P&T News: January 2002

The Adverse Drug Reaction Reporting Program at UIHC
A Focus on Valproic Acid Products

Barbara A. Mutnick, R.Ph., M.H.P., Administrative Pharmacist, Department of Pharmaceutical Care
Internally Peer Reviewed by: Mark A. Granner, M.D., Associate Professor, Department of Neurology

Liver dysfunction, including hepatic failure, had been noted as a potential adverse effect of the drug since it was first marketed. This warning is now included as a boxed warning in the packaging of all the products listed above. The warning of pancreatitis had been listed in the package information since 1981. In June 2000, the FDA asked the manufacturers to change the warning about pancreatitis to a boxed warning in the package inserts of all these products.

Prescribing of valproic acid and its derivatives is no longer limited to the management of seizures; the expanded indications for use offer treatment, and also exposure to the potential adverse effects of these agents, to a greater number of patients. This article briefly reviews the characteristics of valproic acid-associated pancreatitis and hepatotoxicity and provides recommendations to monitor the use of valproic acid and lower the potential for valproic acid-related adverse reactions.

Pancreatitis
Case reports of life-threatening pancreatitis have occurred in both adults and children receiving valproic acid and derivatives. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death.¹ Cases of pancreatitis have been reported to occur shortly after the introduction of these drugs, as well as after several years of use. Symptoms of pancreatitis include abdominal pain, nausea, vomiting, and anorexia and require prompt medical evaluation. The screening of serum amylase levels during the early stages of therapy is not recommended by manufacturers, although at least one group of authors has recommended monthly monitoring of laboratory values during the first six months of therapy.² Another group of authors finds the relationship between elevated serum amylase and the development of pancreatitis unclear and believes routine amylase screening is not warranted.³ If pancreatitis is diagnosed, the drug should be discontinued and alternative therapy initiated.

Hepatotoxicity
Two types of hepatotoxicity have been reported with valproic acid and its derivatives. The most common type is dose-related, reversible, characterized by transient asymptomatic elevations in SGOT and SGPT levels, and has been reported to occur in up to 44% of patients.^4,5 Most often, the transaminase elevation either stabilizes or improves, while the drug is continued. If the patient is asymptomatic, there is no need to withdraw the drug. These serum levels of liver enzymes usually return to normal in instances where the drug is discontinued.

Rarely, a more serious type of hepatotoxicity, irreversible hepatic failure, which results in fatalities has occurred. This type of hepatotoxicity is not dose-related and appears to be idiosyncratic. Its onset is most commonly seen during the first six months of therapy, but can occur later in therapy. The prescribing information for these products states that the drugs should be used with caution in patients that have a prior history of hepatic disease, patients that are on multiple anticonvulsants, children, patients with congenital metabolic disorders, patients with severe seizure disorders accompanied by mental retardation, and those patients with organic brain disease. The primary risk for hepatic fatality was found in children, aged newborn to two, who had received valproic acid or derivatives as part of polytherapy and who had underlying conditions such as mental retardation, congenital anomalies, or other neurological abnormalities in addition to their seizure disorder. ⁶ The risk of hepatic failure fatalities appears to decline with age.^4,6 When valproic acid and derivatives are used in these population groups, they should be used with extreme caution and as a sole agent.

Serious or fatal hepatotoxicity can be preceded by non-specific symptoms, such as malaise, weakness, lethargy, facial edema, anorexia, jaundice, and vomiting. In epileptic patients, loss of seizure control may occur. High-risk patients should be monitored closely for these symptoms and liver function tests (LFTs) should be performed prior to initiation of therapy and at periodic intervals thereafter, especially during the first six months. The frequency of the intervals is not specified in the package insert. An analysis of 10 different recommendations from the literature6 all unanimously suggests a baseline measure of LFTs. Some of the articles recommend levels as frequently as every 2 weeks; some articles recommended sampling levels only at 6 weeks, 3 months, and 6 months; however, the majority of articles recommend every month for the first six months of therapy. Some of the articles suggest continued monitoring at 6 - to 12-month intervals even after the first 6 months of therapy. A final article mentioned in this communication suggests baseline and liver function tests at 2 and 6 months only in high-risk patients. Further lack of consensus is demonstrated by alternative recommendations that suggest that frequent liver function tests during early valproate therapy are unlikely to allow detection of serious hepatotoxicity. These authors recommend educating caregivers of predisposed individuals about the clinical signs and symptoms of hepatotoxicity and use of laboratory tests to confirm the presence of hepatotoxicity.⁷

Overall recommendations for monitoring for hepatotoxicity include:⁵

1. Avoid administering valproic acid and its derivatives as part of polytherapy in children less than 3 years of age;
2. Avoid administering valproic acid and its derivatives in patients with preexisting liver disease or family history of childhood hepatic disease;
3. Administer at lowest possible doses;
4. Avoid concomitant administration with salicylates and avoid fasting in children with concurrent diseases;
5. Monitor for clinical symptoms such as nausea, vomiting, lethargy, edema, jaundice, and seizure breakthrough.

These recommendations should be combined with the judicious use of laboratory monitoring (CBC, AST, ALT) to assure avoidance of this rare, but fatal effect of valproic acid and its derivatives.

Adverse Drug Reaction Reporting Program at UIHC

At UIHC, Department of Pharmaceutical Care staff coordinate the hospital's ADR Reporting Program under the direction of the Pharmacy and Therapeutics (P&T) Subcommittee. All reports are presented to the Subcommittee for review. In cases where a report is identified as severe, unusual, occurring with a newly marketed drug, or taking place in newly emerging clusters or trends, the report is forwarded to the FDA's MedWatch Program and to the manufacturer. Reporting to the FDA and manufacturer is initiated after receiving prior approval from the P&T Subcommittee. In addition, before the MedWatch form is sent to the FDA, the patient's attending physician reviews the form and has the opportunity to make recommendations for corrections or to provide additional information.

Total confidentiality is assured by not including the patient's name or registration number on the MedWatch form. Also, individual reporters' 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.

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 from submission of a new drug to the FDA to the marketing of a new drug has been reduced from a two to three year period to about 12 months. This more rapid approval is due in part to the passage of the Prescription Drug User Fee Act that allows the FDA to collect fees from drug companies to add reviewers and scientific equipment to expedite the drug approval process. Recently, the FDA released information about the number of safety reports it received through the Adverse Event Reporting System. During fiscal year 2001 (and including reports through September 24, 2001), the FDA logged 281,090 reports. The breakdown of the most frequently reported drugs is presented in Table 1.

All health care professionals must perform vigilant post-marketing surveillance in order to continue the necessary monitoring after new agents reach the market. New data are used to update the prescribing information of recently approved agents and, in some cases, drug entities that have been marketed for years. An example of prompt reporting by UIHC physicians occurred in January 2001. A patient was transferred to our institution with a diagnosis of pneumonia and disseminated histoplasmosis, which were suspected to be secondary to infliximab (Remicade®) therapy. Their report to the FDA was among those that prompted the manufacturer to add a boxed warning regarding this adverse effect in the infliximab package labeling.

Table 2 lists some of the recent labeling changes in prescription products prompted by submission of adverse drug event reports to the MedWatch Program. During the past year rapacuronium (Raplon®) was withdrawn from the market after reports of drug-related bronchospasm that was, in some cases, severe enough to lead to permanent injury or death. Cerivastatin (Baycol®) was also withdrawn from the U.S. market because of reports of rhabdomyolysis that were sometimes fatal.

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 8:00 a.m. to 4:30 p.m. to answer questions regarding ADRs and aid in the documentation of suspected ADRs.

Table 1. Products Most Frequently Cited in the FDA's Adverse Event Reports8
Product	Number of Reports in 2001	Product	Number of Reports in 2001
Rofecoxib (Vioxx®)	6994 (2.48%)	Rosiglitazone (Avandia®)	1965 (0.69%)
Etanercept (Enbrel®)	6789 (2.41%)	Sildenafil (Viagra®)	1642 (0.58%)
Isotretinoin (Accutane®)	3605 (1.28%)	Infliximab (Remicade®)	1635 (0.58%)
Alosetron (Lotronex®)	3190 (1.13%)	Orlistat (Xenical®)	1633 (0.58%)
Celecoxib (Celebrex®)	3087 (1.09%)	Tolterodine (Detrol®)	1515 (0.53%)
Sertraline (Zoloft®)	2834 (1.01%)	Olanzapine (Zyprexa®)	1480 (0.52%)
Atorvastatin (Lipitor®)	2641 (0.93%)	Pioglitazone (Actos®)	1464 (0.52%)
Omeprezole (Prilosec®)	2066 (0.73%)	Azithromycin (Zithromax®)	1413 (0.50%)
Cerivastatin (Bacol®)	1992 (0.70%)	Thalidomide (Thalomid®)	1378 (0.49%)

Table 2. Changes in Product Availability and Labeling Due to Post-Marketing Surveillance
Stavudine (Zerit®) & Didanosine (Videx®) January 2001	The FDA has strengthened the Boxed Warning about reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking stavudine and didanosine in combination with other drugs used to treat HIV.
Linezolid (Zyvox®) March 2001	Information has been added to the Warnings section of this product regarding reports of myelosuppression including anemia, leukopenia, pancytopenia, and thrombocytopenia. The warning describes the need for weekly complete blood counts in certain patient populations.
Famotidine (Pepcid®) March 2001	Information about dosage adjustment in patients with moderate renal impairment (CrCl < 50 ml/min.) have been added to the Precautions and Dosage and Administration sections.
Rapacuronium (Raplon®) March 2001	The injectable anesthesia drug is being voluntarily withdrawn from the market after its manufacturer received reports indicating that the drug may be associated with bronchospasm - a mild to severe inability to breathe normally that can lead to permanent injury or death.
Levomethadyl acetate (Orlaam®) April 2001	The FDA is strengthening warnings about serious cardiac adverse events, including QT prolongation and severe cardiac arrhythmia, associated with this drug for opiate addiction treatment and has added a Boxed Warning.
Cerivastatin (Baycol®) August 2001	The manufacturer is voluntarily withdrawing cerivastatin from the U.S. market because of reports of sometimes fatal rhabdomyolysis from this cholesterol-lowering (lipid-lowering) product.
Topiramate (Topamax®) September 2001	The FDA and the manufacturer have strengthened the Warnings and Precautions sections of this drug indicated as adjunctive therapy for adults and pediatric patients ages 2-16 years with seizure disorders. Cases of secondary angle closure glaucoma characterized by ocular pain, acute myopia, and increased intraocular pressure were reported in pediatric and adult populations. The primary treatment is discontinuation of topiramate. If left untreated, serious sequelae, including permanent vision loss, may occur.
Infliximab (Remicade®) October 2001	A new Boxed Warning notifies health professionals that tuberculosis and other serious opportunistic infections, including histoplasmosis, listeriosis, and pneumocystosis, have been reported in patients on infliximab therapy. Some of these infections have been fatal.
Interferon alfa-2b, recombinant injection (Intron A®) and Ribavirin/Interferon alfa-2b capsules (Rebetol®) October 2001	A Boxed Warning was added to interferon alfa-2b labeling about the drug causing or aggravating fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping interferon alfa-2b therapy.
Capecitabine (Xeloda®) November 2001	The FDA and the manufacturer have added a Boxed Warning in the labeling for capecitabine, indicated for the treatment of colorectal and breast cancer. Postmarketing reports have shown clinically significant increases in prothrombin time and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. Patients receiving concomitant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.
Droperidol (Inapsine®) December 2001	The FDA and the manufacturer added a Boxed Warning in the labeling for droperidol, a tranquilizer used as a premedication for anesthesia, as treatment for nausea after anesthesia, and for sedation of agitated patients. Cases of QT prolongation and/or torsades de pointes have been reported at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Nefazodone (Serzone®) December 2001	The FDA and the manufacturer added a Boxed Warning in the labeling warning about reported cases of life-threatening hepatic failure. Patients should be counseled to be alert to signs & symptoms of liver dysfunction.

References

1. Depakote®ER extended release package insert, 2000.
2. Epilepsia 1994;35(5):1005-15.
3. Epilepsia 1993;34(1):177-83.
4. Perry PJ, Alexander B, Liskow BI, eds. Psychotropic Handbook. Washington, DC. American Psychiatric Press,1997:279.
5. Herfindal ET, Gourley DR, eds. Textbook of Therapeutics: Drug and Disease Management. Baltimore. William & Wilkins,1996:1019.
6. Communication with Abbott Laboratories, 2001.
7. Young LY, Koda-Kimble MA, eds. Applied Therapeutics: The Clinical use of Drugs. Vancouver. Applied Therapeutics, Inc, 1995: 52.22.
8. F-D-C Reports &endash; "The Pink Sheet" 2002;64(3):16-17.

 

LOC and AAOC Designated Unsafe Abbreviations for Ordering Medications There has been much published in the literature about the inherent dangers to patients when unclear abbreviations are used to order medications. The Institute for Safe Medication Practices has identified many abbreviations that have been associated with medication errors.1 In addition, the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) has recently stated that the use of ambiguous orders when prescribing medications for inpatients (including "range orders" such as "acetaminophen 1 to 2 tablets every 4 to 6 hours PRN," or "laxative of choice") is acceptable only if policies or protocols exist which clearly specify to the prescriber and other caregivers how such orders are to be interpreted.2 A review of prescribing practices within the UIHC has identified the use of two problematic abbreviations used to order laxatives and antacids. The designations "LOC" (for "laxative of choice") and "AAOC" (for "antacid of choice") are ambiguous abbreviations frequently used by prescribers when ordering these medication therapies. The Pharmacy and Therapeutics Subcommittee noted that these abbreviations are unclear, potentially associated with medication errors, and inappropriate for patient care orders because other caregivers must determine what the prescriber actually intended the patient to receive. In addition, neither designation is an approved abbreviation within the UIHC; "LOC" has been approved within the UIHC as the abbreviation for "loss of consciousness." Subsequently, the Pharmacy and Therapeutics Subcommittee endorsed a proposal to eliminate the use of both "LOC" and "AAOC" when ordering laxatives and antacids for inpatients. Prescribers must instead clearly identify the drugs, doses, routes, intervals, and indications for use when prescribing these therapies. The "Antacid and Adsorbents" section of the UIHC Formulary and Handbook provides information on the eight antacids available for inpatient use. The Formulary and Handbook also provides information in the "Cathartics and Fecal Softener" section on the 16 laxative products available for inpatient use. As with other unclear abbreviations, Pharmacy staff are authorized not to dispense and Nursing staff are authorized not to administer medications ordered via these nonapproved designations. The policies associated with prescribing medications for inpatients may be found in the Formulary and Handbook at: http://www.vh.orghttp://policies.uihc.uiowa.edu/Governing Body Directives/SectionI/I.23.pdf. 1ISMP Medication Safety Alert newsletter, Institute for Safe Medication Practices, May 2, 2001. 2 http://www.jcaho.org/trkhco_frm.html

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