Ezetimibe Side Effect occurred on 2009-01-15
Ezetimibe Side Effect occurred on 2009-01-15
Ezetimibe Side Effect occurred on 2009-01-15
FDA 101: Product Recalls
On this page:
- First Alert
- Alerting the Public
- Effectiveness Checks
- Recall Classifications
- FDA-regulated Products Subject to Recall
Once a product is in widespread use, unforeseen problems can sometimes lead to a recall. Contaminated spinach, for example, led to the recent recall of spinach products under multiple brand names. Contaminated peanut butter led to the recall of thousands of jars of two popular brands. In both cases, FDA responded immediately to minimize harm.
When an FDA-regulated product is either defective or potentially harmful, recalling that product—removing it from the market or correcting the problem—is the most effective means for protecting the public. In most cases, a recall results from an unintentional mistake by the company, rather than from an intentional disregard for the law.
Recalls are almost always voluntary. Sometimes a company discovers a problem and recalls a product on its own. Other times a company recalls a product after FDA raises concerns. Only in rare cases will FDA request a recall. But in every case, FDA’s role is to oversee a company’s strategy and assess the adequacy of the recall.
First Alert
FDA first hears about a problem product in several ways:
- A company discovers a problem and contacts FDA.
- FDA inspects a manufacturing facility and determines the potential for a recall.
- FDA receives reports of health problems through various reporting systems.
- The Centers for Disease Control and Prevention (CDC) contacts FDA.
When it comes to illnesses associated with food products, Dorothy J. Miller, Director of FDA’s Office of Emergency Operations, says that FDA generally first hears of these kinds of problems from CDC.
“CDC hears about such problems from state health departments that have received and submitted illness reports,” she says. “An ongoing outbreak means that we have an emergency, and when there’s a public health crisis like this, you need to tell the public immediately.”
Alerting the Public
FDA seeks publicity about a recall only when it believes the public needs to be alerted to a serious hazard. When a recalled product has been widely distributed, the news media is a very effective way to reach large numbers of people. FDA can hold press conferences, issue press releases, and post updates to its Web site regularly, to alert people.
“It’s about being as transparent as possible,” says Catherine McDermott, public affairs manager in the Division of Federal-State Relations in FDA’s Office of Regulatory Affairs. “If we feel there is that much of a health risk, we will offer media updates every day to give new information, and all that we know gets posted to FDA’s Web site.”
Not all recalls are announced in the media. But all recalls go into FDA’s weekly Enforcement Report. This document lists each recall according to classification (see “Recall Classifications” box), with the specific action taken by the recalling firm.
Effectiveness Checks
FDA evaluates whether all reasonable efforts have been made to remove or correct a product. A recall is considered complete after all of the company’s corrective actions are reviewed by FDA and deemed appropriate. After a recall is completed, FDA makes sure that the product is destroyed or suitably reconditioned, and investigates why the product was defective in the first place.
Recall Classifications
These guidelines categorize all recalls into one of three classes, according to the level of hazard involved:
Class I: Dangerous or defective products that predictably could cause serious health problems or death. Examples include: food found to contain botulinum toxin, food with undeclared allergens, a label mix-up on a lifesaving drug, or a defective artificial heart valve.
Class II: Products that might cause a temporary health problem, or pose only a slight threat of a serious nature. Example: a drug that is under-strength but that is not used to treat life-threatening situations.
Class III: Products that are unlikely to cause any adverse health reaction, but that violate FDA labeling or manufacturing laws. Examples include: a minor container defect and lack of English labeling in a retail food.
FDA-regulated Products Subject to Recall
- human drugs
- animal drugs
- medical devices
- radiation-emitting products
- vaccines
- blood and blood products
- transplantable human tissue
- animal feed
- cosmetics
- about 80 percent of the foods eaten in the United States
FDA Issues Update to Safety Review on Cholesterol-Lowering Drugs
The U.S. Food and Drug Administration today reaffirmed its position that elevated
amounts of low-density lipoprotein (LDL), or “bad cholesterol,” are
a risk factor for cardiovascular diseases such as heart attack, stroke and
sudden death and that lowering LDL cholesterol reduces the risk of these diseases.
FDA’s comments are contained in an update to its Jan. 25, 2008, Early Communication describing the agency’s review of data from ENHANCE, a clinical trial comparing Zocor (simvastatin), a drug that lowers cholesterol production in the liver, to Vytorin, a drug that combines Zocor with another drug, Zetia (ezemtimibe), which inhibits cholesterol absorption.
Preliminary results from ENHANCE (Effect of Combination Ezetimibe and High-Dose
Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients
with Heterozygous Familial Hypercholesterolemia) had indicated there was no
significant difference between Vytorin and Zocor-treated patients in the thickness
of the walls of the blood vessels of the neck (the carotid arteries) although
there was greater lowering of the amount of LDL cholesterol in patients with
Vytorin compared to Zocor.
Measuring the thickness of the carotid arteries via ultrasound imaging is
considered a biomarker of risk for cardiovascular disease.
FDA has now completed its review of the final clinical trial report of ENHANCE.
After two years of treatment, there was no significant difference in carotid
artery thickness between Vytorin patients and Zocor patients. However, the
levels of LDL cholesterol, decreased by 56% in the Vytorin group and decreased
by 39% in the Zocor group.
The results from ENHANCE do not change FDA’s position on the benefits
of lowering LDL cholesterol. Based on currently available data, patients should
not stop taking Vytorin or other cholesterol-lowering drugs and should talk
to their doctor or other health care professional if they have any questions
about Vytorin, Zetia or the ENHANCE trial.
FDA’s Early Communications are disclosures that the agency has begun
evaluating new data about a drug and is considering regulatory action, but
has yet to reach a conclusion.
FDA 101: Medication Errors
FDA 101: Medication Errors
On this page:
A medication error is any preventable event that may cause or lead to inappropriate medication use or harm to a patient. Since 2000, the Food and Drug Administration (FDA) has received more than 95,000 reports of medication errors. FDA reviews reports that come to MedWatch, the agency’s adverse event reporting program.
“These reports are voluntary, so the number of actual medication errors is believed to be higher,” says Carol Holquist, R.Ph., Director of the Division of Medication Error Prevention in FDA’s Center for Drug Evaluation and Research.
FDA works with many partners to track medication errors, including the U.S. Pharmacopeia (USP) and the Institute for Safe Medication Practices (ISMP). “Every report received through the USP/ISMP Voluntary Medication Error Reporting Program (MERP) automatically gets sent to FDA’s MedWatch program,” says Mike Cohen, R.Ph., Sc.D., President of ISMP. “It takes a cooperative approach to monitor errors, evaluate them, and educate the public about strategies to keep errors from happening again.”
Medication errors occur for a variety of reasons. For example, miscommunication of drug orders can involve poor handwriting, confusion between drugs with similar names, poor packaging design, and confusion of metric or other dosing units.
“Medication errors usually occur because of multiple, complex factors,” says Holquist. “All parts of the health care system—including health professionals and patients—have a role to play in preventing medication errors.”
FDA’s Role
- Drug Name Review:
To minimize drug name confusion, FDA reviews about 400 drug names a year that companies submit as proposed brand names. The agency rejects about one-third of the names that drug companies propose. - Drug Labels:
FDA regulations require all over-the-counter (OTC) drug products (more than 100,000) to have a standardized “drug facts label.” FDA has also improved prescription drug package inserts for health care professionals. - Drug Labeling and Packaging:
FDA works with drug companies to reduce the risk of errors that may result from similar-looking labeling and packaging, or from poor product design. - Bar Code Label Rule:
In accordance with an FDA rule that went into effect in 2004, bar codes are required on product labels for certain drugs and biologics such as blood. When used with bar code scanner and computerized patient information systems, bar code technology can help ensure that the right dose of the right drug is given to the right patient at the right time. - Error Analyses:
FDA reviews about 1,400 reports of medication errors per month and analyzes them to determine the cause and type of error. - Guidances for Industry:
FDA is working on three new guidances—one on complete submission requirements for anaylsis of trade names, one about the pitfalls of drug labeling, and another on best test practices for naming drugs. - Public Education:
FDA spreads the message about medication error prevention through public health advisories, medication guides, and outreach partnerships with other organizations.
Examples of Medication Errors
Misuse of Tussionex Prescription Cough Medicine:
On March 11, 2008, FDA informed health care professionals about adverse events and deaths in children and adults who have taken Tussionex Pennkinetic Extended-Release Suspension (Tussionex). Tussionex is a long-acting prescription cough medicine.
Hydrocodone, the narcotic ingredient in this medicine that controls cough, can cause life-threatening breathing problems when too much medicine is given at one time or when the medicine is given more frequently than recommended. Tussionex should not be used in children less than 6 years old.
Reports indicate that health care professionals have prescribed Tussionex for patients younger than the approved aged group of 6 years old and older, more frequently than the labeled dosing interval of every 12 hours (“extended release”), and that patients have administered the incorrect dose due to misinterpretation of the dosing directions and the use of inappropriate measuring devices. Overdose of Tussionex in older children, adolescents, and adults has also been associated with life-threatening and fatal breathing problems.
For more information, see FDA Issues Alert on Tussionex at www.fda.gov/bbs/topics/NEWS/2008/NEW01805.html
and the FDA Public Health Advisory at www.fda.gov/cder/drug/advisory/hydrocodone.htm
Overdoses of Cough and Cold Products in Children:
Roughly 7,000 children ages 11 and younger are treated in hospital emergency rooms each year because of overdoses of OTC cough and cold medication, according to a recent study by the Centers for Disease Control and Prevention. About two-thirds of those incidents occurred when children took medication without a parent’s knowledge. Parents should keep medication out of children’s reach and should never describe medication as “candy.”
OTC cough and cold products can be harmful if more than the recommended amount is used, if they are given too often, or if more than one product containing the same active ingredient is used. In January 2008, FDA issued a public health advisory recommending that OTC cough and cold products not be used in infants and children under 2.
Serious injuries and deaths have resulted from such errors as misunderstanding directions and failing to use the measuring devices that come with the medicine. For more information, see OTC Cough and Cold Products: Not for Infants and Children Under 2 Years of Age. www.fda.gov/consumer/updates/coughcold011708.html
Overdoses of Acetaminophen:
Taking too much of the pain reliever acetaminophen can lead to serious liver damage. The drug is sold under brand names such as Tylenol and Datril, and is also available in many cough and cold products, prescription pain relievers, and sleep aids.
To avoid accidental overdosing, consumers should not take more than the recommended dose on the label. Also, acetaminophen should not be taken for more days than recommended, and should not be taken with other drug products that also contain acetaminophen without direction from a health care provider.
Parents should be cautious when giving acetaminophen to children. For example, the infant drop formula is three times more concentrated than the children’s liquid. So parents need to be sure to give the appropriate dose.
Misuse of Fentanyl Patches:
FDA has issued warnings about the fentanyl transdermal system, an adhesive patch that delivers an opioid called fentanyl through the skin. An opioid is a potent pain medicine. It is also sometimes called a narcotic drug. Other examples of opioids include hydrocodone, morphine, and oxycodone.
The directions on the product label and package insert of the fentanyl transdermal system should be followed exactly in order to avoid overdose. Fentanyl patches should not be used for short-term acute pain, pain that is not constant, or for pain after an operation. The patch is only for moderate-to-severe chronic pain that is expected to last for any number of weeks or longer and that cannot be managed by acetaminophen-opioid combinations, nonsteroidal analgesics, or as-needed dosing with short-acting opioids.
Fentanyl patches are mostly prescribed for patients with cancer. Recent reports to FDA describe deaths and life-threatening side effects after doctors and other health care professionals inappropriately prescribed the patch to relieve pain after surgery, for headaches, or for occasional or mild pain in patients who were not opioid tolerant.
In other cases, patients have used the patch incorrectly. The patients replaced the patch more frequently than directed in the instructions, applied more patches than prescribed, or applied heat to the patch. All of these cases resulted in dangerously high fentanyl levels in the blood.
For more information, see FDA Issues Second Safety Warning on Fentanyl Skin Patch www.fda.gov/bbs/topics/NEWS/2007/NEW01762.html
FDA Public Health Advisory www.fda.gov/cder/drug/advisory/fentanyl_2007.htm
Overdoses with Methadone:
FDA has issued a public health advisory cautioning practitioners to avoid overdoses when they are prescribing methadone or managing patients taking the drug.
Since the 1970s, methadone has been primarily used in treating drug abuse, but it is increasingly being used to treat pain. FDA issued the advisory because of reports of life-threatening adverse events and death in patients receiving methadone for pain control. Like other opioids, methadone causes slowed breathing, affects heart rate, and can also interact with other drugs. An overdose can occur because methadone stays in the body longer than the pain relief lasts.
For more information, see FDA’s Public Health Advisory on methadone www.fda.gov/cder/drug/advisory/methadone.htm
Mix-ups Between Edetate Disodium and Edetate Calcium Disodium:
Both edetate disodium and edetate calcium disodium work by binding with heavy metals or minerals in the body, allowing them to be passed out of the body through the urine. Edetate calcium disodium was approved to treat severe lead poisoning. Edetate disodium was approved as an emergency treatment for certain patients with very high levels of calcium in the blood or certain patients with heart rhythm problems resulting from high amounts of the medication digoxin in the blood.
But a number of uses that are not approved by FDA have emerged. These include the removal of other heavy metals from the blood and the treatment of heart disease, commonly referred to as “chelation therapies.”
In January 2008, FDA issued a public health advisory, warning that some children and adults have died when they were mistakenly given edetate disodium instead of edetate calcium disodium (calcium disodium versenate), or when edetate disodium was used for chelation therapies and other uses not approved by FDA.
The drugs are easily mistaken for each other because they have very similar names and are both commonly referred to only as “EDTA.” One of FDA’s recommendations is that the abbreviation not be used.
For more information, see FDA’s Public Health Advisory on Edetate Disodium (marketed as Endrate and generic products) www.fda.gov/cder/drug/advisory/edetate_disodium.htm
For More Information
6 Tips to Avoid Medication Mistakes
www.fda.gov/consumer/updates/medtips062107.html
Medication Errors (FDA)
www.fda.gov/cder/drug/MedErrors/default.htm
Reporting Adverse Experiences to FDA
www.fda.gov/medwatch/how.htm
Institute for Safe Medication Practices
www.ismp.org
U.S. Pharmacopeia
Date Posted: March 14, 2008
Drug Safety Communications
Drug Safety Communications posted by FDA from May 1, 2008 to August 31, 2008 (advisories are available at www.fda.gov/cder/drug/DrugSafety/DrugIndex.htm)
Footnote:
1 Early Communication about an Ongoing Safety Review
Medication Errors
Medication Errors
Medication errors are “any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the healthcare professional, patient, or consumer” (see http://www.nccmerp.org/aboutMedErrors.html). These errors may be related to professional practice, the product itself, and/or the procedures and systems related to distribution, dispensing and administration of drugs. For instance, drugs may be given names, shapes, or colors similar to other medications. As illustrated below, similarities in product packaging may result in confusion among healthcare professionals charged with dispensing drugs or among patients taking drugs at home (see Illustration 1).
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Illustration 1  Illustration 1. This illustration is an example of similar looking packaging from the same manufacturer for two unrelated drugs. On the left are 50 mg tablets of hydroxyzine HCL, a sedating antihistamine. On the right are 50 mg tablets of hydralazine HCL, an antihypertensive drug. The packaging of these products may lead to a serious medication error. |
Although medication errors can and do occur — FDA has received over 95,000 reports of medication errors since the year 2000 — it is difficult to assess how frequently such errors occur in medical and pharmacy practice. Medication errors such as those involving the wrong drug, an extra or wrong dose, omission of a drug, administering a drug by the wrong route or at an incorrect time are commonly reported to the FDA. Many of these errors can be prevented simply by communicating more effectively. However, some types of errors may require additional interventions such as a change in the product name, labeling and/or packaging to help minimize the likelihood of further confusion. Continued training and vigilance is essential in helping healthcare professionals and FDA reduce the likelihood of an error being made. Reporting medication errors to FDA via MedWatch, or to FDA’s partners in this effort, the Institute for Safe Medical Practices (ISMP) and the U.S. Pharmacopeia via their MedMarx program, helps FDA identify factors leading to errors that can be corrected, lessening the likelihood of their recurrence (see http://www.fda.gov/cder/drug/MedErrors/default.htm).
Challenges to Preventing Medication Errors
There are numerous challenges to preventing medication errors. It is common practice, depending on the healthcare setting, to have many individuals involved in the prescribing, dispensing and administration of a medication (e.g., physicians, nurses, pharmacists, and the patient) with the potential for an error to occur at any step in the process. Healthcare professionals should be aware of the sources and types of medication errors so that they may better identify and avoid potential problems before they occur.
There are many steps that healthcare professionals can take to reduce the occurrence of medication errors at the point of prescribing a medication. Two major sources of errors in prescribing are poor penmanship and the use of error-prone abbreviations. For instance, healthcare professionals should be cognizant of their penmanship and use computerized prescriber order entry (CPOE, see below), if available, to lessen any confusion that may result from poorly written prescriptions (see Illustration 2).
There are certain error-prone abbreviations, symbols and dose designations that healthcare professionals should avoid. For example, the abbreviation for microgram, “μg”, is often misread for milligram, “mg”, when written. FDA and ISMP recommend that the abbreviation “mcg” be used in lieu of “μg”. Another common source of misinterpretation and error is the use of the decimal point and a trailing zero. Writing “1.0 mg” can be read as “10 mg” if the decimal point is not clearly visible. Similarly, “.1″ mg can be misinterpreted as “1 mg”. FDA and ISMP recommend that no trailing zeros be used when denoting doses expressed as whole numbers and that preceding zeros be used whenever a decimal point is needed for a dose that must be administered as a fraction of a whole number. Certain abbreviations can also be misread, for example “HCL”, hydrochloride, and “KCL”, potassium chloride. FDA and ISMP recommend that the complete drug name be used unless expressed as a salt of the drug. By avoiding the use of abbreviations, symbols and dose designations that are easily confused with each other, the risk of error can be greatly reduced. For a list of error-prone abbreviations, symbols and dose designations, healthcare professionals are referred to http://www.ismp.org/Tools/errorproneabbreviations.pdf 
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Illustration 2  Illustration 2. This illustration is an example of a hand-written prescription for Metadate ER 10 mg tablets. Metadate is a drug used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Due to the similarity in name, poor penmanship and the omission of the modifier “ER”, the pharmacy filling the prescription incorrectly dispensed methadone 10 mg tablets. Methadone is a morphine-based product used as a heroin substitution therapy and analgesic. Methadone is not used for the treatment of ADHD. |
As noted above, another way healthcare professionals can minimize the confusion over handwritten prescriptions (and their misinterpretation; see Illustration 2), and/or potential errors that may result in a drug’s misuse, is through the use of technology. For example, CPOE technology is an electronic data entry system that allows healthcare professionals to communicate instructions about a patient at either the point-of-care or remotely. Although not every institution uses CPOE, data have shown that CPOE simplifies and streamlines a patient’s care, and significantly reduces medication errors.1 Estimates of the proportion of hospital that have fully implemented CPOE systems range from 37% to 50%.1 CPOE is capable of storing medical histories and can alert healthcare professionals to, among other things, drug allergies, and dangerous drug-drug or drug-device interactions.
A 2008 review of the effects of CPOE on medication errors [MEDLINE (1966 to April 2006) and EMBASE (1976 to April 2006)] indicated that most studies report significant reductions in the relative risk of medication errors when CPOE is used.2 Specifically, 25 of the 27 studies evaluated show a relative risk reduction for medication errors of 13% to 99%. These data strongly support the use of CPOE for the reduction of medication errors.
Another important way to avoid prescribing errors is for healthcare professionals to be up-to-date on the latest information for a product, especially for a drug that may not be commonly used. The professional product label is the best source for information on indications, proper use, and adverse events associated with a drug. The product label is updated as new information becomes available. The label provides important information that healthcare professionals should know prior to prescribing a drug. For instance, a boxed warning, when used, often contains information about serious adverse reactions (e.g., life-threatening) that should be considered when weighing the benefits of prescribing a drug. Special restrictions and distribution programs are also highlighted in boxed warnings.
Starting in 2006, the professional product label has a new look. Included at the top of the label is a highlights section. This feature makes key prescribing information about the drug readily accessible and provides an index to the rest of the information in the label.3 Healthcare professionals should always consult the drug label prior to prescribing a drug they are unfamiliar with or when there has been an update to the prescribing information. The most recent drug labels can be readily accessed on the National Library of Medicine’s DailyMed website.
FDA’s Role in Reducing Medication Errors
In addition to ensuring that drug labels contain accurate, up-to-date information, FDA also takes an active role identifying factors that may contribute to the incorrect distribution, dispensing, or taking of a medication (see http://www.fda.gov/cder/drug/MedErrors/default.htm). FDA has promulgated regulations (e.g., bar codes) and developed programs aimed at mitigating medication errors. FDA has taken steps to ensure that drug packaging be compatible with emerging technologies (e.g., CPOE). Here are three examples of how FDA is working to reduce medication errors.
Drug names: FDA reviews drug names from both a promotional and safety perspective. The safety review focuses on the avoidance of error. FDA considers whether the proposed name looks and sounds like the names of drug products that are already marketed in the US and evaluates this risk using Failure Mode and Effects Analysis, a process by which potential failures in a system (e.g., drug design) and the effects of such failures (e.g., medication errors) can be assessed. When evaluating the promotional aspects of the name, FDA considers if the proposed name/label is misleading because it overstates the efficacy, minimizes the risk, broadens the indication, makes unsubstantiated superiority claims for the product, or is overly fanciful. The safety goal of this review is to reduce name and label confusion prior to the drug entering the market. Of approximately 400 drug name and labels submitted for approval by pharmaceutical companies each year, FDA rejects one-third for reasons of, but not limited to, appropriateness, similar spelling and pronunciation of the drug name to another currently marketed product, ambiguity in a drug name and/or identifier, or being misleading.
Over-the-counter (OTC) Drug Labeling: For OTC drugs, consumers must rely on the information on the package in order to safely and properly use these medications, or to give them to children or others they are caring for. The OTC label is the primary mechanism by which all necessary safety and effectiveness information associated with the use of the OTC drug is conveyed to the consumer. In 1999, FDA redesigned and standardized the components of the OTC label so that information about the drug is readily available and can be easily read by the consumer. The label describes the purpose of the compound and any safety information and warnings associated with the drug. The label also clearly outlines how to use the drug appropriately. In addition, standardization of the OTC label reduces confusion among OTC drugs as a class.
Bar Codes: In 2004, FDA published a final rule requiring a bar code be placed on all drugs distributed and used in hospital settings. According to the rule, manufacturers, repackers, relabelers and private label distributors of drug products commonly used in hospitals must place a bar code on their product. The function of the bar code is to reduce error by increasing standardization among products so that, in conjunction with bar code scanning technology, the right patient can get the right drug at the right time. Supporting the use of bar codes are reports indicating that bar codes reduce dispensing errors and adverse drug events by 96% and 97%, respectively.4 In 2006, the American Society of Health-System Pharmacists (ASHP) reported that 13.2% of hospitals have adopted technology that utilizes bar code technology. This rate constitutes a 3.8% increase in bar code utilization from the previous year.5 The bar code rule highlights FDA’s commitment to patient safety by integrating new labeling components that works with new technology.
By increasing awareness about medication errors, and instituting rules that standardize the use and promotion of medications, FDA seeks to reduce the incidence of medication errors and the impact these errors have on patients, families and the healthcare system. FDA closely monitors medication error reports as they are received, and issues warnings and/or intercedes when necessary. Healthcare providers are encouraged to continue to report medication errors to MedWatch or through FDA’s partner organizations such as the ISMP.
Relevant Websites
FDA’s medication error website
Institute for Safe Medical Practices
U.S. Pharmacopeia MedMarx Program
References
- Ammenwerth E, Schnell-Inderst P, Machan C, Siebert U. The Effect of Electronic Prescribing on Medication Errors and Adverse Drug Events: A Systematic Review. J Am Med Inform Assoc. 2008 Jun 25. [Epub ahead of print]
- Ford EW, McAlearney AS, Phillips MT, et al. Predicting computerized physician order entry system adoption in US hospitals: can the federal mandate be met? Int J Med Inform. 2008;77(8):539-45.
- Requirements on Content and Format of Labeling for Human Prescription drug and biological Products and Draft Guidances and Two Guidances for Industry on the Content and Format of Labeling for Human Prescription Drug and Biological Products: Final Rule and Notices . Federal Register. January 24, 2006; 71(15):3922-3997.
- Poon EG, Cina JL, Churchill W, et al. Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy. Ann Intern Med. 2006; 145(6):426-34.
- Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration–2005. Am J Health Syst Pharm. 2006; 63(4):327-45.
- Amiodarone (Cordarone) product labeling.
- Simvastatin (Zocor) product labeling.
- Ezetimibe/Simvastatin (Vytorin) product labeling.
- Niacin extended-release/Simvastatin (Simcor) product labeling.
- Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med. 2007;2:210-18.
- Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289(13):1681-90.
- The SEARCH Collaborative Group. SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study. N Engl J Med. 2008 Jul 23. [Epub ahead of print]
- Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother. 2006;40(4):753-57.
- Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Laboratory reference values. N Engl J Med. 2004; 351(15):1548-63.
A Dangerous Drug-Device Interaction
Icodextrin (marketed as EXTRANEAL) and point-of-care glucose monitoring
A Dangerous Drug-Device Interaction
FDA continues to receive reports of adverse events, including fatalities, related to a drug-device interaction associated with the use of icodextrin (Extraneal), a peritoneal dialysis solution, and certain point-of-care glucose monitoring devices that do not use a glucose-specific test strip. Icodextrin is broken down into maltose in vivo. Some test strips used with portable glucose meters cannot differentiate between maltose, glucose and other sugars as they use methods that are not glucose-specific. The test strips associated with this drug-device interaction use glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO) as reagents. Examples of meters currently using these types of test strips include the Accu-Chek (manufactured by Roche) and FreeStyle (manufactured by Abbott) models. We urge healthcare providers and patients to refer to test strip package inserts or to consult the glucose monitoring device and test strip manufacturer(s) to confirm the glucose methodology in any system that is to be used for monitoring patients receiving icodextrin.† A list of toll free numbers for glucose monitor and test strip manufacturers is available at the Baxter Renal Clinical Help Line (1-888-RENAL-HELP).
Due to the presence of maltose in the blood of a patient receiving Extraneal therapy, the use of test strips that are not glucose-specific provides falsely elevated glucose readings. Falsely elevated blood glucose readings may lead to inappropriate insulin administration, which has caused hypoglycemia, coma, and death. Additionally, cases of true hypoglycemia can go untreated if masked by falsely elevated glucose readings.
As indicated in the Warning section of Extraneal’s label, blood glucose measurement in patients receiving Extraneal must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose released from Extraneal. Glucose-specific methods (i.e., methods that are not affected by this interaction) include those that use glucose oxidase, glucose hexokinase, glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), or flavin adenine dinucleotide glucose dehydrogenase (FAD-GDH) based reagents.
This drug-device interaction was identified prior to approval of icodextrin and it is described in product labeling. Several safety measures, including patient/healthcare professional education, have been undertaken by the manufacturer. Because FDA continues to receive reports of this adverse event, we are highlighting this drug-device interaction in additional FDA communications to the public. For a complete discussion on this drug-device interaction, including detailed case reports, see the recent FDA communiqué in the Institute for Safe Medication Practices’ (ISMP) publication Medication Safety Alert.
Footnote
† A comprehensive list of FDA-cleared GDH-PQQ and GDO blood glucose monitoring systems is not provided because any such list may become outdated or inadvertently exclude systems distributed under multiple trade names. Note, some product lines include test strips that use more than one type of enzyme methodology. Further, manufacturers of GDH-PQQ systems currently on the market may subsequently change to non-GDH-PQQ methodology. Thus, patients and healthcare providers should consult the test strip package insert or contact the glucose monitoring device and test strip manufacturer(s) for information on the type of methodology used.
Relevant Links and Related Information
FDA Patient Safety News (Avoiding Glucose Monitoring Errors in Patients Receiving Other Sugars):
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/transcript.cfm?show=55#2
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/transcript.cfm?show=48#4
ISMP Medication Safety Alert (Be aware of false glucose results with point-of-care testing)
Interaction between amiodarone (marketed as CORDARONE and PACERONE) and simvastatin (marketed as ZOCOR and generics)
Interaction between amiodarone (marketed as CORDARONE and PACERONE) and simvastatin (marketed as ZOCOR and generics) or simvastatin-combination products (marketed as VYTORIN and SIMCOR)
Amiodarone potentiates the risk for simvastatin-associated rhabdomyolysis
FDA continues to receive reports of rhabdomyolysis in patients given amiodarone in combination with higher doses of simvastatin. Amiodarone is an antiarrhythmic drug indicated to treat certain types of recurrent ventricular arrhythmias. Simvastatin is a 3-hydroxy-methylglutaryl-coenzyme A reductase inhibitor (statin) used to lower cholesterol levels. As with all statins, the risk of rhabdomyolysis is dose-related and increased by high plasma levels of statin. Patients who take amiodarone with simvastatin doses greater than 20 mg daily have an increased risk of rhabdomyolysis. The precise mechanism for this drug interaction is unknown, but stems, in part, from amiodarone’s inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme, the same enzyme that metabolizes simvastatin (see Illustration 1). This interaction may result in an increase in the levels of simvastatin in the plasma, potentiating the risk of rhabdomyolysis. Labeling for all of the amiodarone (Cordarone and the generic drug Pacerone)1 and simvastatin-containing products [Zocor2, ezetimibe/simvastatin (Vytorin3) and niacin/simvastatin (Simcor4)] describe this potential risk.
Rhabdomyolysis, a severe form of myopathy, involves injury to and breakdown of skeletal muscles, which in some cases leads to renal failure and death.5 There are multiple etiologies for rhabdomyolysis, including, but not limited to, exposure to certain drugs, including statins.6,7 Healthcare professionals should be aware of the increased risk of rhabdomyolysis when amiodarone is taken concomitantly with doses of simvastatin that exceed 20 mg daily. Prescribers should avoid doses of simvastatin greater than 20 mg per day in patients taking amiodarone (the maximum recommended simvastatin dose is 80 mg daily).
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Illustration 1 Amiodarone-Simvastatin Interaction – Postulated Mechanism  Illustration 1. This illustration depicts a postulated mechanism for the amiodarone-simvastatin interaction, including the subsequent impact of this interaction on skeletal muscle and the kidney. In the first column, amiodarone inhibits the enzyme CYP3A4, limiting simvastatin metabolism (depicted by dashed arrow). By limiting the metabolism of simvastatin, there is an increase in levels of circulating simvastatin in the blood. In the second column, high circulating simvastatin levels may result in myotoxicity in the skeletal muscles (rhabdomyolysis). The rapid breakdown of muscle protein produces excessive levels of myoglobin in the blood. In the third column, myoglobin, now at high circulating levels, reaches the kidneys where it can obstruct renal tubules and lead to acute renal failure. *Amiodarone’s direct inhibition of CYP3A4 has been characterized as weak, suggesting that other factors may also contribute to how these two drugs interact. |
Both the simvastatin and amiodarone labels were changed in 2002 to reflect the increase in risk for myopathy when amiodarone is taken concurrently with simvastatin.1-4 The simvastatin label (Warnings, Precautions and Dosage and Administration sections) specifically indicates that the dose of simvastatin should not exceed 20 mg daily in patients concomitantly receiving amiodarone, and that the combined use of simvastatin and amiodarone at simvastatin doses higher than 20 mg daily should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The amiodarone label (Precaution section) notes that there is an increased risk for myopathy/rhabdomyolysis when amiodarone is taken in combination with HMG-CoA reductase inhibitors that are CYP 3A4 substrates, such as simvastatin.
Since this labeling change was made, FDA has received 52 additional U.S. reports of rhabdomyolysis associated with the concurrent use of amiodarone and simvastatin. This article summarizes FDA’s analysis of these 52 cases from FDA’s Adverse Event Reporting System (AERS) database dating from January 1, 2003 to January 1, 2008.
Reported Cases of Rhabdomyolysis
The 52 cases of rhabdomyolysis reported to AERS involved patients ranging in age from 50 to 88 years (median age was 73). Thirty-seven patients (71%) were male and 10 were female (19%). The sex was not reported for the remaining five patients (10%). In half of the reported rhabdomyolysis cases (26/52), amiodarone was being taken in combination with 80 mg simvastatin. Thirteen patients (25%) were taking amiodarone in combination with 40 mg simvastatin, while four patients (8%) were taking amiodarone with 20 mg simvastatin. One patient (2%) developed rhabdomyolysis when taking amiodarone with 5 mg simvastatin. Eight patients (15%) were taking an unknown dose of simvastatin in combination with amiodarone.
Regarding other concomitant medications, 37 patients (71%) were taking medications in addition to amiodarone and simvastatin. These drugs included diuretics (20), beta-blockers (18), angiotensin-converting enzyme inhibitors (16) and insulin (11). Among the concurrent medications taken by these patients, all except for niacin and levofloxacin are either substrates for and/or inhibitors of CYP3A4. These medications included gemfibrozil (9), angiotensin II receptor blockers (3), clarithromycin or levofloxacin (2), protease inhibitors (2), niacin (2), fenofibrate (1), atorvastatin (1), and risperidone (1). The labels of several of these products reflect the risk of rhabdomyolysis when they are used as monotherapy or when administered concurrently with simvastatin.
The mean time interval between the initiation of amiodarone therapy in conjunction with simvastatin (or simvastatin therapy in conjunction with amiodarone) and the onset of rhabdomyolysis was five months (median-2 months). Specifically, 42% of the cases (22) indicated that symptoms of rhabdomyolysis emerged within 2 months of the initiation of concurrent amiodarone-simvastatin therapy. Forty percent of the cases (21) did not report the time interval between the onset of rhabdomyolysis and the initiation of amiodarone-simvastatin therapy.
Ninety-two percent of rhabdomyolysis cases (48) required hospitalization. Twenty-eight percent of the reported cases (15) were considered life-threatening. Ten percent of patients (5) who developed rhabdomyolysis were noted to have become disabled. One death was reported (2%).
Three representative case reports of amiodarone-simvastatin associated rhabdomyolysis are described in Box 1. These cases were selected based on their representation of the demographics and circumstances usually reported with amiodarone/simvastatin-associated rhabdomyolysis. In addition to being reported to AERS, Case 3 has also been published in the scientific literature.8
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Box 1 Case 1 A 74-year-old male was hospitalized with ventricular tachycardia. While hospitalized, the patient underwent coronary artery bypass graft surgery and was subsequently started on ezetimibe/simvastatin (10/40 mg daily). At the time of discharge, the patient was also prescribed amiodarone 200 mg (to be taken twice daily), aspirin, ramipril, and metoprolol. Three weeks following his discharge from the hospital, the patient complained of extreme muscle weakness. His creatinine level was “highly elevated”. A diagnosis of rhabdomyolysis was made. Ezetimibe/simvastastin was discontinued and the patient recovered. Case 2 A 50-year-old male was hospitalized for coronary artery bypass graft surgery. During his hospitalization, the patient developed atrial fibrillation and was started on amiodarone 400 mg (taken three times daily). The next day, the patient was also started on ezetimibe/simvastatin 10/80 mg daily. Six days following the initiation of simvastatin, the patient experienced progressive leg weakness with a creatine kinase (CK) of 117,400 units/L (for males, normal reference range: 60 to 400 units/L) and a serum creatinine (SCr) of 3.5 mg/dL (normal reference range: <1.5 mg/dL).9 The patient was transferred to the intensive care unit and ezetimibe/simvastatin was discontinued. Three days after the discontinuation of simvastatin, the patient’s CK and SCr levels had decreased to 26,700 units/L and 2 mg/dL, respectively. Case 3 In 2004, a 72-year-old white male was hospitalized complaining of aches and weakness in his thighs. He also noted that his urine was dark for the week prior to his admission. He had a history of diabetes mellitus, hyperlipidemia, hypertension, azotemia, and coronary artery disease. In the summer of 2004, the patient had bypass surgery. Immediately following his bypass surgery, the patient was started on 200 mg amiodarone (taken once daily). One month later, simvastatin (80 mg/day) was prescribed. Other concomitant medications included metformin, enalapril, glimepiride, hydrochlorothiazide and aspirin. Laboratory testing at the time of the most recent hospital admission indicated a CK level of 19,620 units/L (for males, reference range: 60 to 400 units/L)9 and a SCr of 2.6 mg/dL (normal reference range: <1.5 mg/dL).9 Rhabdomyolysis was suspected and simvastatin was immediately discontinued. Amiodarone was also discontinued four days after discontinuation of simvastatin. Within one day of stopping simvastatin, CK and SCr levels began to fall. Thirteen days after admission to the hospital, CK was 323 units/L and SCr was 1.7 mg/dL. |
The concomitant use of amiodarone with simvastatin reduces the dose threshold for simvastatin-associated rhabdomyolysis. The cessation of symptoms (and lowering of laboratory values indicative of rhabdomyolysis) after discontinuation of one or both of these drugs indicates that muscle breakdown can be halted and reversed if identified early. Healthcare professionals should be aware that amiodarone may potentiate the risk for simvastatin-associated rhabdomyolysis. Simvastatin doses greater than 20 mg day daily should be avoided in patients taking or initiating amiodarone therapy. Prescribers should consider use of another statin for patients on amiodarone or initiating amiodarone therapy who require simvastatin doses greater than 20 mg daily to meet their lipid goals.
Relevant Website
Patient information sheet on amiodarone
References
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