Written in Blood
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The median time to first response was three months , “ however , four of these responders ( 8 %) achieved their best response six months after treatment completion ,” the authors reported .
The median time to best response was five months , and the median duration of a major response was 64.5 months .
The median progression-free survival ( PFS ) was 43 months ( 95 % CI 23-63 ), and 10 patients ( 17 %) were still in remission after a median of 90 months ( range = 73.5-112 months ).
When investigators looked at PFS according to IPSS risk stage , they found that “ response rates were not affected by IPSS WM and depth of response did not correlate with PFS , but the number of patients who
BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX ® ( tbo-filgrastim ) injection , for subcutaneous use
SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia .
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture , including fatal cases , can occur following administration of human granulocyte colony-stimulating factors . In patients who report upper abdominal or shoulder pain after receiving GRANIX , discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture . 5.2 Acute Respiratory Distress Syndrome ( ARDS ) Acute respiratory distress syndrome ( ARDS ) can occur in patients receiving human granulocyte colony-stimulating factors . Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX , for ARDS . Discontinue GRANIX in patients with ARDS . 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors . Reactions can occur on initial exposure . The administration of antihistamines ‚ steroids ‚ bronchodilators ‚ and / or epinephrine may reduce the severity of the reactions . Permanently discontinue GRANIX in patients with serious allergic reactions . Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim . 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors . Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease . Discontinue GRANIX in patients undergoing a sickle cell crisis . 5.5 Capillary Leak Syndrome Capillary leak syndrome ( CLS ) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension , hypoalbuminemia , edema and hemoconcentration . Episodes vary in frequency , severity and may be life-threatening if treatment is delayed . Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment , which may include a need for intensive care . 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor ( G-CSF ) receptor through which GRANIX acts has been found on tumor cell lines . The possibility that GRANIX acts as a growth factor for any tumor type , including myeloid malignancies and myelodysplasia , diseases for which GRANIX is not approved , cannot be excluded .
6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling :
• Splenic Rupture [ see Warnings and Precautions ( 5.1 )]
• Acute Respiratory Distress Syndrome [ see Warnings and Precautions ( 5.2 )]
• Serious Allergic Reactions [ see Warnings and Precautions ( 5.3 )]
• Use in Patients with Sickle Cell Disease [ see Warnings and Precautions ( 5.4 )]
• Capillary Leak Syndrome [ see Warnings and Precautions ( 5.5 )]
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [ see Warnings and Precautions ( 5.6 )]
The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1 % or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice . GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer ( N = 348 ), lung cancer ( N = 240 ) and non-Hodgkin ’ s lymphoma ( N = 92 ). In the breast cancer study , 99 % of patients were female , the median age was 50 years , and 86 % of patients were Caucasian . In the lung cancer study , 80 % of patients were male , the median age was 58 years , and 95 % of patients were Caucasian . In the non-Hodgkin ’ s lymphoma study , 52 % of patients were male , the median age was 55 years , and 88 % of patients were Caucasian . In all three studies a placebo ( Cycle 1 of the breast cancer study only ) or a non-US-approved filgrastim product were used as controls . Both GRANIX and the non-US-approved fi lgrastim product were administered at 5 mcg / kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 10 6 / L after nadir was reached .
Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1 % or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group . The overall incidence of bone pain in Cycle 1 of treatment was 3.4 % ( 3.4 % GRANIX , 1.4 % placebo , 7.5 % non-USapproved filgrastim product ). Leukocytosis In clinical studies , leukocytosis ( WBC counts > 100,000 x 10 6 / L ) was observed in less than 1 % patients with non-myeloid malignancies receiving GRANIX . No complications attributable to leukocytosis were reported in clinical studies . Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia , headache , vomiting , Sweet ’ s syndrome ( acute febrile neutrophilic dermatosis ), cutaneous vasculitis and thrombocytopenia . 6.2 Immunogenicity As with all therapeutic proteins , there is a potential for immunogenicity . The incidence of antibody development in patients receiving GRANIX has not been adequately determined .
7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed . Drugs which may potentiate the release of neutrophils ‚ such as lithium ‚ should be used with caution . Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes . This should be considered when interpreting bone-imaging results .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women . In animal reproduction studies , treatment of pregnant rabbits with tbo-fi lgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure . GRANIX should be used during pregnancy only if the potential benefi t justifi es the potential risk to the fetus . Animal Data In an embryofetal developmental study , pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1 , 10 and 100 mcg / kg / day . Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg / kg / day . This dose was maternally toxic as demonstrated by reduced body weight . Other embryofetal fi ndings at this dose level consisted of post-implantation loss ‚ decrease in mean live litter size and fetal weight , and fetal malformations such as malformed hindlimbs and cleft palate . The dose of 100 mcg / kg / day corresponds to a systemic exposure ( AUC ) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-fi lgrastim dose of 5 mcg / kg / day . 8.3 Nursing Mothers It is not known whether tbo-fi lgrastim is secreted in human milk . Because many drugs are excreted in human milk , caution should be exercised when GRANIX is administered to a nursing woman . Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates . 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established . 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX , a total of 111 patients were 65 years of age and older . No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients . 8.6 Renal Impairment The safety and effi cacy of GRANIX have not been studied in patients with moderate or severe renal impairment . No dose adjustment is recommended for patients with mild renal impairment . 8.7 Hepatic Impairment The safety and effi cacy of GRANIX have not been studied in patients with hepatic impairment .
10 OVERDOSAGE No case of overdose has been reported .
© 2014 Cephalon , Inc ., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd . All rights reserved . GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd .
Manufactured by : Distributed by : Sicor Biotech UAB Teva Pharmaceuticals USA , Inc . Vilnius , Lithuania North Wales , PA 19454 U . S . License No . 1803
Product of Israel GRX-40580 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information .
achieved CR / VGPR was relatively small .” Seven-year PFS was 62.5 percent for low-risk , 42 percent for intermediate-risk , and 15 percent for high-risk disease ; OS was 87.5 percent for low-risk , 68.2 percent for intermediate-risk , and 48 percent for high-risk disease .
Treatment-related adverse events included peripheral neuropathy ( 46 %) and neuropathic pain ( 20 %). “ At the time of last follow-up , peripheral neuropathy resolved completely or to grade 1 in all patients ,” Dr . Gavriatopoulou noted .
Forty patients ( 68 %) had progressive disease or died due to WM , while nine patients ( 15 %) died due to unrelated causes . Among the patients who progressed , 21 received second-line treatment with rituximab-based regimens ( n = 17 ), rituximab monotherapy ( n = 1 ), fludarabine ( n = 1 ), or alemtuzumab ( n = 2 ). Median time to next treatment was 73 months , and most patients ( 80.9 %; n = 17 ) responded to second-line treatment .
Given these results , the authors concluded that “ BDR given for 23 weeks induced responses even in highrisk patients with a long PFS of 43 months ,” the authors wrote . “ Moreover , patients who relapse after BDR have high probability of response to other rituximab-based regimens .”
The study is limited by its small patient population and single arm design , and the authors noted that future studies should evaluate whether adding ibrutinib ( which was recently approved by the U . S . FDA for treatment-naïve and relapsed / refractory WM patients ) could “ improve disease control and increase CR rate in potentially ‘ curable ’ patients ,” Dr . Gavriatopoulou concluded .
Based on the results from this phase II study , the European WM Consortium is conducting a phase III study of dexamethasone , rituximab , and cyclophosphamide with or without bortezomib in this patient population .
REFERENCE
Gavriatopoulou M , García-Sanz R , Kastritis E , et al . BDR in newly diagnosed patients with WM : final analysis of a phase 2 study after a minimum follow up of 6 years . Blood . In press .
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While infections caused by the Zika virus captured the world ’ s attention in 2016 , much about the virus remains unknown , including the proportion of asymptomatic cases and the duration of the virus ’ presence in the blood , or viremia . In a report published in Blood , Pierre Gallian , of the Aix-
December 2016