1. Aschenbrenner, Diane S. MS, RN, CS

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New warnings and a common error.

Case reports on Adderall and Adderall XR, an amphetamine approved for treatment of attention deficit and hyperactivity disorder, have indicated that the drug is associated with sudden unexplained death in children.


Sudden unexplained death has been associated with amphetamine abuse, but the new reports specifically suggest a possible problem in children with underlying cardiac abnormalities who receive the recommended dosage; in some instances, sudden unexplained death has occurred even in children without an underlying cardiac abnormality. While the case reports prompted Health Canada to suspend sales of Adderall but not remove it from the Canadian market, the U.S. Food and Drug Administration (FDA) has not yet taken any action.


The FDA reviewed its own adverse events reporting system database for the 1999 to 2003 period and identified cases of sudden unexplained death in 12 children, five of whom had undiagnosed cardiac abnormalities. At this time the FDA's opinion is that there are insufficient data showing that the recommended dosages of Adderall can cause sudden unexplained death, but it's recommending that the drug be avoided by both children and adults with structural cardiac abnormalities (see and The FDA is continuing its evaluation.


A warning has been added to the labeling of tiagabine (Gabitril), a drug approved as adjunctive therapy in the treatment of partial seizures. Between 1997 and 2004 there were 59 postmarketing reports of seizures, including status epilepticus, occurring in patients receiving tiagabine who did not have a history of epilepsy and who were taking the drug for off-label usage, usually as adjunctive treatment for a psychiatric illness.


Most of those patients also were receiving drugs believed to lower the seizure threshold, such as antidepressants, antipsychotics, stimulants, or opioid analgesics. Some case reports state that when a patient developed seizures the prescriber either continued tiagabine or increased the dosage as a way to control or prevent further seizures. The dosing of tiagabine is based on the premise that the concurrent administration of an antiepileptic drug that induces the activity of the cytochrome P-450 enzyme system would decrease the amount of circulating tiagabine, which is metabolized by that system.


But patients taking tiagabine alone therefore would not metabolize the drug as rapidly, and a level of circulating tiagabine higher than that expected would be achieved, possibly causing seizures, the exact mechanism of which is unknown. Prescribers are being strongly encouraged to avoid the off-label applications of tiagabine, but if it is prescribed for reasons other than to treat partial seizures, nurses should be alert to potential seizure activity.


A warning has been added to the labeling of promethazine (Phenergan), and revisions have been made to its contraindications and dosage and administration sections, after the emergence of postmarketing case reports of possibly fatal respiratory depression when it's used in children less than two years of age. Promethazine, available in tablets and suppositories, is now labeled as contraindicated for use in that population. Caution should be exercised in giving it to children two years of age or older.


A significant newly discovered drug interaction has prompted the revision of the warnings on the labeling of saquinavir (Invirase, Fortovase). Drug-induced hepatitis with significantly elevated hepatic enzyme levels (as high as 20 times normal) has occurred when "ritonavir-boosted saquinavir" (ritonavir 100 mg-saquinavir 1,000 mg) is administered with rifampin. Ritonavir and the various formulations of saquinavir are antiretroviral agents used in the treatment of HIV infection. Rifampin is an antitubercular drug.


Because tuberculosis has become an increasingly prevalent comorbidity among HIV-infected patients, the drugs often are administered concurrently. However, rifampin should not be administered to patients receiving "ritonavir-boosted saquinavir."


Recent medication errors have been reported in regard to two drugs with similarly spelled names. Zyprexa, the trade name of olanzapine, an atypical antipsychotic, has been confused with Zyrtec, the trade name of cetirizine, an antihistamine used to treat allergic rhinitis and chronic urticaria. In addition to the names starting with the same letter, the drugs have congruous dose denominations (5 mg and 10 mg), are both taken once daily, and commonly are stored near each other on pharmacy shelves.


Patients who take Zyrtec instead of Zyprexa may have relapses of psychosis. Prescribers of either drug should use either the generic name only or both the trade and generic names when writing prescriptions. They should specify the reason for the prescription to prevent any confusion as to which of the two drugs is intended.


For more information on these safety alerts, visit the FDA's Safety Information and Adverse Reporting Program-MedWatch-at


U.S. Food and Drug Administration. FDA fact sheet: FDA improvements in drug safety monitoring. 2005.



Cardiovascular risk possibly a 'class effect.'

Shortly after the withdrawal of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib (Vioxx) from the market after it had been shown to increase the risk of cardiovascular events, there emerged concern regarding the other two COX-2 inhibitors, valdecoxib (Bextra) and celecoxib (Celebrex).


Rather than there being an adverse effect specific to one drug, as first was suggested when rofecoxib was taken off the market, it appears that the COX-2 inhibitors have a "class effect," meaning that all drugs in the class produce comparable adverse effects.


The National Cancer Institute and Pfizer, the manufacturer of celecoxib, stopped the administration of the drug in an ongoing clinical trial (the Adenoma Prevention with Celecoxib study) conducted to investigate whether it is effective in preventing colon polyps because it was found to significantly increase the risk of cardiovascular events among patients in the trial groups receiving it, in comparison with those receiving placebo. Patients participating in that study received drug therapy for 2.8 and 3.1 years, and the adverse effects seen were related to dose, the higher ones being more likely to produce the cardiovascular events. Although not all of the research into celecoxib has revealed those adverse effects, most of the other studies have been short-term ones.


The preliminary findings of an unpublished, comparable study (the Prevention of Spontaneous Adenomatous Polyps trial) comparing celecoxib taken once daily with placebo do not reveal an increase in cardiovascular risk, and neither did one in which the use of the drug among older adults was investigated. The findings of the latter study, however, do support others that have indicated that rofecoxib heightens the risk of myocardial infarction, especially at higher doses. The third COX-2 inhibitor, valdecoxib, has been shown to increase the risk of cardiovascular events in patients who have recently undergone coronary artery bypass grafting and was one of five drugs identified at a U.S. Senate committee meeting on November 18, 2004, as drugs that should be withdrawn from the market.


The FDA has withdrawn valdecoxib from the market, but celecoxib still is available, despite the class effect that has been identified, apparently because of the conflicting findings of the various clinical studies. Rofecoxib must be reevaluated by the FDA if the manufacturer seeks to have the drug reinstated. The labeling of celecoxib will include both a boxed warning, pertaining to the entire nonsteroidal antiinflammatory drug (NSAID) class, of the heightened risk of cardiovascular events as well as of gastrointestinal effects (gastric bleeding and ulceration), and clinical trial data representing findings of the increased cardiovascular risk associated with the drug.


Also, a Medication Guide for patients, describing the cardiovascular and gastrointestinal risks associated with NSAIDs, especially celecoxib, will be dispensed with the drug. The FDA has requested also that Pfizer conduct a long-term study on the safety of celecoxib, in comparison with that of naproxen and other NSAIDs, and that manufacturers of over-the-counter NSAIDs also revise drug labels to include more specific information on cardiovascular and gastrointestinal risks. And because valdecoxib has been determined to increase the risk of serious skin reactions, such as Stevens-Johnson syndrome, the labels of over-the-counter NSAIDs also will bear warnings of possible skin reactions, representing the first time that a drug that bears a black box warning in its prescription form is allowed to be sold in over-the-counter strengths. No research to date indicates that the latter drugs pose a risk to patients who use low doses of them (the recommended over-the-counter dose) for short periods of time to treat acute pain, and they are not being considered for removal from the market at present.


Understandably, patients are confused by the recent changes. Nurse practitioners who prescribe drugs should be aware that the most prudent action at this time is to choose an alternate therapy for patients who would otherwise be taking a COX-2 inhibitor. At least, the identified risks should be minimized by keeping the daily dosage as low as possible.


Bresalier RS, et al. N Engl J Med 2005; 352(11):1092-102; Levesque LE, et al. Ann Intern Med 2005;142(7):481-9; Nussmeier NA, et al. N Engl J Med 2005;352(11): 1081-91; Solomon SD, et al. N Engl J Med 2005;352(11):1071-80.



Drug trials, approval process questioned.

This month, Drug Watch looks at the continuing Food and Drug Administration (FDA) alerts concerning Adderall and other drugs. Recent columns have discussed the possible serious adverse effects of other approved drugs, such as the pediatric "suicidality" with which anti-depressants have been associated and cardiovascular incidents associated with the cyclooxygenase-2 (COX-2) inhibitors rofecoxib (Vioxx), valdecoxib (Bextra), and celecoxib (Celebrex).


The FDA approval process calls for the conducting of clinical trials involving enough patients to provide statistical reliability, but the number required is far lower than the number who receive the drug in general practice after its approval. So it is only after a vast number of patients have been taking a drug for extended periods that all of its possible adverse effects can be known. Nurses and other providers should help to educate patients in the drug approval process and in the unknown potential for risk inherent in the use of a newly approved drug.


The FDA has received much public criticism in light of reports of serious adverse effects of approved drugs. In an effort to regain the public trust, and to create a climate of candor, forthrightness, and enhanced oversight, the agency has announced that it will institute an independent drug safety board to oversee the management of important drug safety issues within its Center for Drug Evaluation and Research. The members of it will be appointed by the FDA commissioner and will be FDA experts and medical experts at other U.S. Department of Health and Human Services agencies. Further, in response to criticism to the effect that it withholds data, and that those that it does post on its Web site are difficult to find and understand, the FDA plans to create special Web pages to improve access to emerging data and risk information for the benefit of providers and consumers.


The FDA's action on the COX-2 inhibitors furthered the controversy. In February of this year, an FDA advisory committee recommended that all of the COX-2 drugs be allowed to remain on the market, but with black box warnings (see page 30). The swiftness of the FDA's April 7 decision to withdraw valdecoxib, but not celecoxib, and later reconsider rofecoxib (at the request of the manufacturer), and the stringency of the restriction were somewhat unexpected. The official FDA position is that the advisory committee's recommendations are never binding, yet its decision is interesting in light of the emergence, in news articles, of the concern that some of the committee members had been engaged in a "conflict of interest." Some served as consultants in the drug industry, an issue that the agency, in fact, addressed in a Web posting (, in which it states that members were assessed for conflict of interest and that although some was identified, it was not deemed sufficient to warrant their exclusion from voting.


Controversy as to whether the FDA went too far in its decision, or not far enough, persists, and some feel that celecoxib should also be removed from the market.


U.S. Food and Drug Administration. FDA fact sheet: FDA improvements in drug safety monitoring. February 15, 2005.; U.S. Food and Drug Administration. FDA statement on the halting of a clinical trial of the COX-2 inhibitor celebrex. 2004.; U.S. Food and Drug Administration. FDA public health advisory: FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). 2005.

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