47:1342-5. 8. AMH/91 Accreditation Manual for Hospitals, vol 1. Standards Joint Commission on Accreditation of Healthcare Organizations Accreditation Manual. Chicago: JCAHO. 1991, H-91 . 9. Slone D, Shapiro S, Miettinen 0, et al. Drug education after marketing. Ann Intern Med. 1979;90:257- 61. 10. Fincham JE, Garner DD, Brown TR. Occurrence and reporting of adverse drug reactions in Mississippi nursing homes. Consult Pharm. 1988;3:267-70. 11. Fincham JE. Hospital and nursing home pharmacists' attitudes toward adverse drug reaction reporting. J Soc Admin Pharm. 1990:7(3):117-22. 12. Ramsey LE, Tucker GT. Clinical pharmacology: drugs and the elderly. Br Med J. 1981;1:125--7. 13. Sbon JA. Assessment of an adverse drug reactions monitoring program in nursing homes. Can J Hasp Pharm. 1985;38:120-5. 14. George J, Twomey JA. Causes of polyneuropathy in the elderly. Age Ageing. 1986;15:241-6. 15. Jue SG. Adverse drug reactions in the elderly. In: Vestal RE, ed. Drug treatment in the elderly. Boston: Adis Health Science Press;1984:29-42. 16. Budden F. Adverse drug reactions in long-term care facility residents. J Am Geriatr Soc. 1985;33:449- 50. 17. Berlinger WG, Spector R. Adverse drug reactions in the elderly. Geriatrics. 1984;39(5):45--58. 18. Burkholder DF. Adverse drug effects and their impact on patient care. Drug Inte" Clin Pharm. 1979;13:421-4.
February 1992/172 Vol. NS32, No.2
19. Kidder SW. The cost benefit of drug review s in long-term care facilities. Am Pharm. 1982;NS22:399- 401.
7.
Which of the fo llowing is true? a. ] CAHO has criteria in place dealing with the monitoring of ADRs in hospitals. b. ] CAHO requires hospitals to submit ADR repons to FDA. c. ] CAHO has no criteria relating to ADRs in the hospital setting. d. All of the above are true. e. None of the above are true.
8.
One tangible be nefit of FDA's voluntary ADR reporting program is that da ta collected can be used to update product labeling. a. True b. False
9.
Adverse drug reactions that occur in nursing ho mes should be reponed because of which of the following? a. The e lderly are susceptible to ADRs for several reasons. b. Drug inte ractions may occur due to multiple drug regimens used to treat illness in the elderly. c. Elderly patients who previously had ADRs are more likely to have reactions again. d. All of the above. e. None of the above.
20. Piepho RW. Culbertson VL. Rhodes RS. Drug interactions with the calcium entry blockers. Circulation. 1987;75:V-181-V-194. 21 . Carskadon MAo Seidel WF. Greenblatt DJ. et al. Daytime carryover of triazolam and temazepam in elderly insomniacs. Sleep. 1982;5(4)361 - 71 . 22. Blazer DG. Federspiel CF. Ray WA. et al. The risk of anticholinergic toxicity in the elderly: a study of prescribing practices in two populations. J Gerontal. 1983;38( 1):31 - 5. 23. Hale WE. Stewart RB. Marks RG . Central nervous system symptoms of elderly subjects using antihypertensive drugs. JAm Geriatr Soc. 1984;32(1 ): 5-10. 24. Prosser TR. Kamysz PL. Multidisciplinary adverse drug reaction surveillance program. Am J Hasp Pharm. 1990;47:1334-9.
AssesslTlent Questions
1.
Pharmaceutical manufacturers must re port ADRs to FDA within 30 days of notification of company personnel by a health professional. a. True b. False
2.
Which of the fo llowing statements regarding FDA vo luntaIY ADR reporting program is true? a. Because ADR repo rting by health professio nals is so thorough, FDA receives repo ns of vinually all ADRs in the United States. b. Every item o n Form FDA 1639 must be completed. c. Because ADR reponing is inadequate, pharmacists need to become more involved. d. All of the above are true. e. None of the above are true.
3.
4.
5.
6.
In which of the following types of reactio ns is FDA most interested? a. Serious reactions occurring with newly marketed drugs. b. Minor reactio ns occurring with drugs that have been on the market for a long period of time. c. Reactions that occur with a drug that has been o n the market for a long period of time and that are documented in the package labeling, e.g., nausea and vomiting. d. All of the above are true. e . None of the above are true. Which of the following stat. orders for a drug in a hospital setting may indicate an ADR with the orde red drug being used to reverse o r slow the reaction? a. Docusate b. Epinephrine c. Terfenadine d. Milk of magnesia e . All of the above Which of the following does not indicate a potential ADR in institutional practice? a. Return of medication cans with prn drugs unadministered b. Discontinuation of an antibiotic after one or two administered doses c. Abrupt discontinuation of a maintenance medication d. Return of intravenous piggybacks or large-volume parenterals e. Laboratory values indicative of he matologic d isturbances Which of the following statements is correct? a. FDA maintains a compulsory ADR reponing program for health profeSSionals. b. Pharmaceutical manufacturers are not required to submit reponed ADRs after their notification. c. ADRs occurring in hospitals must be reponed to FDA. d. All of the above are correct. e. None of the above is correct.
Vol. NS32, No. 2 February 1992/ 173
10. Researchers have determined in one study that more than 75% of ADRs in three nursing home populations were due to digitalis glycosides, anti psychotics, sedatives, hypnotics, diuretics, and anti-inflammatory agents. a. True b. False 11. Research indicates that ADR occurrence decreases as the number of med ications consumed increases. a. True b. False 12. LaboratOIY values indicating elevated levels of which of the following ma y indicate the pote ntial for occurrence of an ADR? a. Digoxin b. Theophylline c. PhenytOin d. Aminoglycosides e . All of the above 13. Adverse drug reactions that are usually self-limiting include all of the following except: a. Hives b. Itching c. Rashes d. Respiratory depression e. Dizziness 14. In genera l, pharmacists in community o r chain pharmacy p ractice have more contact w ith patients tha n institutional phannacists, and as such have broader levels of concerns to deal with when patients have ADRs. a. True b. False 15. Concerning pharmaCist involvement in the management of ADRs in the ambulatory setting, which of the following is true? a. Pharmacists should counsel patients to allow them to differentiate those reactions that are minor annoyances from those that require funher care. b. Many reactions can be dealt with by the pharmacist working with the patient, and some patients need not be referred to physicians. c. The physician should be notified when patients have severe ADRs. d. All of the above. e. Both a and b are correct.
AMERICAN PHARMACY
16. Patients prescribed drugs with significant anticholinergic activity leading to dry mouth should be counseled to do which of the following? a. Use alcohol-containing mouthwashes in place of nonalcoholic-based mouthwashes. b . Suck on sugar-free lozenges. c. Chew sugar-free gum. d. All of the above. e. Both band c. 17. Which of the following reactions would not necessitate discontinuation of a drug? a. Anaphylaxis after administration of penicillin b. Bullous dermatitis after administration of a nonsteroidal anti-inflammatolY drug. c. Reaction occurs upon rechallenge with the drug in question d. Reaction does not recur upon rechallenge with the drug in question e. All of the above 18. Pharmacists should be concerned about assessing the absolute cause of ADRs before submitting reports to FDA. a. True b. False 19. The logical department for distributing the findings of ADRs in the hospital setting is: a. The nursing staff b . The pharmacy staff c. The medical staff d. The administration e. None of the above. 20. Which of the following cardiovascular ADRs requires referral to the prescribing physician or other suitable sources of treatment? a. Angina b. Arrhythmias c. Palpitations d. Syncope e . All of the above
Instructions Monitoring and Managing Adverse Drug Reactions
To receive two (2) hours of continuing education credit, or 0.2 CEUs, for the successful completion of this program , you must: 1. Type or print your name, address, and Social Security number in the space provided in the boxed area below. 2. Mail your completed answer sheet for scoring to :
Processing Desk/ Edu cation An1erican Pharmaceutical Association 22 15 Constitution Ave., NW Washington, DC 20037 3. Enclose handling fee ($5.00 for APhA members; $15.00 for
no nmembers; 12-month CE program enrollees are exempt from this fee) for grading the assessme nt instrument and for issuing the certificate . Certificates w ill be iss ued upon successful completion of the assessment exercise (70% or better). If you do not achieve 70% or better, no credit will be recorded , and you will be notified . Please allow f our weeks f or processing. Each exercise must be submitted within two years after the date of issue. Answer Sheet
5.
0 0 0 0 0
6.
0
7.
0 0 0 0
1. 2. 3. 4.
8. 9. 10.
R In an emergency your Medic Alert --- X emblem triggers access to your
computerized medical record 24 hours a day,
wherever you are i:~~
I
fHdU~: _AL,ER.t,
l~lgOo~
~d4~f MedicAlert® AMERICAN PHARMACY
® ® ® ® ® ® ® ® ® ®
© © © © © © © © © ©
@ @ @ @ @ @ @ @ @ @
® ® ® ® ® ® ® ® ® ®
11 .
0
12.
0
13.
0
14.
0 0
15.
19.
0 0 0 0
20.
0
16. 17. 18.
® ® ® ® ® ® ® ® ® ®
© © © © © © © © © ©
@
@
® ® ® ® ® ® ®
@
®
@
® ®
@ @ @ @ @
@
Monitoring and Managing Adverse Drug Reactions APhA provider number for this program is: 680-202-92-002
o o o
Make paY111ents to APhA: $5 fee enclosed (member rate) $15 fee enclosed (nonmember rate) $45 annual continuing education program fee already paid
Name __________________________________________ Address _________________________________________ City _____________________ State Social Security
ZIP __________
# _____________________________
Program Evaluation Please rate this program for: Overall Quality Excellent Fair Poor Good Content Excellent Good Fair Poor How well did this program achieve its educational obj ectives? _ VelY Well Well Somewhat ot at all Suggestions for other programs: _____________________________
February 19921174 Vol. NS32, No.2
