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Recalls and Safety Alerts from the FDA

Ashley Glode, PharmD BCOP
Clinical Oncology Pharmacy Specialist; Assistant Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
Aurora, CO


Recalls

Mitoxantrone
In December 2014 Hospira, Inc., announced a voluntary recall of 10 lots of mitoxantrone (human and veterinary) for confirmed subpotency and elevated impurity levels. Hospira has not yet received any reports of adverse effects associated with this issue. The impacted lots were distributed to hospitals and veterinary clinics worldwide from February 2013 through November 2014. A root-cause analysis initiated improvements for batches manufactured March 2014 and later. For a full list of recalled products, visit www.fda.gov/ Safety/ Recalls/ ucm427952.htm.

Sodium Chloride Injection
In January 2015 Hospira, Inc., issued a voluntary nationwide recall of one lot of 0.9% sodium chloride injection, USP, 250 ml (NDC 0409-7983-02) because of particulate matter found in a single unit. Hospira has identified the particulate as a human hair sealed inside the bag at the additive port area. There have been no reports of adverse effects associated with this issue for this lot. This lot was distributed nationwide from September to November 2014. Hospira is conducting a root-cause analysis to determine corrective and preventive actions. For more information, refer to www.fda.gov/ Safety/ Recalls/ucm430929.htm.

Safety Alerts

Lanreotide (Somatuline Depot Injection)
The list of contraindications for lanreotide has been updated to include patient history of hypersensitivity to lanreotide. Postmarketing reports indicate some patients have experienced allergic reactions, including angioedema and anaphylaxis, after receiving lanreotide.

The package insert has been updated to include additional warnings and precautions. In a postmarketing study of 81 patients treated with lanreotide who had baseline heart rates of at least 60 beats per minute (bpm), 23% (19/81) had a heart rate < 60 bpm after lanreotide ad- ministration versus 16% (15/94) of patients treated with placebo. Ten patients (12%) had more than one episode of a heart rate < 60 bpm. In both intervention and control groups, 1% in each experienced a heart rate < 50 bpm and had bradycardia reported as an adverse event. www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm429783.htm

Paclitaxel Protein-Bound Particles (Abraxane)
The use of paclitaxel protein-bound particles in patients with hepatic impairment may put them at increased risk of toxicity, particularly myelosuppression requiring close monitoring. Use is not recommended for patients with total bilirubin values > 5 × upper limit of normal (ULN) or aspartate transaminase (AST) > 10 × ULN. Paclitaxel protein-bound also is not recommended for patients with metastatic adenocarcinoma of the pancreas with moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and AST = 10 × ULN). www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm359951.htm

Ramucirumab (Cyramza)
Several labeling updates were made for ramucirumab. Additional information was added to warnings and precautions for hemorrhage and hypertension. In one study assessing patients with non-small-cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% with ramucirumab and docetaxel compared with 2.3% with placebo. This trial excluded patients who were receiving therapeutic anticoagulation or chronic nonsteroidal anti-inflammatory drug (NSAID) therapy or other antiplatelet therapy besides once daily aspirin. Patients with major airway or blood vessel invasion or intratumor cavitation were also excluded. The risk of pulmonary hemorrhage for these patients is unknown because of their exclusion from the study. The incidence of hypertension also was updated to indicate occurrence in 6% of patients who received ramucirumab plus docetaxel compared with 2% of patients who received docetaxel alone.

Information regarding immunogenicity was edited in the context of the study on ramucirumab with docetaxel for NSCLC. No pharmacokinetic interactions were found between ramucirumab and docetaxel. The study included several geriatric patients, allowing outcomes in this group to be assessed in an exploratory subgroup analysis. The hazard ratio for overall survival (OS) for patients < 65 years was 0.74 (95% CI:0.62, 0.87) and for patients ≥ 65 years 1.10 (95% CI: 0.89, 1.36).

Information regarding ramucirumab use in hepatic impairment was added to clarify the definition of mild hepatic impairment (AST > ULN or total bilirubin > 1.0–1.5 × ULN), for which ramucirumab does not require a dose adjustment.
www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm429773.htm

Obinutuzumab (Grazyva)
The warnings and precautions section was updated to include fatal infections reported with use of obinutuzumab. The percent incidence was updated to 33% for grades 3 or 4 neutropenia and 10% for grades 3 or 4 thrombocytopenia when used in combination with chlorambucil. www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm404996.htm

Ruxolitinib (Jakafi)
The ruxolitinib package insert was updated to include information regarding symptom exacerbation to pretreatment levels after discontinuation of ruxolitinib. This may occur over a period of 1 week, and patients may experience one or more of the following: fever, respiratory distress, hypotension, disseminated intravascular coagulation, or multiorgan failure. Periodic skin evaluations should also be conducted for patients taking ruxolitinib because nonmelanoma skin cancers (basal cell, squamous cell, Merkell cell carcinoma) have occurred.

Myelosuppression, thrombocytopenia, anemia, and neutropenia were added to the list of adverse reactions.

Additional information was included in the organ dysfunction section. In patients with polycythemia vera and moderate (creatinine clearance [CrCl] 30–59 ml/min) or severe (CrCl 15–29 ml/min) renal impairment, a dose reduction of ruxolitinib is recommended. Hepatic impairment is another factor that can necessitate dose reductions.
www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm377314.htm

Sunitinib (Sutent)

Additional information regarding risk for hypoglycemia was included in the warnings and precautions and patient counseling sections of the sunitinib package insert. Hypoglycemia was seen in 2% of patients with renal cell carcinoma and gastrointestinal stromal tumor who received sunitinib and 10% of patients with primitive neuroectodermal tumor. Not all patients had preexisting abnormalities in glucose control. Glucose values should be regularly assessed during and after discontinuing treatment with sunitinib.

www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm224050.htm

Everolimus (Afinitor)
An increased incidence of angioedema has been recorded with concomitant use of everolimus and angiotensin-converting enzyme inhibitors (ACEIs). The incidence of angioedema for patients taking everolimus and an ACEI was 6.8% versus 1.3% for patients taking an ACEI only in a pooled analysis of randomized double-blind oncology clinical trials.
www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm433415.htm

Imatinib (Gleevec)
Warnings and precautions about the use of imatinib have been updated. Patients with chronic phase, newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+CML) were given imatinib or nilotinib. In this trial the incidence of severe, grade 3 or 4 fluid retention was seen in 2.5% of patients taking imatinib and in 3.9% of patients taking nilotinib 300 mg twice daily (BID). Similar rates of effusions (pleural or pericardial effusions or ascites) and pulmonary edema occurred: 2.1% (0% grade 3 or 4) in the imatinib arm and 2.2% (0.7% grade 3 or 4) in the nilotinib arm.

The incidence of congestive heart failure and left ventricular dysfunction was assessed in another randomized trial in the same population. Cardiac failure occurred in 1.1% of patients (0.7% grade 3 or 4) in the imatinib arm and 2.2% of patients (0.7% grade 3 or 4) in the nilotinib 300 mg BID arm.

Gastrointestinal (GI) hemorrhage was also evaluated in a randomized trial comparing imatinib and nilotinib as initial treatment for patients with chronic phase Ph+CML; 1.4% of patients receiving imatinib and 2.9% of patients receiving nilotinib 300 mg BID experienced GI hemorrhage (0% grade 3 or 4 and 0.7% grade 3 or 4, respectively). Gastric antral vascular ectasia has been reported through postmarketing experience.
www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm255333.htm

Nilotinib (Tasigna)
Changes have been made to the warnings and precautions associated with nilotinib. Additional clinical trial results are available to describe the incidence of cardiac and arterial vascular occlusive events and hemorrhage seen with nilotinib use. The incidence of cardiovascular events seen among patients receiving a median of 60 months of treatment was dose-related, occurring in 9.3% of patients on nilotinib 300 mg BID and 15.2% of patients on nilotinib 400 mg BID. The rates of GI hemorrhage were 2.9% in patients on 300 mg BID (0.7 % grade 3 or 4) and 5.1% in patients on 400 mg BID (1.4% grade 3 or 4). Fluid retention has also been a reported adverse event in clinical trials. Severe, grade 3 or 4 retention occurred in 3.9% of patients receiving nilotinib 300 mg BID and 2.9% of patients receiving 400 mg BID. It is recommended to monitor for signs of severe fluid retention and symptoms of respiratory or cardiac compromise and evaluate and treat patients according to etiology. Additional information on regular monitoring of lipid profiles and glucose (periodically during the first year, at least yearly during chronic therapy) and the use of HMG-CoA reductase inhibitors has been included. Drug-drug interactions should be assessed before initiating lipid lowering therapy.
www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm218929.htm

Abiraterone (Zytiga)

The drug interactions section for abiraterone has been updated to include information on CYP2C8 drug-drug interactions in healthy subjects. The area under the curve of pioglitazone, which is a CYP2C8 substrate, was increased by 46% when patients were given pioglitzone and a single dose of 1,000 mg abiraterone. Patients should be monitored closely when given CYP2C8 substrates with narrow therapeutic indexes and abiraterone.
www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm314608.htm

Goserelin Acetate Implant (Zoladex)
Reports of injection-site injury and vascular injury comprising pain, hematoma, hemorrhage, and hemorrhagic shock requiring blood transfusions and surgical intervention have been documented with the use of goserelin acetate implant. Extra care and caution should be utilized in patients with a low body-mass index and patients receiving full-dose anticoagulants.

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