P&T News: December 1998

Adverse Drug Reaction Reporting At UIHC

Barbara A. Mutnick, R.Ph., M.H.P.
Peer Review Status: Internally Peer Reviewed

During fiscal year 1997-98, 303 adverse drug reaction (ADR) reports were generated by UIHC personnel and reviewed by the Pharmacy and Therapeutics Subcommittee. Figure 1. ADRs by Drug Class July 1997 - June 1998

Of these reports, 92 were recommended for forwarding to the Food and Drug Administration (FDA) via the Medwatch Program because they were identified as severe, unusual, or occurring with a newly marketed drug. During the year, the nine most frequently reported causative agents were: phenytoin, cimetidine, gentamicin, vancomycin, heparin, immune globulin IV, morphine, warfarin, and ketorolac and accounted for 24% of all reports (see Figure 1).

FDA's Medwatch Program And Newly Released Drugs
Clinical trials effectively assess efficacy and risk-benefit ratios, but they are generally not large enough or of long enough duration to provide all the information on a new drug's safety. Vigilant post-marketing surveillance must be performed by all health care professionals in order to continue the necessary monitoring of newly marketed agents. New data are used to update the prescribing information of recently approved agents. Table 1 lists some of the recent labeling changes prompted by submission of adverse drug reaction reports to the MedWatch Program.

Table 1. Changes In Product Availability And Labeling Due To Post-Marketing Surveillance
Bromfenac (Duract[R]) February, 1998 June,1998	Boxed warning added about severe hepatic reactions, including jaundice, potentially fatal fulminant hepatitis and liver failure. Product voluntarily withdrawn from market.
Isotretinoin (Accutane[R]) February, 1998	Information added to Warnings & Adverse Reactions section about cases of depression, psychosis, and (rarely) suicidal ideation.
Terfenadine (Seldane[R]) February, 1998	Distribution and marketing voluntarily discontinued.
Sildenafil (Viagra[R]) May, 1998 November, 1998	Contraindicated with concomitant use of organic nitrates. New labeling information includes: post-marketing reports of heart attacks, sudden cardiac deaths, and hypertension. Labeling also discusses the risk of sexual activity in patients with pre-existing cardiovascular disease, vasodilatory effects, cautions for use in groups of patients who were not studied in clinical trials, and prolonged erections or priapism. Additionally, there have been several reports of patients without cardiovascular disease experiencing cardiac symptoms and death after taking sildenafill.
Mibefradil (Posicar[R]) June, 1998	Product voluntarily withdrawn from market.
Cisapride (Propulsid[R]) June,1998	Revised labeling includes new information about cardiac risks including rhythm disorders and death associated with the use of this drug and certain other medications or in patients who have underlying medical conditions.
Troglitazone (Rezulin[R]) July 1998	Revised labeling information added about requirements for more stringent liver enzyme monitoring to reduce the risk of rare but serious liver injury, including liver failure.
Ticlopidine (Ticlid[R]) August, 1998	Changes in labeling will more prominently describe an adverse reaction to the drug, thrombotic thrombocytopenic purpura (TTP).
OTC Pain Relievers & Fever Reducers October, 1998	FDA announces that all over-the-counter pain relievers and fever reducers must carry a warning label advising people who consume three or more alcoholic drinks every day to consult their doctors before using these products.
Intranasal & Oral Inhaled Corticosteroids November, 1998	FDA informs companies of need for new pediatric labeling about reduction of rate of growth in children. Lowest effective doses and routine monitoring of children's growth are recommended.
Tolcapone (Tasmar[R]) November, 1998	New warning in the labeling pertains to reports of potentially life-threatening cases of severe hepatocellular injury.
Trovofloxacin (Trovan[R]) November, 1998	New prescribing information encourages monitoring liver function tests in patients who develop symptoms consistent with hepatitis or pancreatitis. Dosage reduction is indicated for patients with mild or moderate cirrhosis.
Montelukast (Singulair[R]) December, 1998	Labeling changes are made based on post-marketing reports of patients presenting with eosinophilic conditions sometimes consistent with the Churg-Strauss syndrome (CSS).

Preventable Adverse Drug Reactions
Some adverse drug reactions are by their nature predictable, and therefore, preventable. Recently, discussions about the identification and ultimate prevention of these types of ADRs have been seen more frequently in the literature.

The importance of identifying and understanding preventable adverse drug reactions was first discussed in an article in 1971.1 The author estimated that 70% to 80% of adverse drug reactions that occurred could be prevented. More current literature suggests that preventable ADRs occur at a rate between 5% to 80%.2,3 Some of the variation in the 5% to 80% range can be explained by several factors. First, the information from various studies can not always be directly compared, as some studies measure rates of adverse drug events (ADE), a more inclusive term that takes into account injuries resulting from incorrect or inappropriate drug use. ADRs only include injuries resulting from "doses used in man for prophylaxis, diagnosis, or therapy" as stated in the World Health Organization's definition. Although, on occasion, the line between ADEs and ADRs is not easy to discern, these are not interchangeable terms as is occasionally seen in the literature, and their indiscriminate use may be a source of confusion.

A review of recent studies shows that several institutions report preventable adverse drug effects at 56%,(40 19%,(2) 28 %(5) and 19%.(3) At UIHC, a 1997 medical records review of patients with ADRs secondary to warfarin therapy showed that 36% of the identified ADRs were preventable. Regardless of the various reported rates at any institution, these data are a cause for alarm considering the serious nature and higher costs of treatment of preventable ADRs or ADEs. Preventable ADEs were more serious in nature and on average doubled the additional length of hospital stay from 2.2 to 4.6 days over non-preventable ADEs. Likewise, preventable ADEs were generally almost twice as expensive to treat; the estimated postevent costs were $2,595 per non-preventable ADE case versus $4,685 per preventable ADE case.5

Another reason for the wide variation in the reported percentages of preventable ADRs may be the difficulty in determining which ADRs are actually preventable. The different methods used to assess preventability include expert panel review, individual clinicians' judgement, set criteria, and determination of reaction type (A versus B).

Type A (predictable) reactions are expected extensions of the pharmacology of the drug. Hypotension due to treatment with antihypertensive agents is an example of such a reaction. Additionally, a reaction may occur due to a secondary pharmacologic property of an agent as seen with the anticholinergic effects experienced by patients using tricyclic antidepressants. Type A reactions are usually dose-dependant, but they can be due to concomitant disease states, drug-drug interactions, or food-drug interactions. This type is responsible for the majority of adverse drug reaction reports and is preventable. Early recognition of a Type A reaction can lead to early intervention and prevention of a more serious event. Ways to minimize these types of reactions include: understanding the pharmacology of the drug, proper dosing of drugs, monitoring drugs with narrow therapeutic indices, sound patient education, and minimizing polypharmacy whenever possible.

Type B reactions include idiosyncratic reactions, immunologic or allergic (e.g., anaphylactic) reactions, and carcinogenic or teratogenic events. These events are usually not an extension of the pharmacology of the drug but instead are more a function of patient susceptibility rather than an inherent toxicity secondary to a drug. These types of reaction are not common, but when they do occur, many times they manifest themselves in serious or life-threatening events. Type B reactions that result from first-time use are not preventable. However, type B reactions that result from an overlooked, but known, drug allergy in a patient are preventable. Accurate reporting and documentation of medication allergies, including an accurate report of the specific types of adverse reactions experienced by a patient, in the medical record can prevent a patient from experiencing this type of adverse drug reaction. A thorough review of agents that may be cross-sensitive with known allergans should also be carried out.

The following list of questions6 was developed to help assess the preventability of ADRs. Answering "yes" to one, or more of the following questions suggests that an ADR may have been preventable.

Preventability Assessment

1. Was the drug involved in the ADR not considered appropriate for the patient's clinical condition?
2. Was the dose, route, and frequency of administration not appropriate for the person's age, weight, or disease state?
3. Was required therapeutic drug monitoring or other necessary laboratory tests not performed?
4. Was there a history of allergy or previous reactions to the drug?
5. Was a drug interaction involved in the reaction?
6. Was a toxic serum drug level documented?
7. Was poor compliance involved in the reaction?

The ultimate goal of characterizing ADRs as preventable is to be able to intervene before the ADR occurs, thus decreasing patient morbidity and decreasing the cost of health care.

Summary
Adverse drug reactions continue to be a major source of concern for all health care providers. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires hospitals to develop written procedures for recording and reporting ADRs and to take proper steps to reduce their incidence. The Food and Drug Administration states that a concurrent surveillance system is the best method of documenting ADRs. Ongoing attention, education, and the cooperation of all members of the health care team are required to control these events and prevent future occurrences.

All staff at UIHC are encouraged to report adverse drug reactions encountered in their practices. Pharmacists are able to assist in reporting and documenting ADRs. Also, the staff of the Drug Information Center (6-2600) are available Monday through Friday from 8 a.m. to 5 p.m. to answer questions regarding ADRs and aid in the documentation of suspected ADRs.

References

1. N Engl J Med 197 1;284:1361-7.

2. Am J Hosp Pharm 1994;51:2268-72.

3. Pharmacotherapy 1998; 18:1284-9.

4. J Gen Intem Med 1993;8:289-94.

5. JAMA 1997;277:307-11.

6. Hosp Pharm 1992;27:538.

DRUGS ADDED TO STOCK

ADAPALENE Topical Gel: 0.1% Adapalene (Differin' - Galderma) is a retinoid-like compound that is indicated for the treatment of acne vulgaris.

ALBENDAZOLE Tablets: 200 mg Albendazole (Albenza' - SKB) is a broad spectrum antihelmintic agent.

CAPECITABINE Tablets: 150 mg, 500 mg Capecitabine (Xeloda[R] - Roche) is an oral antineoplastic agent indicated for the treatment of resistant metastatic breast cancer.

EFAVIRENZ Capsule: 100 mg, 200 mg Efavirenz (Sustiva[R] - DuPont) is a non-nucleoside reverse transcriptase inhibitor indicated for combination use with other antiretroviral agents for the treatment of HIV-1 infection.

FEXOFENADINE WITH PSEUDOEPHEDRINE Tablets: 60 mg fexofenadine with 120 mg pseudoephedrine This combination product (Allegra-D[R] - Hoechst Marion Roussel) is indicated for the relief of symptoms associated with seasonal allergic rhinitis in patients 12 or more years of age.

HYDROQUINONE Topical Solution: 4% Hydroquinone (Solaquin-Forte[R] - ICN) topical solution is indicated for bleaching of hyperpigmented skin conditions.

INFLIXIMAB Injection: 100 mg Infliximab (Remicade[R] - Centocor) is a monoclonal antibody indicated for the treatment of moderately to severely active Crohn's disease (in patients who have had an inadequate response to conventional therapy) and for the treatment of fistulating Crohn's disease. Note: The prescribing of infliximab is restricted to Gastroenterology.

LEPIRUDIN Injection: 50 mg Lepirudin (recombinant hirudin, Refludan[R] - Hoechst Marion Roussel) is indicated as an anticoagulant in patients with heparin-induced thrombocytopenia and associated thromboembolic disease in order to prevent further thromboembolic complications. Note: The prescribing of lepirudin is restricted to Adult and Pediatric Hematology/Oncology.

PALIVIZUMAB Injection: 100 mg Palivizurnab (Synagis[R] - Medimmune) is a monoclonal antibody that binds to respiratory syncytial virus preventing its ability to infect cells.

Note: Palivizumab is a protocol drug. Criteria for use include:

1. Infant below 2 years of age who requires home oxygen therapy (or who just came off oxygen therapy in the 2 months prior to the onset of RSV season) but does not meet any of the criteria for RSV-IG.

2. Infant of gestational age of 28 weeks or less that is discharged during RSV season or shortly before and is less than 6 months old (even if home oxygen therapy is not required).

3. Single dose at discharge for an infant born between 29 and 32 weeks of gestation who is discharged during RSV season.

4. Infant or child less than 2 years of age who has a cardiac lesion with systemic-to-pulmonary shunting (e.g., those lesions accompanied by pulmonary hypertension, poorly controlled congestive heart failure, or pulmonary venous congestion).

ROTAVIRUS ORAL, LIVE, TETRAVALENT VACCINE Oral Solution: 2.5 ml Rotavirus vaccine (RotaShield[R] Wyeth-Ayerst) is indicated for the prevention of gastroenteritis caused by rotavirus as part of a three-dose series.

TAZAROTENE Topical Gel: 0.05%, 0.1% Tazarotene (Tazorac[R] - Allergan) is a retinoid prodrug. The 0. 05 % concentration is indicated for the treatment of plaque-type psoriasis; the 0. 1 % concentration is indicated for the treatment of plaque-type psoriasis or acne vulgaris.

THALIDOMIDE Capsule: 50 mg Thalidomide (Thalomid[R] - Celgene) is an immunomodulating agent that is indicated for the treatment of cutaneous manifestations of moderate to severe erythema nodosurn leprosum, as well as prevention and suppression of recurrence. Note: Thalidomide is a potent teratogen. Prescribing is restricted to physicians who have registered with the manufacturer. Prescribing and dispensing must comply with the terms of the "System for Thalidomide Education and Prescribing Safety " (S. T. E. P. S.) Program as mandated by the FDA.

TIROFIBAN Injection: 12.5 mg per 50 ml Tirofiban (Aggrastat[R] - Merck) is a synthetic glycoprotein llb/Illa receptor antagonist used in combination with heparin for the treatment of acute coronary artery syndrome, including patients undergoing PTCA. Note: The prescribing of tirofiban is restricted to Cardiology attending staff andjellows.

TRASTUZUMAB

Injection: 440 mg vial

Trastuzumab (Herceptin[R] - Genentech) is a monoclonal antibody that mediates antibody dependent cellular toxicity. It preferentially exerts its activity on HER2 overexpressing cancer cells and is indicated for the treatment of patients with metastatic breast cancer where tumors overexpress HER2 protein.

Note: The prescribing of trastuzumab is restricted to Adult Hematology/Oncology.

ADDITIONAL ACTIONS

MIDAZOLAM 2 mg per ml ORAL SOLUTION This commercially available product replaces an extemporaneously compounded product.

MUPIROCIN 2% TOPICAL CREAM A topical cream (Bactroban' - SKB) has been added to stock.

DRUGS DELETED FROM STOCK

ASCORBIC ACID 100 mg TABLETS Discontinued by all manufacturers. Oral solution and 250 mg tablets are available.

COAL TAR SOLUTION 5% AND SALICYLIC ACID 2.5% IN AQUAPHILIC OINTMENT Discontinued due to low use.

HYDROCORTISONE ACETATE 1% IN P.E.G. OINTMENT Discontinued due to low use. Hydrocortisone I % cream is available.

MEASLES AND RUBELLA (MR Vax Il') VACCINE Discontinued by the manufacturer. Individual components are available.

NEOMYCIN 1% IRRIGATION SOLUTION Deleted due to the availability of less ototoxic and nephrotoxic alternatives. Neosporin' GU Irrigant, gentarnicin irrigation solution, and acetic acid 0.25 % irrigation solution are available.

NITROGLYCERIN 0.5 mg per ml INJECTION Discontinued by the manufacturer. A 5 mg per ml injection is available.

PENTAGASTRIN (PEPTAVLON[R]) INJECTION Discontinued by the manufacturer.

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