FDA TO STRENGTHEN RISK MANAGEMENT FOR ISOTRETINOIN
Goal is to decrease fetal exposure.
Isotretinoin (Accutane), a medication used to treat acne, is classified as a pregnancy category X drug and is known to produce serious birth defects and spontaneous abortions. Risk management programs designed to decrease the risk of fetal exposure to isotretinoin have been in effect since 2002. However, several similar programs were in use concurrently, and when the FDA reviewed them in February 2004 it was found that the current practice was not sufficiently effective in preventing fetal exposure to the drug. It was then determined that the concurrency of the several risk management programs confused the health care industry, leading to patients not receiving appropriate counseling and testing before the medication was prescribed. At that time, the FDA recommended that a single program of risk management be used for all versions of isotretinoin, and at the end of November 2004 announced that an agreement between the Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee had been reached and a strengthened risk minimization action plan for the drug would be adopted. Under the revised plan, all of the pharmaceutical companies that market isotretinoin would jointly create a central, common registration database of the prescribers (as was done in the past), and incorporate into it the pharmacies that dispense isotretinoin and the patients who use it (a new feature). The registration system will be redesigned to incorporate physician and patient identification codes for the purpose of protecting the privacy of patients. In addition to maintenance of the registry, the plan will require the completion of several steps before the drug can be dispensed to the patient, as follows:
* complete and thorough education of the patient provided by the prescriber
* an appropriately timed and documented negative pregnancy test
* completion of informed consent, education, and risk management forms by the patient
* electronic or other verification of all of the preceding
The steps are to be completed each time a prescription for isotretinoin is filled, with the exception of the informed consent form, which is to be signed only at the time the first one is written. Other aspects, such as monitoring for unauthorized sale of the drug, are expected to be incorporated into the revised plan.
If any of the steps have not been taken, the drug cannot be dispensed. The reason for the denial of authorization (a positive pregnancy test result, for example) will not be directly communicated to patients through the registry-they will be obliged to obtain the information from the health care provider. The tentative date for implementation of the revised risk minimization action plan is July 2005.
Isotretinoin is one of the five drugs that David Graham, MD, MPH, associate director for science, Office of Drug Safety at the FDA, and an FDA drug reviewer, identified at a U.S. Senate committee meeting held November 18, 2004, as ones that should be withdrawn from the market because of their serious adverse effects. (The others are the lipid-lowering agent Crestor [rosuvastatin], the COX-2 inhibitor analgesic Bextra [valde-coxib], the weight loss drug Meridia [sibutramine], and the asthma drug Serevent Diskus [salmeterol].) While FDA officials were quick to state their official position that those drugs are safe if used correctly, it is interesting that the announcement of the strengthened risk minimization action plan for isotretinoin was made only a few days after Graham's testimony. The FDA states that the proposed revised risk minimization action plan for isotretinoin will not make it substantially more difficult for a woman of childbearing age to obtain the drug.
Nurses should very carefully educate women on the risk that might be incurred if they become pregnant while taking isotretinoin and on the new requirements that must be met in order to have a prescription for the drug filled.
U.S. Food and Drug Administration. FDA talk paper: FDA announces enhancement to isotretinoin risk management program. 2004. http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01328.html; U.S. Food and Drug Administration. Accutane (isotretinoin) questions and answers. 2004. http://www.fda.gov/cder/drug/infopage/accutane/accutane-qa20041123.htm.
LIPID-LOWERING AGENTS AND RHABDOMYOLYSIS
Research study examines their association.
A recently published study provides clarity in regard to the incidence of rhabdomyolysis in patients treated with drugs of the lipid-lowering class, the statins and fibrates.
Myopathy, a disease or abnormality of skeletal muscle, is identified when the serum creatine kinase level is higher than 10 times the upper limit of normal, and has been estimated to occur in 0.1% to 0.5% of patients treated with statins during randomized clinical trials. Rhabdomyolysis is a severe form of myopathy, an acute and sometimes fatal disease in which skeletal muscle is destroyed, releasing myoglobin (known also as myohemoglobin), the pigment that carries oxygen in the muscle. Systemic movement of myoglobin results in myoglobinuria (myoglobin in the urine), which can result in renal damage (manifesting as acute tubular necrosis), especially if the patient is also acutely dehydrated.
The study involved 252,460 patients treated with lipid-lowering agents. The data were retrieved from pharmacy claims records of 11 managed care health plans across the United States and from patient medical records. The information was divided into cohorts according to the specific drug prescribed (statins: atorvastatin, fluvastatin, lovastatin [fluvastatin and lovastatin were excluded from subsequent statistical analysis because the rate of their usage was very low in comparison with that of the other statins], pravastatin, simvastatin, and cerivastatin [cerivastatin was withdrawn from the market after the study began]; fibrates: fenofibrate and gemfibrozil; or combinations of statins and fibrates).
The study revealed 24 cases of patients admitted to the hospital with rhabdomyolysis, all of whom had been receiving doses either within or below the recommended daily range, and almost all of whom presented with muscle pain or weakness. The serum creatine kinase levels among the patients ranged from 15 to 1,780 times the upper limit of normal. Rhabdomyolysis in patients receiving monotherapy with a statin occurred after a mean duration of therapy of 348 days with atorvastatin or simvastatin, 56 days with cerivastatin, and 77 days with gemfibrozil. Combination therapy with a statin and a fibrate decreased the duration of therapy before the incidence of rhabdomyolysis to a mean of 32 days. The estimated incidence rates of rhabdomyolysis induced by monotherapy with any one of the statins currently on the market were statistically the same at 0.44 cases per 10,000 person-years of use. The incidence rate of rhabdomyolysis caused by the fibrates was 2.82 per 10,000 person-years of use, representing a five-and-one-half-fold increase in the risk of the disease, in comparison with statin monotherapy. Combination therapy increased the risk another twofold. Patients receiving combination therapy who were older than 65 and who had diabetes were at particularly great risk.
While it is reassuring to know that the incidence of rhabdomyolysis as a consequence of statin monotherapy is low, the significantly greater risk of the disease associated with combination statin and fibrate therapy, especially in older and diabetic patients, warrants the close monitoring of such patients by the nurse. The education of patients taking lipid-lowering agents should include information describing rhabdomyolysis and the instruction to report any muscle pain or weakness experienced. When a patient reports those symptoms, the nurse should closely examine the serum creatine kinase level for significant elevation. Patients diagnosed with rhabdomyolysis usually need hydration to prevent renal damage.
Graham, DJ, et al. JAMA 2004;292(21): 2585-90.
MULTIPLE SCLEROSIS DRUG PULLED FROM MARKET
After 'fast track' approval, the FDA issues an advisory on natalizumab.
On February 28, after reports of one death and a case of a rare but potentially lethal disease, progressive multifocal leukoencephalopathy, linked to the administration of natalizumab (Tysabri), Biogen Idec voluntarily suspended sales of its drug and halted further clinical trials. That same day, the Food and Drug Administration (FDA) issued a public health advisory to patients and clinicians (see http://www.fda.gov/cder/drug/advisory/natalizumab.htm), after having approved the drug in November 2004 under its "fast track" approval process.
Fast track approval requires the manufacturer to continue its trials of the drug for another year. The findings must demonstrate that it is therapeutic; if they do not, the FDA can withdraw the product from the market more easily than it could according to the standard process. Both patients with reported adverse effects were involved in a clinical trial.
The drug, a monoclonal antibody, was used for limiting exacerbations in patients with remitting-relapsing multiple sclerosis. No other interventions were suggested for the estimated 5,000 patients who have received natalizumab since its approval. -Thomas Schwarz, RN, editorial director, and Diane S. Aschenbrenner, MS, RN, CS
U.S. Food and Drug Administration. First monoclonal antibody treatment for multiple sclerosis approved. 2004. http://www.fda.gov/bbs/topics/news/2004/NEW01141.html; U.S. Food and Drug Administration. Questions and answers on Tysabri (natalizumab).http://www.fda.gov/cder/drug/infopage/natalizumab/natalizumab_QA.htm; U.S. Food and Drug Administration. Label for Tysabri.http://fda.gov/cder/foi/label/2004/125104lbl.pdf