Recalls and Safety Alerts from the FDA

Jennifer Kwon, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
VA Medical Center
West Palm Beach, FL

RECALLS

Baxter Recall on IV Solutions
Baxter International Inc. issued a voluntary recall on two lots of intravenous (IV) solutions due to the potential presence of particulate matter. The particulate matter has been determined to be an insect and was identified from a customer complaint. There have been no adverse events reported. For a full list of recalled products, visit http://www.fda.gov/ Safety/ Recalls/ucm479877.htm.

Downing Labs Recall in Texas
Downing Labs, LLC, in Farmers Branch, TX, voluntarily recalled all lots of sterile products compounded and packaged by Downing Labs due to concerns of sterility assurance. These products were distributed in the United States and the United Kingdom to patients and providers between April 20, 2015, and September 15, 2015. The recall does not affect any nonsterile, compounded medications prepared by Downing Labs. There have been no adverse events reported related to this recall. http://www.fda.gov/ Safety/ Recalls/ucm468215.htm

 Medistat RX Recall in Alabama

Medistat RX, LLC, in Foley, AL, issued a voluntary recall of all non- expired products produced for sterile use due to possible contamination. These products were distributed between November 1, 2014, and September 3, 2015. The U.S. Food and Drug Administration (FDA) has received reports of several adverse events that are possibly associated with Medistat drug products. Healthcare professionals and patients are encouraged to report adverse reactions or quality problems experienced with the use of drug products produced by Medistat to the FDA’s MedWatch Adverse Event Reporting program. http://www.fda.gov/ Safety/ Recalls/ucm461939.htm

Medline Industries Recall on Acetaminophen
Medline Industries, Inc. announced a voluntary nationwide recall on lot #45810 of Acetaminophen tablets, 500 mg, uncoated compressed tablets. This recall was due to an error in labeling. The Acetaminophen tablets of 500 mg are incorrectly labeled as being 325 mg. The recalled lot was distributed nationwide from June 12, 2015–September 18, 2015. There have been no adverse events reported related to this recall. http://www.fda.gov/ Safety/ Recalls/ucm467049.htm

 Pharmedium Recall on Norepinephrine Bitartrate
Pharmedium Services, LLC, in Lake Forest, IL, has recalled 29 lots of 4 mg norepinephrine bitartrate (16 mcg/mL) added to 0.9% sodium chloride in 250 mL Viaflex Bag and three lots of 8 mg norepinephrine bitartrate (32 mcg/mL) added to 0.9% sodium chloride in 250 mL Viaflex Bag distributed to hospitals. This recall was due to discoloration in the admixture, which could be indicative of degradation leading to decreased potency. There have been no adverse events reported related to this recall. For a full list of affected products, visit http://www.fda.gov/ Safety/ Recalls/ucm479677.htm.

Sanofi Recall on Auvi-Q®
Sanofi US issued a voluntary recall on all Auvi-Q® (epinephrine injection, USP), including all Auvi-Q® currently on the market, due to inaccurate dosage delivery. The lot numbers involved are 2081278 through 3037230 with expiration dates of October 2015 through December 2016. The recall applies to both the 0.15 mg and 0.3 mg strengths for hospitals, retailers, and consumers. As of October 26, 2015, Sanofi has received 26 reports of suspected device malfunctions in the United States and Canada, but these device malfunction reports have not yet been confirmed. No fatal outcomes have been reported in these cases. http://www.fda.gov/ Safety/ Recalls/ucm469980.htm

 US Compounding, Inc. Recall in Arkansas
US Compounding, Inc. (USC) of Conway, AR, voluntarily recalled all lots of sterile products compounded and packaged by USC. This recall was due to the lack of sterility assurance. These products were distributed nationwide to patients, providers, hospitals, and clinics be- tween March 14, 2015, and September 9, 2015. The recall does not apply to any nonsterile compounded medications made by USC. http://www.fda.gov/ Safety/ Recalls/ucm464071.htm

SAFETY ALERTS

Afatinib (Gilotrif®)
The updated adverse reactions section of the drug labeling includes the incidence of nausea and vomiting seen in clinical trials experience. Reports of pancreatitis have been added to the postmarketing experience. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm480999.htm

 Azacitadine (Vidaza®)
The postmarketing experience has been updated to include reported cases of necrotizing fasciitis. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm289980.htm

Bendamustine (Treanda®)
The warnings and precautions section of the package labeling for bendamustine has been revised to include the risk for reactivation of infections including hepatitis, cytomegalovirus, mycobacterium tuberculosis, and herpes zoster. Clinical and laboratory monitoring, prophylaxis, and treatment should be provided for infection and infection reactivation prior to administration of the drug. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm204021.htm

 Bevacizumab (Avastin®)
Nonmandibular osteonecrosis and posterior reversible encephalopathy syndrome (PRES) are now included in the postmarketing experience section of the prescribing information. Nonmandibular osteonecrosis can be found in the pediatric use section, as well. The risk of renal injury has been added to the adverse reactions section of the drug labeling. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm275758.htm

 Bortezomib (Velcade®)
The updated prescribing information for bortezomib includes use in the pediatric population. This update was based on a pediatric study, Study AALL071P1, which was a phase 2 pilot trial using bortezomib in combination with intensive reinduction therapy for children with re- lapsed acute lymphoblastic leukemia and lymphoblastic lymphoma. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ SafetyRelatedDrugLabelingChanges/ucm123444.htm

Clofarabine (Clolar®)
Hepatobiliary disorders have been added to the postmarketing experience under the adverse reactions section of the package labeling. The warnings and precautions now include the risk of hepatitis and hepatic failure. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm338244.htm

 Crizotinib (Xalkori®)
The warnings and precautions section of the prescribing information for crizotinib has been updated to include a subsection for severe visual loss, inclusion of safety information across multiple clinical studies, and modifications to the embryofetal toxicity subsection. The use in specific populations has also been updated to comply with the Pregnancy and Lactation Labeling Rule (PLLR). http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm295722.htm

 Deferasirox (Jadenu®)
Renal tubular necrosis and gastrointestinal perforation has been added to the postmarketing experience. In the warnings and precautions section of the prescribing information, the risk of gastrointestinal (GI) hemorrhage, and severe skin reactions are now listed. Reports have been made including deaths from GI hemorrhage, especially in elderly patients who had advanced hematologic malignancies or low plate- lets. Patients on deferasirox therapy should be monitored for signs and symptoms of GI ulceration and hemorrhage. The risk of GI hemorrhage may be increased with concurrent administration of drugs that have hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs, corticosteroids, oral bisphosphonates, or anticoagulants. Rashes may occur while on deferasirox therapy. For mild to moderate rashes, deferasirox may be continued since the rash will likely resolve on its own. Severe skin reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported. If any of these serious skin reactions are suspected, deferasirox should be discontinued immediately. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm472530.htm

 Docetaxel (Taxotere®)
Reported cases of permanent alopecia have been added in the post- marketing experience for docetaxel. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm212079. htm

Everolimus (Zortress®)
The risk of interstitial lung disease and noninfectious pneumonitis has been added to the warnings and precautions section of the package labeling for everolimus. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm303659.htm

 Granisetron (Sancuso®)
The warnings section of the package labeling for granisetron patch has been edited to address external heat sources to the patch. A heat pad should not be applied over or near the granisetron patch as heat exposure increases the drug plasma concentrations. Application site reactions (i.e., pain, erythema, rash, irritation, urticarial) and cardiac dis- orders (i.e., bradycardia, chest pain, palpitations) have been added to the postmarketing experience under the adverse reactions section of the package labeling. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm466191.htm

 Ipilimumab (Yervoy®)
Major edits were made to the following sections under the warnings and precautions part of the labeling information: immune-mediated enterocolitis, immune-mediated hepatitis, immune-mediated dermatitis, immune-mediated neuropathies, and immune-mediated endo- crinopathies. The embryo-fetal toxicity section has been added to address the risk of fetal harm ipilimumab could cause when given to pregnant women. Education should be provided to females of reproductive potential to use effective contraception during treatment with an ipilimumab-containing regimen and for 3 months after the last dose of ipilimumab. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm328023.htm

 Methotrexate Injection
The boxed warning for methotrexate now has information to use the preservative-free formulation for intrathecal and high-dose therapy. There is a warning to avoid using the preserved formulation for intra- thecal or high-dose therapy because it contains benzyl alcohol. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ ucm476298.htm

Nivolumab (Opidvo®)
The prescribing information for nivolumab has been revised to update information on several immune-mediated adverse reactions. Across the clinical trial experience, 0.4% of patients with solid tumors receiving nivolumab as a single agent experienced fatal immune-mediated pneumonitis. In patients with melanoma receiving nivolumab in combination with ipilimumab, fatal immune-mediated pneumonitis occurred in 0.5% of the patients across the clinical trial experience. Immune-mediated colitis can occur when administering nivolumab in combination with ipilimumab and therapy should be held formoderate colitis. For any severe or life-threatening colitis, nivolumab should be permanently discontinued. Immune-mediated endocrinop- athies, including hypophysitis, adrenal insufficiency, and hypothyroid- ism, have occurred with nivolumab treatment. Patients should be monitored for immune-mediated rash with nivolumab therapy. Corti- costeroids should be administered for severe (Grade 3) or life-threat- ening (Grade 4) rash, or nivolumab should be held or discontinued depending on the severity of the rash. Immune-mediated encephalitis is another adverse reaction that can occur with nivolumab treatment. Patients with new-onset moderate to severe neurological signs or symptoms should undergo therapy. Nivolumab should be permanent- ly discontinued for immune-mediated encephalitis. From the clinical studies, less than 1% of the patients receiving nivolumab had encepha- litis. Other clinically significant, immune-mediated adverse reactions seen in less than 1% of patients receiving nivolumab as a single agent or in combination with ipilimumab in the clinical trials were uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatic, autoimmune neuropathy, Guillain-Barre syndrome, and hypopituitarism. Infusion-related reactions (e.g., fevers, chills, rigors, flushing, rash, hy- potension), including severe and life-threatening reactions, have been reported in patients on therapy with nivolumab. Discontinue the drug for any severe or life-threatening infusion-related reactions. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ ucm472431.htm

Obinutuzumab (Gazyva®)
The warnings and precautions section of the package labeling for obinutuzumab has been revised to include the fatal cases from tumor lysis syndrome (TLS). Patients with high tumor burden, high circulat- ing lymphocyte count (>25 x 109/ L), or renal impairment are at greater risk for TLS and appropriate TLS prophylaxis should be implemented prior to administering obinutuzumab. The use in specific populations in the prescribing information has also been updated to comply with PLLR. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm404996.htm

 Oxaliplatin (Eloxatin®)
The updated warnings and precautions section of the prescribing in- formation for oxaliplatin addresses severe neutropenia, cardiovascular toxicity, and rhabdomyolysis. There have been reports of sepsis, neu- tropenic sepsis, and septic shock in patients treated with oxaliplatin, including fatal outcomes. Recommendations to delay oxaliplatin until neutrophils are equal to 1.5 x 109/ L, withhold treatment for sepsis and septic shock, and dose reduce after recovery from Grade 4 neutropenia or febrile neutropenia have been added. Due to reports of QT prolongation and ventricular arrhythmias, even fatal Torsade de Pointes after oxaliplatin administration, there are recommendations to monitor the electrocardiogram in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong QT interval, and electrolyte abnormalities. Oxaliplatin should not be used in patients with congenital long QT syndrome. Reports have been made of rhab- domyolysis, including fatal cases in patients treated with oxaliplatin. Therapy should be discontinued if any signs or symptoms of rhabdo- myolysis occur. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm287508.htm

 Pazopanib (Votrient®)
Interstitial lung disease (ILD)/pneumonitis is now included in the warnings and precautions section and listed in the adverse reactions section of the package labeling. ILD/pneumonitis occurred in 0.1% of patients treated with pazopanib in clinic trials. Patients should be counseled on reporting pulmonary signs or symptoms indicative of ILD or pneumonitis. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm303649.htm

 Pegfilgrastim Injection (Neulasta®)
Updates have been made to the warnings and precautions section of the package insert for pegfilgrastim. The update includes the risk for glomerulonephritis, leukocytosis, and capillary leak syndrome. Glomer- ulonephritis has been diagnosed based on azotemia, hematuria, pro- teinuria, and renal biopsy. These events usually are resolved after dose reduction or discontinuation of pegfilgrastim. If glomerulonephritis is suspected due to pegfilgrastim, this medication should be discontin- ued. White blood cell counts of 100 x 109/ L or greater have been ob- served in patients receiving pegfilgrastim. Monitoring of complete blood counts during therapy is recommended. Reports of capillary leak syndrome have been made in patients getting pegfilgrastim in- jections. Patients who develop capillary leak syndrome, which can be a life-threatening condition, should receive standard symptomatic treat- ment, which may include intensive care. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm262864.htm

 Ponatinib (Iclusig®)
The updated warning and precautions section of the prescribing in- formation includes vascular occlusion, arterial occlusion and throm- bosis, and hypertension. Renal artery stenosis leading to worsening or treatment-resistant hypertension has occurred in patients treated with ponatinib. Treatment should be interrupted if there is significant worsening of hypertension. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm380782.htm

 Temozolomide (Temodar®)
Infections including primary and reactivated cytomegalovirus and re- activation of hepatitis B infections have been added to the postmarketing experience section of the drug labeling. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm262708.htm