Recalls and Safety Alerts from the FDA
Jennifer Kwon, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
VA Medical Center
West Palm Beach, FL
Carboplatin, Cytarabine, Gemcitabine, and Methotrexate
Mylan has issued a voluntary recall of select lots of injectable products including gemcitabine, carboplatin, methotrexate, and cytarabine. This is because of the presence of visible particles observed during a rou- tine quality testing. There have been no adverse events reported related to this recall. http://www.fda.gov/Safety/ Recalls/ucm450140.htm
Fluorouracil Injection (Adrucil)
Teva Parenteral Medicines issued a voluntary recall of eight lots of fluorouracil injection (5 g/100 mL) due to the potential presence of silicone rubber pieces from a filter diaphragm and fluorouracil crystals. There have been no adverse events reported. http://www.fda.gov/ Safety/ Recalls/ucm445584.htm.
Prescription Center Pharmacy Recall in North Carolina
The North Carolina Board of Pharmacy has ordered a recall for all nonsterile and sterile products compounded, repackaged, and distributed by Prescription Center Pharmacy in Fayetteville, NC, during the time period between September 10, 2014 and March 10, 2015. Prescription Center Pharmacy distributed products in all 50 states and Canada during the time period of the recall. The recall was mandated because the pharmacy was unable to ensure sterility, stability, and potency for their products. Furthermore, the North Carolina Board of Pharmacy has ordered the Prescription Center Pharmacy to close. There have been no adverse events reported from the recalled products. http://www.fda.gov/ Safety/ Recalls/ucm441046.htm
An embryo-fetal toxicity section has been added to the warnings and precautions for bevacizumab. Animal studies resulted in congenital malformations with the administration of bevacizumab to pregnant rabbits. These animal models also have linked angiogenesis and vascular endothelial growth factor (VEGF) and VEGF Receptor 2 to essential aspects of female reproduction, embryo-fetal development, and postnatal development. Pregnant women should be aware of the potential risk to a fetus and be counseled on using effective contraception during treatment and for 6 months after completion of therapy with bevacizumab. The package labeling on use in specific populations has been updated to include the animal data in pregnancy and a section on females and males of reproductive potential. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm287610.htm
Patients with certain homozygous or compound heterozygous mutations in the dihydropyrimidine dehydrogenase deficiency (DPD) gene that result in absence of DPD activity are at increased risk for capecitabine toxicity; acute early-onset, severe, life-threatening, or fatal (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity also may be at increased risk for toxicity. These findings were based on postmarketing reports. Capecitabine should be held or discontinued based on clinical assessment of the patient and observed toxicities. There is no capecitabine dose shown to be safe for patients with absence of DPD activity and there is Interferon alfa-2b (Intron A)
The warnings and precautions section for interferon alfa-2b has been updated to include the risk of gastrointestinal disorders, neuropsychiatric disorders, and hepatic monitoring parameters. There is an in- creased risk of hepatic decompensation in patients with cirrhosis. Patients who develop liver function abnormalities during treatment should be monitored closely. Liver function tests (serum bilirubin, ala- nine transaminase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase) should be monitored at 2, 8, and 12 weeks after starting interferon alfa-2b, then every 6 months afterwards. Interferon alfa-2b should be discontinued for severe (grade 3) hepatic damage or hepatic decompensation (Child-Pugh score > 6; class B and C). In patients who experience worsening psychiatric symptoms or those who develop suicidal ideation or aggressive behavior towards others, interferon alfa-2b should be discontinued and patients should be monitored closely with psychiatric interventions as appropriate. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm311115.htm
The updated warnings and precautions address the lack of benefit of panitumumab in patients with metastatic colorectal cancer with RAS- mutations; specifically somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of KRAS or NRAS. Results from a retrospective subset analyses across several randomized clinical trials showed no clinical benefit in patients with tumors having the RAS mutations, and exposed those patients to anti- EGFR-related adverse reactions. In study 3 of the package insert, the subgroup analysis demonstrated the overall survival was shorter in patients with metastatic colorectal cancers with RAS mutations who re- ceived panitumumab and FOLFOX versus FOLFOX alone. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm319207. Htm
The updated warnings and precautions section for pazopanib includes the increased risk for hepatotoxicity in patients >65 years. Liver function tests should be monitored regularly while on pazopanib therapy. There have been reports of retinal detachment and this has been added in the postmarketing section under adverse reactions. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm303649.htm
The package labeling for pertuzumab has been updated with additional information on embryo-fetal toxicity. If a patient becomes pregnant while receiving pertuzumab or within 7 months following the last dose of this drug in combination with trastuzumab, the patient should be informed of the potential hazard to the fetus. Female patients of reproductive potential should be counseled on avoiding becoming pregnant while receiving pertuzumab therapy or within 7 months after completion of pertuzumab therapy in combination with trastuzumab. Women who may be exposed to pertuzumab during pregnancy or become pregnant within 7 months after the last dose of pertuzumab should enroll in the Mother Pregnancy Registry by contacting insufficient data to recommend a specific dose in patients with partial DPD activity. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm422806.htm
The warnings and precautions section of the prescribing information for carfilzomib has been updated to include thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/ HUS) and posterior reversible encephalopathy syndrome (PRES). Therapy should be interrupted if TTP/ HUS is suspected and the syndromes should be managed appropriately. The safety of starting carfilzomib therapy after a TTP/ HUS diagnosis is unknown. Though rare, there have been reports of PRES with carfilzomib use. Symptoms of PRES include seizure, headaches, lethargy, confusion, blindness, altered consciousness, hypertension, and other visual or neurological disturbances. Therapy should be discontinued if PRES is suspected. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm441458.htm
The updated warnings and precautions section now includes information about increased tumor progression and increased mortality in patients with RAS-mutant metastatic colorectal cancer. Cetuximab is not indicated for the treatment of patients with colorectal cancer having mutations in the exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either K-RAS or N-RAS. Sub- set analyses of RAS-mutant and wild-type populations across several randomized clinical trials showed cetuximab given to patients with RAS mutations had no clinical benefit with treatment-related toxicity. Reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, and life-threatening and fatal bullous mucocutaneous disease have been made with cetuximab use. These dermatologic toxicities are now included in the warnings and precautions section of the product labeling. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm289979.htm
The new labeling for ferumoxytol includes a boxed warning regarding the risk of serious and potentially fatal hypersensitivity reactions. Ferumoxytol should only be administered when personnel and therapies are immediately available to treat anaphylaxis and other hypersensitivity reactions. Patient should be observed for signs and symptoms of hypersensitivity for at least 30 minutes following the infusion. Blood pressure and pulse should also be monitored during and after the in- fusion. Hypersensitivity reactions have occurred in patients that previously tolerated ferumoxytol. A contraindication also has been added for patients with a history of allergic reaction to any intravenous iron product. The warnings and precautions section for ferumoxytol has been updated to caution use in elderly patients (>65 years of age) or patients with multiple comorbidities, as these patients may have more severe outcomes if they experience a serious hypersensitivity reaction. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ ucm235636.htm 800.690.6720. If a patient becomes pregnant while receiving treatment with pertuzumab or within 7 months following the last dose of this drug, immediately report the exposure to the Genentech Adverse Event Line at 888.835.2555. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm450065.htm
The risk of venous and arterial thromboembolism has been added to the black box warnings and the warnings and precautions section of the package labeling for pomalidomide. There is an increased risk of both arterial and venous thromboembolic events in patients with multiple myeloma receiving pomalidomide with dexamethasone. Due to the increased risk of thrombotic events, modifiable risk factors should be minimized and antithrombotic prophylaxis should be administered. Several updates have been made to the warnings and precautions section of the package insert for pomalidomide, including the risk for hematologic toxicity, hepatotoxocity, hypersensitivity reactions, dizziness and confusion, neuropathy, and tumor lysis syndrome. The most frequently reported grade 3/4 adverse reaction was neutropenia, followed by anemia and thrombocytopenia in patients receiving pomalidomide in combination with dexamethasone. Cases of hepatic failure have been reported in patients receiving pomalidomide. Liver function tests should be monitored at least monthly and pomalidomide therapy should be stopped if elevation in liver enzymes is present. Angioedema and severe dermatologic reactions have occurred with pomalidomide use. The medication should be permanently dis- continued for any severe dermatologic reactions. Patients receiving both pomalidomide and dexamethasone may experience dizziness and a confused state. Patients should be instructed to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause overlapping symptoms. Neuropathy and tumor lysis may also occur in patients treated with pomalidomide. Appropriate monitoring and precautions should be taken for patients at risk for tumor lysis syndrome. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm446484.htm
Updates have been made to the warnings and precautions section to include the risk of thrombotic microangiopathy (TMA). Incidences of thrombotic thrombocytopenic purpura and hemolytic uremia have been reported in clinical trials and in postmarketing surveillance of patients receiving sunitinib. For patients who develop TMA, sunitinib therapy should be discontinued. Additional elements of the warnings and precautions section have been updated. “Left ventricular dysfunction” has been changed to “cardiovascular events,” and “myocardial disorders” has been replaced with “myocardial ischemia, myocardial infarctions.” Sunitinib should be used with caution in patients who are at risk or who have a history of these events. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm224050.htm
The package labeling for trastuzumab has been updated to include in- formation on potential embryo-fetal toxicity. Female patients of reproductive potential should be counseled on avoiding becoming pregnant while receiving trastuzumab therapy. If contraceptive methods are utilized, patients should be advised to use effective contraception during treatment and for at least 7 months after the last dose of trastu- zumab. If a patient becomes pregnant while receiving trastuzumab or within 7 months following the last dose of the medication, inform the patient of the potential hazard to the fetus. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392225.htm
The boxed warning for vismodegib has been edited to address the embryo-fetal toxicity of the drug. Teratogenic effects of vismodegib include severe midline defects, missing digits, and other irreversible malformations, as well as embryo-fetal death. The pregnancy status of females of reproductive potential should be verified within 7 days prior to starting vismodegib therapy. Education for using effective contraception during and after vismodegib therapy should be provided for female patients. Male patients should be counseled on the risk of vismodegib exposure through semen and to use condoms with a pregnant partner or female partner of reproductive potential.
The updated warnings and precautions section for vismodegib also addresses measures for blood donation and semen donation. Patients should not donate blood or blood products while taking vismodegib and for 7 months after the completion of therapy. Male patients should not donate semen during and for 3 months after the last dose of vismodegib.
The use in specific populations section of the package labeling now discusses pregnancy risk, lactation, and hepatic impairment. In animal reproduction studies, oral administration of vismodegib at doses lower than the recommended doses for humans led to embryotoxicity, fetotoxicity, and teratogenicity in rats. There are no available data on the use of vismodegib in pregnant females. Pregnant woman should be counseled on the potential risk to a fetus. No data are available ad- dressing the presence of vismodegib in human milk, the effects of the drug on breastfed infants, or the effects of the drug on milk production. Due to the potential for serious adverse reactions in breastfed infants from vismodegib, nursing women should be instructed not to breastfeed while on vismodegib therapy. In patients with hepatic impairment, there are no dose adjustments required for vismodegib.
An additional section, females and males of reproductive potential, has been added to the package labeling for the drug. Both female and male patients need to be counseled on vismodegib causing fetal harm and to use effective contraception measures or condoms during sexual intercourse. Vismodegib can potentially cause infertility as amenorrhea can occur in females, and the reversibility of amenorrhea is unknown at this time. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm450147.htm