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DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health ServiceFood and Drug AdministrationSilver Spring, MD 20993TRANSMITTED BY FACSIMILEStephanie H. Jameison, MBA, RACSenior Manager, Labeling and Promotion ComplianceOtsuka Pharmaceutical Development and Commercialization, Inc.2440 Research BoulevardRockville, MD 20850RE: NDA #020954Busulfex® (busulfan) InjectionMA #77Dear Ms. Jameison,As part of its routine monitoring and surveillance program, the Office of Prescription DrugPromotion (OPDP) of the US Food and Drug Administration has reviewed the US productwebsite (0608W-0013) for Busulfex® (busulfan) Injection (Busulfex) submitted by OtsukaPharmaceutical Development and Commercialization, Inc. (OPDC) under cover of FormFDA-22531. This website is misleading because it omits material facts, minimizes importantrisk information about Busulfex, makes unsubstantiated claims, overstates the efficacy ofBusulfex, and makes a misleading claim. Therefore, the website misbrands the drug inviolation of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 352(a) & (n);321(n). See 21 CFR 202.1(e)(5); (e)(6)(i); (e)(7)(i) & (iii).BackgroundBelow is the indication and summary of the most serious and most common risks associatedwith the use of Busulfex.2According to the INDICATIONS AND USAGE section of the FDA-approved product labeling(PI):BUSULFEX® (busulfan) Injection is indicated for use in combination withcyclophosphamide as a conditioning regimen prior to allogeneic hematopoieticprogenitor cell transplantation for chronic myelogenous leukemia.The PI for Busulfex includes a Boxed Warning regarding the risk of profoundmyelosuppression at recommended doses and the need for supervision by a qualifiedphysician experienced in allogeneic hematopoietic stem cell transplantation, the use of1Last accessed October 3, 2011.2This information is for background purposes only and does not necessarily represent the risk information thatshould be included in the promotional piece cited in this letter.Reference ID: 3029738Ms. Stephanie H. Jameison, MBA, RAC Page 2Otsuka Pharmaceutical Development and Commercialization, Inc.NDA# 020954 / MA# 77chemotherapeutic drugs, and the management of patients with severe pancytopenia. ThePI for Busulfex also includes the following Warnings: seizures; hepatic veno-occlusivedisease (HVOD); cardiac tamponade in pediatric patients with thalassemia who receivedhigh doses of oral busulfan and cyclophosphamide as the preparatory regimen forhematopoietic progenitor cell transplantation; bronchopulmonary dysplasia with pulmonaryfibrosis; and use in pregnancy. The PRECAUTIONS section of the PI also includesrecommendations for monitoring serum transaminases, alkaline phosphatase, and bilirubinto detect hepatotoxicity.The most common non-hematologic adverse reactions in adult patients treated withBusulfex were nausea, stomatitis (mucositis), vomiting, anorexia, diarrhea, insomnia, fever,hypomagnesemia, abdominal pain, and anxiety.The PRECAUTIONS – Special Populations: Pediatric section of the PI discusses the use ofBusulfex in pediatric patients participating in an open-label, uncontrolled study thatevaluated the pharmacokinetics of Busulfex therapy when used as part of a conditioningregimen administered prior to hematopoietic progenitor cell transplantation for a variety ofmalignant hematologic or non-malignant diseases. Adverse events reported for thesepatients include vomiting, nausea, stomatitis, HVOD, graft-versus host disease (GVHD), andpneumonia.Omission of Material FactsPromotional materials are misleading if they fail to reveal material facts in light ofrepresentations made by the materials or with respect to consequences that may result fromthe use of the drug as recommended or suggested by the materials.The Dosing and Straightforward IV Administration – Infusion Examples webpages of theBusulfex website present information regarding dosage and administration for pediatricpatients, but omit important material information regarding the risks associated with the useof Busulfex in this patient population. Specifically, these presentations omit the risk ofcardiac tamponade observed in pediatric patients receiving high doses of oral busulfan. Thewebpages also fail to include the adverse events reported for pediatric patients includingvomiting (100%), nausea (83%), stomatitis (79%), GVHD (25%), HVOD (21%), andpneumonia (21%). By failing to communicate this important risk information, the websitemisleadingly suggests that Busulfex is safer than has been demonstrated by substantialevidence or substantial clinical experience.The Important Safety Information section on the bottom of each webpage and the ClinicalTrial Results – Safety Profile webpage present some information regarding the risk ofHVOD, but omit material facts regarding HVOD and hepatotoxicity. In particular, theWARNINGS – Hepatic section of the PI states, “Patients who have received prior radiationtherapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor celltransplant may be at an increased risk of developing HVOD with the recommendedBUSULFEX dose and regimen.” Moreover, the PRECAUTIONS section of the PI states, “ToReference ID: 3029738Ms. Stephanie H. Jameison, MBA, RAC Page 3Otsuka Pharmaceutical Development and Commercialization, Inc.NDA# 020954 / MA# 77detect hepatotoxicity, which may herald the onset of hepatic veno-occlusive disease, serumtransaminases, alkaline phosphatase, and bilirubin should be evaluated daily through BMTDay +28.” Finally, the ADVERSE REACTIONS – Hepatic section of the PI indicates thathyperbilirubinemia occurred in 49% of patients, was grade 3/4 in 30% of patients, and wasconsidered life-threatening in 5% of these patients. Hyperbilirubinemia was associated withboth GVHD and HVOD. By omitting these material facts, the website suggests thatBusulfex is safer than has been demonstrated by substantial evidence or substantial clinicalexperience.The Dosing webpage and Straightforward IV Administration – Infusion Examples webpagepresent information on the dosage and administration of Busulfex. However, thesepresentations omit material facts regarding the need to pre-medicate patients withantiemetics prior to the first dose of Busulfex therapy and on a fixed schedule for theduration of Busulfex treatment. This treatment recommendation is particularly relevant inlight of the fact that nausea and vomiting occurred in 98% and 95% of patients, respectively,in the pivotal clinical trial.Minimization of Risk/Unsubstantiated ClaimsPromotional materials are misleading if they contain a representation or suggestion that adrug is safer than has been demonstrated by substantial evidence or substantial clinicalexperience.Several pages of the Busulfex product website contain the claim, “Low incidence of severetoxicities” (emphasis original). The PI contains a BOXED WARNING which indicates thatBusulfex is a cytotoxic drug associated with profound myelosuppression that occurs in allpatients as well as other significant warnings and precautions. For example, some of themost common adverse events include nausea (98%), stomatitis (mucositis) (97%), vomiting(95%), anorexia (85%), diarrhea (84%), insomnia (84%), and fever (80%). Given thefrequency and severity of profound myelosuppression, and the potential for other serious andsignificant adverse events with Busulfex therapy, the claim, “Low incidence of severetoxicities” is misleading and significantly minimizes the risks associated with the drug. Wenote that this presentation includes the claim that, “100% (61/61) completed the 16-doseregimen.” Although it is true that 61/61 patients completed the 16-dose regimen, theinclusion of this statement does not mitigate the misleading impression created by this claim.The Straightforward IV Administration – Concomitant Medications webpage claims:● “In a retrospective review, 29 pediatric patients (ages 6 months to 19 years) whoreceived lorazepam for seizure prophylaxis did not develop seizures whilereceiving or within 48 hours of last dose of IV BUSULFEX[3]”3 Chan KW, Mullen CA, Worth LL, et al. Lorazepam for seizure prophylaxis during high-dose busulfanadministration. Bone Marrow Transplant. 2002;29:963-965.Reference ID: 3029738Ms. Stephanie H. Jameison, MBA, RAC Page 4Otsuka Pharmaceutical Development and Commercialization, Inc.NDA# 020954 / MA# 77● “During high dose IV BUSULFEX treatment, PK data showed no alteration inabsorption and clearance of busulfan during concomitant administration oflorazepam[3]”This presentation is misleading because it suggests that the use of lorazepam for seizureprophylaxis eliminates the risk of seizures with Busulfex therapy, when this has not beendemonstrated by substantial evidence or substantial clinical experience. The referencecited (Chan, et al.) to support the above presentation is a retrospective review of the use ofvariable doses of lorazepam for seizure prophylaxis in 29 pediatric patients receivingbusulfan as part of a conditioning regimen for hematopoietic stem cell transplantation(HSCT). A retrospective analysis of a study in a limited pediatric population does notconstitute substantial evidence or substantial clinical experience to support claims implyingthat lorazepam eliminates the risk of seizures associated with Busulfex therapy. We notethat the DOSAGE AND ADMINISTRATION section of the PI specifically states that “[a]llpatients should be premedicated with phenytoin as busulfan is known to cross the bloodbrain barrier and induce seizures. . . . Use of other anticonvulsants may result in higherbusulfan plasma AUCs, and an increased risk of VOD or seizures. In cases where otheranticonvulsants must be used, plasma busulfan exposure should be monitored . . .”(emphasis added). Furthermore, the totality of this presentation is particularly concerninggiven that the Busulfex PI contains a warning regarding the risk of seizures. In fact, oneseizure (1/42 patients) was reported during an autologous transplantation clinical trial ofBusulfex, despite prophylactic therapy with phenytoin.Unsubstantiated ClaimsThe Busulfex website includes claims and presentations such as the following (underlinedemphasis added):● “Begin with Precision”● “For optimal HSCT conditioning”● “Outcomes through accuracy”● “Predictable pharmacokinetics”● “Predictable pharmacokinetic profile[4]”● “Controlled Myeloablation”● “Predictable and consistent intrapatient and interpatient AUC values[4]”● “Excellent interdose reproducibility (Cmax at dose 1 accurately predicted Cmax atdose 9)[4]”● “Delivers precise, predictable control”● A line graph entitled, “Pharmacokinetics Results: Doses 1, 9, and 13 (n=59)[4]”that presents maximum concentration (Cmax), AUC, and minimum concentration(Cmin) data across these timepoints.4Andersson BS, Kashyap A, Gian V, et al. Conditioning therapy with intravenous busulfan andcyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: aphase II study. Biol Blood Marrow Transplant. 2002;8:145-154.Reference ID: 3029738Ms. Stephanie H. Jameison, MBA, RAC Page 5Otsuka Pharmaceutical Development and Commercialization, Inc.NDA# 020954 / MA# 77Claims and presentations implying that Busulfex has a “predictable pharmacokinetic profile,”“predictable and consistent” area under the curve (AUC) values, and “excellent interdosereproducibility” are misleading. The reference cited to support these claims is a publication(Andersson, et al.) that describes the pivotal study for Busulfex. In this study, bloodsamples were only collected up to 4 hours after the end of infusion. However, the half-life ofbusulfan is approximately 3 hours. An acceptable sampling schedule to determine first doseAUC would need to extend up to 15 hours post infusion. Therefore, the first dose AUC wasextrapolated by a range of 2% to 68% in order to calculate AUC0-∞. This renders acomparison between first dose AUC values to AUC values of subsequent doses invalid andclaims implying that Busulfex has a predictable pharmacokinetic profile based on itscalculated AUC are misleading. For similar reasons, claims implying that Busulfex haspredictable and consistent inter- and intrapatient AUC values are unsubstantiated.Additionally, in this study there was a significant difference between dose one and dose nineCmax (ng/ml) values (944 + 25% vs. 1222 + 18%, respectively) which demonstrates that theCmax of dose one cannot be used to accurately predict Cmax of dose nine. Therefore, claimssuggesting that Busulfex has “excellent interdose reproducibility” based on dose one Cmaxpredicting dose nine Cmax are misleading.Furthermore, the totality of this presentation misleadingly implies that there is a directcorrelation between a “predictable pharmacokinetic profile” and the ability to inducemyeloablation in an “accurate,” “controlled” or “optimal” way. OPDP is not aware ofsubstantial evidence or substantial clinical experience that supports any kind of causal orcorrelative relationship between pharmacokinetic profile and such clinical benefits.Overstatement of EfficacyThe Clinical Trial Results – 100% Engraftment webpage presents a Kaplan-Meier graphtitled, “Overall Survival and Disease-free Survival.” The references cited to support thispresentation are the Busulfex PI and publication of the single-arm open-label pivotal trial(Andersson, et al.). The graph depicts the probability of overall survival (OS) and diseasefree survival (DFS) from day 0 to day 583 post-transplant and calls out an 86.9% probabilityof overall survival at day 100 post transplant. This presentation is misleading because itmakes efficacy claims regarding the probability of OS and DFS following Busulfex therapywhich have not been demonstrated by substantial evidence or substantial clinical experience.OS and DFS are time-to-event endpoints that represent the likelihood that patients will bealive or free from disease at a given point in time. The accurate method of calculatingprobability estimates for these endpoints takes into consideration the number of patients whoare still alive or free from disease after each pre-specified event has occurred (defined as thepopulation at risk) as well as the number of patients censored from analysis at each timepoint during the period of observation. In contrast, the 86.9% OS probability estimatereported on the website for day 100 was derived by dividing the number of patients alive atday 100 by the total number of patients who received Busulfex during the entire clinical trial.This calculation does not accurately reflect the number of patients still at risk for the definedevents (i.e., OS, DFS). Failure to incorporate these principles into the derivation of thisReference ID: 3029738Ms. Stephanie H. Jameison, MBA, RAC Page 6Otsuka Pharmaceutical Development and Commercialization, Inc.NDA# 020954 / MA# 77statistic overestimates the probability of OS and DFS. Therefore, the 86.9% OS probabilityreported on the webpage is misleading because it overstates the efficacy of Busulfex.Moreover, the results of the single-arm, open label pivotal study in 61 patients, as reported inthe Busulfex PI, do not support the Kaplan-Meier presentation that approximately 70% ofpatients were alive at day 583 and approximately 40% of patients were disease-free at thistime. The PI states that “twenty-three patients (38%) relapsed at a median of 183 days posttransplant (range 36 to 406 days). Sixty-two percent of patients (38/61) were free fromdisease with a median follow-up of 269 days post-transplant (range 20 to 583 days). Fortythree patients (70%) were alive with a median follow up of 288 days post-transplant (range 51to 583 days).” We note that this information is included on this webpage. These data,however, are not OS and DFS probability estimates, nor do they support such implications ina Kaplan Meier presentation. Single-arm trials do not adequately characterize time-to-eventendpoints.5 Therefore, neither the PI nor the referenced publication support the misleadingOS and DFS implications made by this presentation.Misleading ClaimThe Busulfex website presents the following claim:• “Straightforward IV administration”This claim is misleading because it suggests that the administration of IV Busulfex isstraightforward when this is not the case. The Busulfex PI contains several instructionspertaining to the administration of Busulfex. Specifically, the DOSAGE andADMINISTRATION section of the PI indicates that Busulfex therapy should be administeredintravenously via a central venous catheter using an infusion pump to deliver the entireprescribed dose over two hours. An administration set with minimal residual hold-up volume(2-5cc) should be used for administration. Prior to and following each infusion the indwellingcatheter should be flushed with five milliliters of 0.9% sodium chloride injection or 5%dextrose injection. Dosing of Busulfex is repeated every six hours for four consecutive daysfor a total of 16 doses. In light of the several instructions required for the properadministration of Busulfex, it is misleading to suggest that the administration of Busulfex is“straightforward.” We acknowledge that the administration information for Busulfex ispresented on the website; however, this is not sufficient to mitigate the misleadingimpression created by the above claim.Conclusion and Requested ActionFor the reasons discussed above, the US product website for Busulfex misbrands the drug inviolation of the FD&C Act, 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(5); (e)(6)(i);(e)(7)(i) & (iii).5 Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.(May 2007)Reference ID: 3029738Ms. Stephanie H. Jameison, MBA, RAC Page 7Otsuka Pharmaceutical Development and Commercialization, Inc.NDA# 020954 / MA# 77OPDP requests that OPDC immediately cease the dissemination of violative promotionalmaterials for Busulfex such as those described above. Please submit a written response tothis letter on or before October 31, 2011, stating whether you intend to comply with thisrequest, listing all promotional materials (with the 2253 submission date) for Busulfex thatcontain violations such as those described above, and explaining your plan for discontinuinguse of such violative materials.Please direct your response to the undersigned at the Food and Drug Administration,Center for Drug Evaluation and Research, Office of Prescription Drug Promotion,Division of Professional Promotion, 5901-B Ammendale Road, Beltsville, Maryland20705-1266 or by facsimile at (301) 847-8444. Please note that the Division of DrugMarketing, Advertising, and Communications (DDMAC) has been reorganized and elevatedto the Office of Prescription Drug Promotion (OPDP). OPDP consists of the ImmediateOffice, the Division of Professional Promotion (DPP) and the Division of Direct-to-ConsumerPromotion (DDTCP). To ensure timely delivery of your submissions, please use the fulladdress above and include a prominent directional notation (e.g. a sticker) to indicate that thesubmission is intended for OPDP. In addition, OPDP recently migrated to a different trackingsystem. Therefore, OPDP letters will now refer to MA numbers instead of MACMIS numbers.Please refer to the MA # in addition to the NDA number in all future correspondence relatingto this particular matter. OPDP reminds you that only written communications are consideredofficial.The violations discussed in this letter do not necessarily constitute an exhaustive list. It isyour responsibility to ensure that your promotional materials for Busulfex comply with eachapplicable requirement of the FD&C Act and FDA implementing regulations.Sincerely,See appended electronic signature pageAdam George, Pharm.D.Regulatory Review OfficerDivision of Professional PromotionOffice of Prescription Drug PromotionReference ID: 3029738———————————————————————————————————This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.———————————————————————————————————/s/—————————————————-ADAM GEORGE10/17/2011Reference ID: 3029738

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