Pradaxa (dabigatran): Drug Safety Communication – Lower Risk for Stroke and Death, but Higher Risk for GI Bleeding Compared to Warfarin
AUDIENCE: Cardiology, Patient, Pulmonology, Internal Medicine, Orthopedics, Neurology
ISSUE: The FDA recently completed a new study in Medicare patients comparing Pradaxa to warfarin, for risk of ischemic or clot-related stroke, bleeding in the brain, major gastrointestinal (GI) bleeding, myocardial infarction (MI), and death. The new study included information from more than 134,000 Medicare patients, 65 years or older, and found that among new users of blood-thinning drugs, Pradaxa was associated with a lower risk of clot-related strokes, bleeding in the brain, and death, than warfarin. The study also found an increased risk of major gastrointestinal bleeding with use of Pradaxa as compared to warfarin. The MI risk was similar for the two drugs.
Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of post-market data, and employed a more sophisticated analytical method to capture and analyze the events of concern. This study’s findings, except with regard to MI, are consistent with the clinical trial results that provided the basis for Pradaxa’s approval. As a result of these latest findings, the FDA still considers Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use.
BACKGROUND: Pradaxa and warfarin are used to reduce the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non-valvular atrial fibrillation (AF).
RECOMMENDATION: Patients should not stop taking Pradaxa (or warfarin) without first talking with their health care professionals. Stopping the use of blood-thinning medications such as Pradaxa and warfarin can increase the risk of stroke and lead to permanent disability and death. Health care professionals who prescribe Pradaxa should continue to follow the dosing recommendations in the drug label.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:
• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the MedWatch safety alert, including links to the Press Release and Class I Recall notice, here. (Posted 05/14/14)
Methylphenidate ADHD Medications: Drug Safety Communication – Priapsim
Including Concerta, Daytrana, Focalin/Focalin XR, Metadate CD/Metadate ER, Methylin/Methylin ER, Quillivant XR, Ritalin/Ritalin LA/Ritalin SR
ISSUE: FDA is warning that methylphenidate products, one type of stimulant drug used to treat attention deficit hyperactivity disorder (ADHD), may in rare instances cause prolonged and sometimes painful erections known as priapism. Based on a recent review of methylphenidate products, FDA updated drug labels and patient Medication Guides to include information about the rare but serious risk of priapism. If not treated right away, priapism can lead to permanent damage to the penis.
Priapism can occur in males of any age and happens when blood in the penis becomes trapped, leading to an abnormally long-lasting and sometimes painful erection. Another ADHD drug, Strattera (atomoxetine), has also been associated with priapism in children, teens, and adults.
Priapism appears to be more common in patients taking atomoxetine than in those taking methylphenidate products; however, because of limitations in available information, FDA does not know how often priapism occurs in patients taking either type of product.
See the FDA Drug Safety Communication for additional information, including a Data Summary.
BACKGROUND: Methylphenidate products are central nervous system (CNS) stimulants used to treat attention deficit hyperactivity disorder (ADHD).
RECOMMENDATION: Healthcare professionals should talk to male patients and their caregivers to make sure they know the signs and symptoms of priapism and stress the need for immediate medical treatment should it occur. Younger males, especially those who have not yet reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs.
Encourage your patients to read the Medication Guide they receive with every filled prescription. Use caution when considering switching patients from methylphenidate to atomoxetine. Patients should not stop taking a methylphenidate product without first discussing it with your health care professional.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:
• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication. (Posted 12/17/13)
Onfi (clobazam): Drug Safety Communication – Risk of Serious Skin Reactions
AUDIENCE: Neurology, Pharmacy, Dermatology
ISSUE: FDA is warning the public that the anti-seizure drug Onfi (clobazam) can cause rare but serious skin reactions that can result in permanent harm and death. FDA approved changes to the Onfi drug label and the patient Medication Guide to describe the risk of these serious skin reactions.
These skin reactions, called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), can occur at any time during Onfi treatment. However, the likelihood of skin reactions is greater during the first 8 weeks of treatment or when Onfi is stopped and then re-started. All cases of SJS and TEN in the FDA case series have resulted in hospitalization, one case resulted in blindness, and one case resulted in death. See the FDA Drug Safety Communication for a Data Summary and additional information.
The Onfi drug label has been revised to add information about the risk for serious skin reactions to the Warnings and Precautions section and to the Medication Guide.
BACKGROUND: Onfi is a benzodiazepine medication used in combination with other medicines to treat seizures associated with a severe form of epilepsy called Lennox-Gastaut Syndrome.
RECOMMENDATION: Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment or when re-introducing therapy. Health care professionals should discontinue use of Onfi and consider an alternate therapy at the first sign of rash, unless it is clearly not drug-related.
Patients taking Onfi should seek immediate medical treatment if they develop a rash, blistering or peeling of the skin, sores in the mouth, or hives. Patients should not stop taking Onfi without first talking to their health care professionals. Stopping Onfi suddenly can cause serious withdrawal problems, such as seizures that will not stop, hallucinations, shaking, nervousness, and stomach or muscle cramps.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:
– Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the MedWatch safety alert, including links to the FDA Drug Safety Communication and prescribing information (label).
FDA MedWatch – Low Molecular Weight Heparins: Recommendations to Decrease Risk of Spinal Column Bleeding and Paralysis
ISSUE: The U.S. Food and Drug Administration (FDA) is recommending that health care professionals carefully consider the timing of spinal catheter placement and removal in patients taking anticoagulant drugs, such as enoxaparin, and delay dosing of anticoagulant medications for some time interval after catheter removal to decrease the risk of spinal column bleeding and subsequent paralysis after spinal injections, including epidural procedures and lumbar punctures. These new timing recommendations, which can decrease the risk of epidural or spinal hematoma, will be added to the labels of anticoagulant drugs known as low molecular weight heparins, including Lovenox and generic enoxaparin products and similar products.
BACKGROUND: Serious adverse events continue to occur (see Data Summary). To address this safety concern, FDA worked with the manufacturer of Lovenox, Sanofi-Aventis, to further evaluate this risk and to update the Warnings and Precautions section of the Lovenox label with these additional timing recommendations. The labels for generic enoxaparin products will also be revised accordingly, as will those of other low molecular weight heparin-type products.
RECOMMENDATION: Health care professionals and institutions involved in performing spinal/epidural anesthesia or spinal punctures should determine, as part of a preprocedure checklist, whether a patient is receiving anticoagulants and identify the appropriate timing of enoxaparin dosing in relation to catheter placement or removal. To reduce the potential risk of bleeding, consider both the dose and the elimination half-life of the anticoagulant:
*For enoxaparin, placement or removal of a spinal catheter should be delayed for at least 12 hours after administration of prophylactic doses such as those used for prevention of deep vein thrombosis. Longer delays (24 hours) are appropriate to consider for patients receiving higher therapeutic doses of enoxaparin (1 mg/kg twice daily or 1.5 mg/kg once daily).
*A post procedure dose of enoxaparin should usually be given no sooner than 4 hours after catheter remova
*In all cases, a benefit-risk assessment should consider both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.
For Complete MedWatch Safety Alert including link to Drug Safety Communication please click here.
Iclusig (Ponatinib): Reports Of Serious Blood Clots In Arteries And Veins
UPDATED 10/31/2013. FDA has asked, and Ariad Pharmaceuticals has agreed, to suspend marketing and sales of Iclusig (ponatinib), a leukemia chemotherapy drug, because of the risk of life-threatening blood clots and severe narrowing of blood vessels.
ISSUE: FDA is investigating an increasing frequency of reports of serious and life-threatening blood clots and severe narrowing of blood vessels (arteries and veins) of patients taking the leukemia chemotherapy drug Iclusig (ponatinib). Data from clinical trials and postmarket adverse event reports show that serious adverse events have occurred in patients treated with Iclusig, including heart attacks resulting in death, worsening coronary artery disease, stroke, narrowing of large arteries of the brain, severe narrowing of blood vessels in the extremities, and the need for urgent surgical procedures to restore blood flow.
BACKGROUND: Iclusig is a prescription medicine used to treat adults diagnosed with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), who are no longer benefiting from previous treatment or who did not tolerate other treatment. In the most recent clinical trial data submitted by the manufacturer to FDA, at least 20 percent of all participants treated with Iclusig have developed blood clots or narrowing of blood vessels.
RECOMMENDATION: Health care professionals should consider for each patient, whether the benefits of Iclusig treatment are likely to exceed the risks of treatment. Patients taking Iclusig should seek immediate medical attention if they experience symptoms suggesting a heart attack such as chest pain or pressure, pain in their arms, back, neck or jaw, or shortness of breath; or symptoms of a stroke such as numbness or weakness on one side of the body, trouble talking, severe headache, or dizziness.
More information is available here.
FDA Drug Safety Communication: Anti-seizure drug Potiga (ezogabine) linked to retinal abnormalities and blue skin discoloration
Safety Announcement
[04-26-2013] The U.S. Food and Drug Administration (FDA) is warning the public that the anti-seizure medication Potiga (ezogabine) can cause blue skin discoloration (See Photos) and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. All patients taking Potiga should have a baseline eye exam, followed by periodic eye exams. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available.
Pigment changes in the retina have the potential to cause serious eye disease with loss of vision. It is not yet known whether the retinal pigment changes caused by Potiga lead to visual impairment, although several patients have been reported to have impaired visual acuity.
The skin discoloration in the reported cases appeared as blue pigmentation, predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Scleral and conjunctival discoloration, on the white of the eye and inside eyelids, has been observed as well. The skin discoloration generally occurred after four years of treatment with Potiga, but has appeared sooner in some patients (See Data Summary). In some cases, retinal abnormalities have been observed in the absence of skin discoloration.
In light of this new safety information, all patients taking Potiga or about to start Potiga should have an eye exam, followed by periodic eye exams thereafter (See Information for Health Care Professionals). Potiga should be discontinued if ophthalmic changes are observed unless no other treatment options are available. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication.
Patients should not stop taking Potiga or any anti-seizure medication without talking to their health care professional, as stopping anti-seizure treatment suddenly can precipitate withdrawal seizures, a serious and life-threatening medical problem.
Gilenya (fingolimod) – Drug Safety Communication: Investigating Rare Brain Infection
ISSUE: FDA is alerting the public that a patient in Europe diagnosed with possible multiple sclerosis (MS) has developed a rare and serious brain infection after taking the drug Gilenya (fingolimod). This is the first case of progressive multifocal leukoencephalopathy (PML), reported following the administration of Gilenya to a patient who had not previously received Tysabri (natalizumab), an MS drug associated with a higher risk of PML.
BACKGROUND: PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that damages the fatty covering of the brain called myelin. PML usually causes death or severe disability. Gilenya is used to treat relapsing forms of MS, a nervous system disease that affects the brain and spinal cord. Novartis reports that approximately 71,000 patients worldwide have been treated with Gilenya.
RECOMMENDATION: Patients should not stop taking Gilenya without first discussing any questions or concerns with their health care professionals. FDA is providing this alert while continuing to investigate the PML case, and is working with Gilenya’s manufacturer, Novartis, to obtain and review all available information about this occurrence. FDA will communicate its final conclusions and recommendations after the evaluation is complete.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of this product to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:
• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the complete MedWatch Safety Alert, including a link to the Drug Safety Communication. (Posted 08/29/13)
FDA MedWatch – AED Potiga (Ezogabine) Linked To Retinal Abnormalities And Blue Skin Discoloration
FDA is warning the public that the anti-seizure medication Potiga (Ezogabine) can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available. More (05/06/13)
FDA MedWatch – Valproate: Changed to Pregnancy Category X in Prevention of Migraine Headaches
ISSUE: FDA is advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, are contraindicated and should not be taken by pregnant women for the prevention of migraine headaches. Based on information from a recent study, there is evidence that these medications can cause decreased IQ scores in children whose mothers took them while pregnant. Stronger warnings about use during pregnancy will be added to the drug labels, and valproate’s pregnancy category for migraine use will be changed from “D” (the potential benefit of the drug in pregnant women may be acceptable despite its potential risks) to “X” (the risk of use in pregnant women clearly outweighs any possible benefit of the drug). More (05/06/13)
Zolpidem – FDA Lowers Recommended Dose
Including Ambien, Ambian CR, Edluar, and Zolpimist
ISSUE: The FDA recommends that the bedtime dose (see below) be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving.
For zolpidem products, data show the risk for next-morning impairment is highest for patients taking the extended-release forms of these drugs (Ambien CR and generics). Women appear to be more susceptible to this risk because they eliminate zolpidem from their bodies more slowly than men.
Because use of lower doses of zolpidem will result in lower blood levels in the morning, FDA is requiring the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower the recommended dose.
RECOMMENDATIONS:
**The recommended dose of zolpidem for women should be lowered from 10 mg to 5 mg for immediate-release products (Ambien, Edluar, and Zolpimist) and from 12.5 mg to 6.25 mg for extended-release products (Ambien CR).
**For zolpidem and other insomnia drugs, prescribe the lowest dose that treats the patient’s symptoms.
**Inform patients that impairment from sleep drugs can be present despite feeling fully awake.
**The recommended doses of Intermezzo, a lower dose zolpidem product approved for middle-of-the-night awakenings, are not changing. At the time of Intermezzo’s approval in November 2011, the label already recommended a lower dosage for women than for men.
Click here for more information. (01/14/2013)
Teva’s Adderall 30 mg Tablets: Counterfeit Product – Contains Wrong Active Ingredients
FDA is warning consumers and health care professionals about a counterfeit version of Teva Pharmaceutical Industries’ Adderall 30 milligram tablets that is being purchased on the Internet. FDA’s preliminary laboratory tests revealed that the counterfeit version of Teva’s Adderall 30 mg tablets contained the wrong active ingredients. Adderall contains four active ingredients – dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate. Instead of these active ingredients, the counterfeit product contained tramadol and acetaminophen, which are ingredients in medicines used to treat acute pain. More(05/30/12)
FDA Safety Communication: Chronic Cerebrospinal Venous Insufficiency Treatment in Multiple Sclerosis Patients
The FDA is alerting people with MS to the risks of serious injuries and death associated with procedures to treat chronic cerebrospinal venous insufficiency (CCSVI). Furthermore, the benefits of these experimental procedures have not been proven, and their promotion as a treatment for MS may lead people with the disease to make treatment decisions without being aware of the serious risks involved. The communication is also intended to notify physicians and clinical investigators planning or conducting clinical trials using medical devices to treat CCSVI that they must comply with FDA regulations for investigational devices. The FDA sent a warning letter to a sponsor/investigator who was conducting a clinical study of CCSVI treatment without an approved IDE. Because the FDA currently considers clinical studies evaluating CCSVI treatment with balloon angioplasty devices and/or stents to be significant risk, this study was in violation of the FDA’s regulations. The sponsor/investigator has reported the study has been voluntarily closed.
See here for more information. (05/16/12)
From John W. Henson, MD, FAAN
Neurological Complications of New Melanoma Drug Ipilimumab
Imilimumab (YERVOY) is a new monoclonal antibody used in the treatment of melanoma. It can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; including the peripheral nervous system. Other severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. See:http://packageinserts.bms.com/pi/pi_yervoy.pdf. [Ed note: Neurological cases have included GBS, “motor” neuropathy, and a myoenteric inflammatory neuropathy presenting with severe constipation. JWH] (March 23, 2012)
Tysabri (natalizumab): New Risk Factor for PML
ISSUE: FDA notified healthcare profesisonals that testing positive for anti-JC virus (JCV) antibodies has been identified as a risk factor for progressive multifocal leukoencephalopathy (PML). PML is a rare but serious brain infection associated with use of Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) or Crohn’s disease. A patient’s anti-JCV antibody status may be determined using an anti-JCV antibody detection test that has been analytically and clinically validated, and has been ordered by a healthcare professional. The Stratify JCV Antibody ELISA test2 was cleared by FDA on January 20, 2012. Testing positive for anti-JCV antibodies means that a person has been exposed to JCV in the past. RECOMMENDATION: The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more of the other known risk factors for PML. Patients with all three known risk factors* have an estimated risk of PML of 11/1,000 users See the Drug Safety Communication Data Summary section for additional information. Read more. Editor’s note: The three risk factors are: 1) greater than two years on therapy, 2) prior use of immunosuppressant therapy, and 3) JC virus antibody positivity. See hereregarding test availability. (January 23, 2012)
FDA MedWatch: Valproate – Risk of Impaired Cognitive Development in Children Exposed In Utero
FDA notified healthcare professionals that children born to mothers who take the anti-seizure medication valproate sodium or related products (valproic acid and divalproex sodium) during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy. This conclusion is based on… (see more at this link) (06/30/11)
FDA MedWatch – Coumadin 5 mg Tablets May Have Higher than Expected Potency
Bristol-Myers Squibb initiated a voluntary recall of one lot of 1,000-count bottles of Coumadin (warfarin sodium) Crystalline 5 mg tablets. Company testing of tablets from a returned bottle found a tablet to be higher in potency than expected. The lot number affected in the U.S. is 9H49374A with an expiry date of September 30, 2012. Patients who may have 5 mg tablets should not interrupt their therapy but should seek advice from their pharmacist to see if they have tablets originating from the affected lot and if so, should consult their physician for appropriate medical advice. More (05/04/11)
FDA MedWatch: Tysabri (natalizumab): Update of Healthcare Professional Information
FDA has updated the Tysabri (natalizumab) Prescribing Information to give new information about the size of the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection, associated with use of Tysabri for the treatment of multiple sclerosis (MS) and Crohn’s disease. The update includes new safety information about patients who have taken other drugs that suppress the immune system, who may be at a higher risk for PML. More (04/26/11)
FDA MedWatch – Topamax (topiramate): Recall – Musty Odor
NOTICE: Ortho-McNeil Neurologics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., is recalling two lots of Topamax (topiramate) 100mg Tablets. The recall stems from four consumer reports of an uncharacteristic odor thought to be caused by trace amounts of TBA (2,4,6 tribromoanisole). While not considered to be toxic, TBA can generate an offensive odor and a small number of patients have reported temporary gastrointestinal symptoms. There have been no reported serious adverse events caused by the presence of TBA in Topamax. RECOMMENDATION: Patients taking Topamax 100mg Tablets who experience an uncharacteristic odor associated with their medication should return the tablets to their pharmacist, and contact their healthcare professional if they have questions. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program. More (04/15/11)
CDC Clinical Reminder: Spinal Injection Procedures Performed without a Facemask Pose Risk for Bacterial Meningitis
The Centers for Disease Control and Prevention (CDC) is concerned about the occurrence of bacterial meningitis among patients undergoing spinal injection procedures that require injection of material or insertion of a catheter into epidural or subdural spaces (e.g., myelogram, administration of spinal or epidural anesthesia, or intrathecal chemotherapy). Outbreaks of bacterial meningitis following these spinal injection procedures continue to be identified among patients whose procedures were performed by a healthcare provider who did not wear a facemask (e.g., may be labeled as surgical, medical procedure, or isolation mask),[1] with the most recent occurrence in October 2010 (CDC unpublished data). This notice serves as a reminder that facemasks should always be worn by healthcare providers when performing these spinal injection procedures. More (04/06/11)
FDA MedWatch – Dabigatran Capsules: Special Requirements
Due to the potential for product breakdown from moisture and loss of potency, dabigatran capsules should only be dispensed and stored in the original bottle or blister package. Pharmacists should only dispense Pradaxa in the original manufacturer bottle with the original dessicant cap. Do not repackage Pradaxa capsules in standard amber pharmacy vials. Patients should not store or place Pradaxa capsules in any other container, such as pill boxes or pill organizers. Open only one bottle of Pradaxa at a time. Once the bottle is opened, the product must be used within 60 days. More (03/31/11)
FDA Approves Gadavist (gadobutrol) on March 14, 2011
Gadavist is the sixth gadolinium-based contrast agent (GBCA) approved by the FDA for use in patients undergoing magnetic resonance imaging of the central nervous system. It is indicated for adults and children ages 2 years and older. Gadavist is more concentrated than the other GBCAs and should be administered at half the volume. Gadavist is currently considered to be one the GBCAs with a lower risk of nephrogenic systemic fibrosis NSF, and is not one of the GBCAs that is contraindicated in patients with acute kidney injury or chronic, severe kidney disease. Those receiving Gadavist during the studies reported headache and nausea as the most common adverse reactions. Other adverse events associated with Gadavist included hypersensitivity reactions, involving cardiovascular, respiratory, or skin effects ranging from mild to severe. More(03/17/11)