P&T News: December 2000

Adverse Drug Reaction Reporting System at UI Hospitals and Clinics

Barbara A. Mutnick, R.Ph., M.H.P., Clinical Pharmacist, Department of Pharmaceutical Care
Peer Review Status: Internally Peer Reviewed: Adapted from the Recommendations of the Advisory Committee on Immunization Practices

Total confidentiality is assured by not including the patient's name or registration number on the MedWatch form. Also, individual reporter's names are not included. If the FDA requires additional information, the name of the patient's physician is supplied only after permission for disclosure is received from the physician.

During fiscal year 1999-2000, 292 adverse drug reaction reports were received into the UIHC ADR Reporting Program. Sixty-seven of the reports were recommended to be forwarded to the FDA via the MedWatch Program.

The seven most frequently reported causative agents during the year were: warfarin, phenytoin, vancomycin, cimetidine, heparin, celecoxib, and paclitaxel.

The Important Role of Health Care Professionals
Clinical trials effectively assess efficacy and risk-benefit ratios, but they are generally not large enough to provide all the information on a new drug's safety. The FDA reports that the time period between submission to the FDA and marketing has been reduced from two to three years to about 12 months. This more rapid approval is due in part to the passage in 1992 of the Prescription Drug User Act that allows the FDA to collect fees from drug companies to add reviewers and scientific equipment to expedite the drug approval process. Despite several recent highly publicized market withdrawals (e.g., alosetron, phenylpropanolamine, troglitazone, and cisapride), the percentage of drugs removed from the market each year has actually decreased (3.5% in 1988 versus 1.2% in 1998).¹ These withdrawals are due to health care professionals performing vigilant post-marketing after new agents reach the market. Post-marketing ADR data submitted to the FDA's MedWatch Program are also used to update product prescribing information. Table 1 lists some of the recent labeling changes and market withdrawals for prescription products prompted by submission of adverse drug event reports to the MedWatch Program.

Patients as Active Participants in Medicine Safety
In late 1999, the Institute of Medicine (IOM) of the National Academies of Sciences released its report, "To Err Is Human," which stated that deaths from medication errors that take place both in and out of hospitals - more than 7,000 annually - exceed those from workplace injuries.² This report was much publicized in the lay press, as well as the medical community. In October 2000, the American Hospital Association compiled the following list titled, "The Most-Made Mistakes" that contribute to medication errors:³

Most-Made Mistakes Incomplete patient information (not knowing a patient's allergies, other medications they are taking, previous diagnosis or lab results). Unavailable drug information. Miscommunication of drug orders (involving poor handwriting, confusion between drugs with similar names, confusion of metric and other dosing units, misuse of zeroes and decimal points, and inappropriate abbreviations). Lack of appropriate labeling as drug is prepared and repackaged. Environmental factors that distract health professionals from their medical tasks.

Heading this list is "incomplete patient information." Patients have always been encouraged to be knowledgeable about their drug therapy and recent initiatives encourage consumers to become active participants in the safe use of their medications. The role of health care providers in empowering patients to be partners in their medical care is even more important after the media frenzy surrounding the IOM report.⁴

The National Council for Patient Information and Education (NCPIE) supplied some frightening statistics in a December 1999 American Medical News online article.⁵ The organization estimates that 14% to 21% of patients never fill their original prescriptions and that about 50% of the 2 billion prescriptions filled each year are not taken correctly. Jerome Avorn is quoted in the same article: "As much as 50% of medication prescribed for chronic use never get taken." These types of statistics prompted the NCPIE to select the theme, "Educate Before You Medicate: Knowledge Is The Best Medicine," for the October 2000 "Talk About Prescription" month. This message is further reinforced by the organization making available Medication Wallet Cards for patients and "Talk About Prescription" posters.

Patient education does not stop with prescription medications. A study⁶ reviewed patient's medication bottles and their reported use as compared to the physician's records of outpatients seen in a private practice setting affiliated with an academic medical center. Results showed 51% of patients taking medications not recorded, 29% of patients not taking medications recorded, and 20% of the patients taking a different dosage than the one recorded. One third of all discrepancies involved over-the-counter drugs or herbal therapies. Misinformation about herbal products are particularly common because they are typically self-prescribed by the patient. A study of cancer patients⁷ revealed that 40% of the patients were taking unconventional medical therapies, but they did not disclose this information unless specifically asked.

A JAMA Patient Page⁸ featured an article that gave patients an overview of the kinds of medication issues to discuss with their doctors. In this article, patients were encouraged to find out information about new medications, keep records of prescription and non-prescription drugs they are using, and share records of all medications with each new doctor.

Things to Discuss with Your Doctor At the time that your doctor gives you a prescription, you should understand the following information At the time that your doctor gives you a prescription, you should understand the following information: The name of the medication and what it is supposed to do. How and when to take it, and for how long. What foods, drinks, other medications, or activities to avoid while taking the medicine. Any side effects, and what you should do if they occur. Whether the new prescription will work safely with other prescription and nonprescription medicines, vitamin supplements, or herbal or alternative therapies you may be taking. Any written information available about medicine.

The Office of Women's Health at the FDA began a major public awareness campaign by enlisting over 80 national organizations, businesses, professional associations, women's, and ethnic groups to reach consumers. The goal of the Take Time to Care program is to educate women and their families by distributing millions of "My Medicine" brochures. These brochures include tips about taking medication properly and using medication tracking charts. The "My Medicine" brochure was made available by the FDA in 13 languages on the Internet at http://www.fda.gov/womens/tttc.html.

Consumer groups are also initiating similar programs.⁹ In California, a program sponsored by the non-profit consumer group, 21st Century Consumer scheduled a three-month pilot test this year. The pilot program offers a variety of tools, such as videos, pamphlets, posters, medication lists and schedules, and patient-tracked bedside charts aimed at keeping the hospitalized patient and family members informed about the patient's care. An initiative launched by the Massachusetts Coalition for the Prevention of Medication Errors includes publication of a new patient guide, "Your Role in Safe Medication Use." The guide contains advice about safe medication use in the home, at the doctor's office, and in the pharmacy and is available at http://www.mhalink.org/publications/publications.htm. Both initiatives encourage the patient to become an active participant in the health care team. Health care professionals are positioned to welcome their patients' new roles and assist them in attaining it.

Summary
The Institute of Medicine Academies includes a critical goal in its groundbreaking report "To Err Is Human." This committee has set a minimum goal of reducing medication errors by 50% over the next five years. With such a monumental task ahead, all players in health care need to take an active role in preventing medication errors. Patient involvement should be not only accepted, but it should be strongly encouraged.

References:
1. Nordenberg,T. When is a medical product too risky? FDA Consumer Magazine. 1999; Sept-Oct. (from site: http://www.fda.gov/fdac/features/1999/599_med.html)

2. N Engl J Med. 2000; 342:1123-5.

3. Nordenberg,T. Make no mistake: medical errors can be deadly serious. FDA Consumer Magazine. 2000; Sept-Oct. (from site: http://www.fda.gov/fdac/features/2000/500_err.html)

4. National Council on Patient Information and Education (resource on World Wide Web). URL: http://www.talkaboutrx.org/latest.html. Available form Internet. Accessed 2000 Dec 5.

5. Wiebe, C. Following orders: New solutions to the age-old problem of patient noncompliance with prescription drug orders. Am Med News 1999; Dec 20. (from site: http://www.ama-assn.org/amednews/1999/pick_99/hlta1220.htm)

6. Arch Intern Med. 2000: 160:2129-34.

7. JAMA. 2000; 283:3189.

8. JAMA. 1999; 282:298.

9. Hosp Pharm Rep. 2000;August: 23, 33.

Changes in Product Availability and Labeling Due to Post-marketing Surveillance
Abacavir (Ziagen®) January 2000, July 2000	The company marketing the drug warned health professionals of severe hypersensitivity reactions following reintroduction with abacavir. Fatal hypersensitivity reactions were described with the use of abacavir in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy.
Cisapride (Propulsid®) January 2000	A boxed warning about serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation being reported in patients taking cisapride was added to package information.
Troglitazone (Rezulin®) March 2000	FDA asked the manufacturer of troglitazone to remove the product from the market. FDA took this action after its review of safety data on troglitazone and two similar drugs, rosiglitazone and pioglitazone, showed that troglitazone is more toxic to the liver than the other two drugs and that they offer the same benefits without the risk.
Lamotrigine (Lamictal®) & Terbinafine (Lamisil®) June 2000	The manufacturer received reports of prescription dispensing errors involving LAMICTAL® (lamotrigine) and LAMISIL® (terbinafine) resulting in serious adverse events. Patients with epilepsy who do not receive their antiepileptic drug LAMICTAL due to dispensing errors would be inadequately treated and could experience serious consequences including status epilepticus. Conversely, patients erroneously receiving Lamictal instead of their antifungal drug LAMISIL would be unnecessarily subjected to a risk.
Cisapride (Propulsid®) July 2000	The manufacturer decided to discontinue marketing of cisapride.
Valproate sodium (Depacon®), divalproex (Depakote®), & valproic acid (Depakene®) July 2000	A boxed warning was added for all three agents discussing their association with life-threatening pancreatitis.
Alosetron (Lotronex®) August 2000	New warnings about serious complications of constipation, including obstruction, perforation, impaction, toxic megacolon, and secondary ischemia which sometimes required surgery were added to the package insert and patient information summary.
Mesoridazine (Serentil®) September 2000	A boxed warning was added about dose-related QTc interval prolongation and the association with torsades de pointes-type arrhythmias and sudden death.
Zafirlukast (Accolate®) September 2000	More specific recommendations were added for patient management of liver dysfunction associated with zafirlukast use.
Basiliximab (Simulect®) October 2000	Label changes discuss the possibility of severe acute hypersensitivity reactions that have been observed both on initial exposure and/or following re-exposure.
Etanercept (Enbrel®) October 2000	New warnings were added about rare cases of central nervous system demyelinating disorders and reports of pancytopenia, including aplastic anemia, which have at times been fatal.
Trastuzumab (Herceptin®) October 2000	Boxed warnings were added to include new information on serious adverse events of hypersensitivity, infusion, and pulmonary reactions.
Alosetron (Lotronex®) November 2000	The company marketing the drug voluntarily withdrew the product from the market after the FDA received reports of cases of ischemic colitis and severe constipation resulting in hospitalization without surgery, surgical procedures, and death.
Phenylpropanolamine (Various cold & weight loss products) November 2000	The FDA requested that all drug companies discontinue marketing products containing phenylpropanolamine because of an increased risk of hemorrhagic stroke.
Source: http://www.fda.gov/medwatch/safety.htm.

In early December 1998, the Food and Drug Administration (FDA) blocked domestic shipments of urokinase (Abbokinase®-Abbott Laboratories) due to deviations from Good Manufacturing Practice regulations. As a result of these actions, a nationwide shortage of urokinase became apparent, and a replacement for urokinase needed to be identified. Based on urokinase usage patterns at UIHC, guidelines for the use of an alternate thrombolytic agent were necessary in the following situations: 1) the treatment of patients with peripheral arterial occlusive (PAO) disease; 2) catheter clearance for both the pediatric and adult population; 3) infusions for catheter clearance in both adult bone marrow transplant (BMT) and hemodialysis patients; and 4) the treatment of patients with venous occlusive disease (VOD).

Data from studies of thrombolytics comparing dosing and administration, efficacy, bleeding risks, and infusion time were then presented to a multidisciplinary group consisting of pharmacists, nurses, and physicians from the areas of Hematology-Oncology, Bone Marrow Transplantation (BMT), Cardiology, and Pediatrics. After careful consideration of all commercially available thrombolytics, alteplase (Activase®-Genentech) was selected as the alternative thrombolytic for use at UIHC. This group then proceeded to develop guidelines for the use of alteplase for each of the above listed indications. These guidelines were further reviewed and approved by two additional multidisciplinary groups, the Medication Use Evaluation and the Pharmacy and Therapeutics Subcommittees.

The doses of alteplase needed as the replacement for urokinase ranged from 0.2 mg (pediatric catheter clearance) to 10 mg (VOD). Alteplase is only available in 50 and 100 mg vials that expire within 24 hours of reconstitution and costs approximately $1000 per 50 mg. The short expiration dating had the potential to create large amounts of wasted product and to be significantly more expensive than the urokinase regimens. In order to avoid such waste, it was determined that the UIHC IV Admixture Service could draw up 2 and 5 mg aliquots and freeze them at -70^oC. At this temperature, alteplase could be stored for six months with very little waste. Once the syringes are thawed, the expiration returns to 24 hours.

References Used for the Development of Guidelines:
1. J Vasc Med Biol 1993; 4:311-4.

2. Ann Emerg Med. 1988; 17:1210-5.

3. Ann Surg 1994; 220:251-68.

4. Eur J Radiol 1996; 22:129-32.

5. Radiology 1990; 175:75-8.

6. Thromb Haemost 1994; 72:543-7.

7. CHEST 1998; 114:666S-82S.

Drugs Added to Stock

DOFETILIDE

Capsules: 125 mcg, 250 mcg, 500 mcg

Dofetilide (Tikosyn® - Pfizer) is a class III anti-arrhythmic agent indicated for the maintenance of normal sinus rhythm in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm.

Note: Due to the potential for dofetilide to induce life-threatening arrhythmias (e.g., torsades de pointes,) the prescribing of dofetilide is restricted to Electrophysiology attending staff physicians.

ESTRAMUSTINE

Capsules: 140 mg

Estramustine (Emcyt® - Pharmacia & Upjohn) is an antineoplastic agent used for the management of hormone-resistant prostate cancer.

LOPINAVIR/RITONAVIR

Capsules: 133.3 mg lopinavir/33.3 mg ritonavir

Oral Solution: 400 mg lopinavir/100 mg ritonavir per 5 ml

This combination product (Kaletra® - Abbott) of protease-inhibitors is indicated to be used in combination with other antiretroviral agents for the treatment of HIV-infection.

NEDOCROMIL

Ophthalmic Solution: 2%

This mast cell stabilizer (Alocril® - Allergan) is indicated for the treatment of itching associated with allergic conjunctivitis in patients > 3 years of age.

PENTOSTATIN

Injection: 10 mg vials

Pentostatin (Nipent® - SuperGen) is an antineoplastic agent used for the treatment of hairy cell leukemia and chronic lymphocytic leukemia.

ZONISAMIDE

Capsules: 100 mg

Zonisamide (Zonegran® - Elan) is an anticonvulsant indicated as adjunct therapy in the treatment of partial seizures in adult patients with epilepsy.

Additional Actions

ACETAMINOPHEN, BUTALBITAL, AND CAFFEINE TABLETS

This product containing acetaminophen 325 mg, butalbital 50 mg, and caffeine 40 mg (Fioricet®) has been added to stock.

DIDANOSINE DELAYED-RELEASE CAPSULES

A 400 mg delayed-release capsule has been added to stock.

DIVALPROEX SODIUM EXTENDED-RELEASE TABLETS

A 500 mg extended-release tablet (Depakote ER®) has been added to stock.

METHYLPHENIDATE SUSTAINED-RELEASE (CONCERTA®) TABLETS

This sustained-release methylphenidate product that is dosed once daily has been added to stock.

NIACIN EXTENDED-RELEASE (NIASPAN®) TABLETS

This extended-release product was added to stock for the treatment of hyperlipidemia.

PRENATAL MULTIVITAMIN (PREMESIS Rx ®) TABLETS

This prenatal multivitamin with controlled-release pyridoxine (pyridoxine 75 mg, cyanocobalamin 12 mcg, folic acid 1 mg, calcium 200 mg) has been added to stock.

Drugs Deleted From Stock

ALOSETRON (LOTRONEX®)

Deleted due to market withdrawal.

ISOPROTERENOL 1:5,000 and 1:50,000 INJECTION

These strengths have been discontinued by all manufacturers.

LODOXAMIDE (ALOMIDE®) OPHTHALMIC SOLUTION

This product has been replaced with nedocromil (Alocril®) ophthalmic solution.

PHENYLPROPANOLAMINE TABLETS

Deleted due to market withdrawal. Pseudoephedrine tablets, extended-release capsules, and oral syrup are available.

PHENYLPROPANOLAMINE PLUS BROMPHENIRAMINE (DIMETAPP®) EXTENDED-RELEASE TABLETS AND ORAL ELIXIR

Deleted due to market withdrawal of phenylpropanolamine. Other decongestant plus antihistamine products (e.g., Actifed®, Drixoral®, Allegra-D®, and Claritin-D 24-Hour®) are available.

PHENYLPROPANOLAMINE PLUS CHLORPHENIRAMINE (ORNADE®) SUSTAINED-RELEASE CAPSULES

Deleted due to market withdrawal of phenylpropanolamine. Other decongestant plus antihistamine products (e.g., Actifed®, Drixoral®, Allegra-D®, and Claritin-D 24-Hour®) are available.

TRIAMCINOLONE 0.025% WITH UREA 10% IN AQUAPHILIC OINTMENT

Deleted due to low use. The individual components are available.

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